Faculty Profiles - TOYOOKA Shinichi

Papers - TOYOOKA Shinichi

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Novel pulmonary abdominal normothermic regional perfusion circuit for simultaneous in-donor evaluation and preservation of lungs and abdominal organs in donation after circulatory death.

Shin Tanaka, Masashi Umeda, Hiroyuki Ujike, Tsuyoshi Ryuko, Yasuaki Tomioka, Kentaroh Miyoshi, Mikio Okazaki, Seiichiro Sugimoto, Shinichi Toyooka

General thoracic and cardiovascular surgery 2025.3

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: To overcome limitations of traditional ex vivo lung perfusion (EVLP) for controlled donation after circulatory death (cDCD) lungs, this study aimed to evaluate a novel pulmonary abdominal normothermic regional perfusion (PANRP) technique, which we uniquely designed, for in situ assessment of lungs from cDCD donors. METHODS: We modified the abdominal normothermic regional perfusion circuit for simultaneous lung and abdominal organ assessment using independent extracorporeal membrane oxygenation components. Blood was oxygenated via a membrane oxygenator and returned to the body, with pulmonary flow adjusted to maintain pressure < 25 mmHg. Femoral cannulation was performed, and the lungs were ventilated with standard settings. Organ function was assessed over 2 h using PaO2/FiO2, AST, ALT, BUN, and Cr measurements to monitor perfusion and oxygen delivery. RESULTS: PANRP maintained stable lung function, with P/F ratios above 300, and preserved abdominal organ parameters, including stable AST, ALT, BUN, and Cr levels. Adequate urine output was observed, indicating normal renal function. Pulmonary artery pressure remained < 20 mmHg, and pulmonary vascular resistance was kept at 400 dyn・s/cm5, showing no signs of lung dysfunction or injury throughout the circuit. CONCLUSIONS: PANRP offers a promising alternative to traditional EVLP for cDCD lung evaluation, allowing in situ assessment of multiple organs simultaneously. This approach may overcome logistical and economic challenges associated with ex vivo techniques, enabling a more efficient evaluation process. Further studies are warranted to confirm its clinical applicability and impact on long-term outcomes.

DOI： 10.1007/s11748-025-02137-y

Nightmare case of repeated hemorrhagic pancreatitis due to pancreatic head cancer in the acute stage after two-stage lung transplantation

Tatsuya Hayashi, Shin Tanaka, Tsuyoshi Ryuko, Yasuaki Tomioka, Kentaroh Miyoshi, Mikio Okazaki, Seiichiro Sugimoto, Shinichi Toyooka

JHLT Open 100245 - 100245 2025.3

Survival and functional outcomes after pediatric living-donor lobar lung transplantation and deceased-donor lung transplantation: A Japanese multicenter retrospective study. International journal

Yuki Morimura, Kei Matsubara, Satona Tanaka, Haruki Choshi, Shin Tanaka, Takashi Kanou, Yojiro Yutaka, Akihiro Ohsumi, Daisuke Nakajima, Yasushi Shintani, Seiichiro Sugimoto, Shinichi Toyooka, Hiroshi Date

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2025.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: In pediatric living-donor lobar lung transplantation, whether transplanting adult lobes could result in satisfactory long-term survival and respiratory functional outcomes during and after the growth period in pediatric patients remains unclear. This study aimed to evaluate the long-term survival and functional prognosis after pediatric living-donor lobar lung transplantation and deceased-donor lung transplantation. METHODS: We retrospectively reviewed clinical data of pediatric patients (age: ≤17 years) who underwent lung transplantation between March 2001 and December 2022 at three institutions in Japan. RESULTS: Seventy and 24 patients who underwent living-donor and deceased-donor transplantation, respectively, were included. The 5-year and 10-year overall survival rates were 84.6% and 75.0% after living-donor transplantation and 85.8% and 85.8% after deceased-donor transplantation (p = 0.75), respectively. With a median follow-up period of 89.2 months, 48 living-donor cases (100%) and 16 deceased-donor cases (84.2%) had performance status 0-2 among 48 living-donor cases and 19 deceased-donor cases who were alive without re-transplantation. They showed height growth (median +9.7 cm, p < 0.01); however, the height standard deviation score decreased after transplantation (median -0.22, p = 0.03). The difference in height standard deviation score between the last follow-up and pre-transplantation was negative (median -0.42) in living-donor cases and significantly smaller than that in deceased-donor cases (median +0.19, p = 0.02). CONCLUSIONS: Pediatric living-donor lobar lung transplantation provided satisfactory long-term survival and functional prognosis that were comparable to those of deceased-donor lung transplantation. The limited post-transplant height growth in living-donor cases might be attributed to this favorable functional prognosis.

DOI： 10.1016/j.healun.2025.01.012

Myeloid Cells Induce Infiltration and Activation of B Cells and CD4+ T Follicular Helper Cells to Sensitize Brain Metastases to Combination Immunotherapy. International journal

Toshifumi Ninomiya, Naoya Kemmotsu, Fumiaki Mukohara, Masaki Magari, Ai Miyamoto, Youki Ueda, Takamasa Ishino, Joji Nagasaki, Tomohiro Fujiwara, Hidetaka Yamamoto, Hidetoshi Hayashi, Kota Tachibana, Joji Ishida, Yoshihiro Otani, Shota Tanaka, Shinichi Toyooka, Isamu Okamoto, Yosuke Togashi

Cancer research 2025.1

Language：English Publishing type：Research paper (scientific journal)

Brain metastasis (BM) is a poor prognostic factor in cancer patients. Despite showing efficacy in many extracranial tumors, immunotherapy with anti-PD-1 monoclonal antibody (mAb) or anti-CTLA-4 mAb appears to be less effective against intracranial tumors. Promisingly, recent clinical studies have reported that combination therapy with anti-PD-1 and anti-CTLA-4 mAbs has a potent antitumor effect on BM, highlighting the need to elucidate the detailed mechanisms controlling the intracranial tumor microenvironment (TME) to develop effective immunotherapeutic strategies. Here, we analyzed the tumor-infiltrating lymphocytes in murine models of BM that responded to anti-CTLA-4 mAb to anti-PD-1 mAb. Activated CD4+ T follicular helper (TFH) cells with high CTLA-4 expression characteristically infiltrated the intracranial TME, which were activated by the combination anti-CTLA-4 and anti-PD-1 treatment. Loss of TFH cells suppressed the additive effect of CTLA-4 blockade on anti-PD-1 mAb. B cell-activating factor belonging to the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) produced by abundant myeloid cells, particularly CD80hiCD206lo pro-inflammatory M1-like macrophages, in the intracranial TME, induced B cell and TFH cell infiltration and activation. Furthermore, the intracranial TME of patients with non-small cell lung cancer featured TFH and B cell infiltration as tertiary lymphoid structures. Together, these findings provide insights into the immune cell crosstalk in the intracranial TME that facilitates an additive anti-tumor effect of CTLA-4 blockade with anti-PD-1 treatment, supporting the potential of a combination immunotherapeutic strategy for BM.

DOI： 10.1158/0008-5472.CAN-24-2274

Histological Features and Gene Expression Profiling in Lung Transplantation From Donation After Circulatory Death. International journal

Mikio Okazaki, Tomohisa Sakaue, Shin Tanaka, Yujiro Kubo, Tatsuya Hayashi, Elvira Ramil, Antonio J Sánchez-López, María Jose Coronado, Lucas Hoyos, Alejandra Romero, Shinichi Toyooka, David Gomez-de-Antonio

Archivos de bronconeumologia 2025.1

The role of C1orf50 in breast cancer progression and prognosis.

Yusuke Otani, Atsushi Tanaka, Masaki Maekawa, Tirso Peña, Anna Rogachevskaya, Teruhiko Ando, Takuto Itano, Haruyoshi Katayama, Eiji Nakata, Toshifumi Ozaki, Shinichi Toyooka, Hiroyoshi Doihara, Michael H Roehrl, Atsushi Fujimura

Breast cancer (Tokyo, Japan) 2024.11

Language：English Publishing type：Research paper (scientific journal)

Although the prognosis of breast cancer has significantly improved compared to other types of cancer, there are still some patients who expire due to recurrence or metastasis. Therefore, it is necessary to develop a method to identify patients with poor prognosis at the early stages of cancer. In the process of discovering new prognostic markers from genes of unknown function, we found that the expression of C1orf50 determines the prognosis of breast cancer patients, especially for those with Luminal A breast cancer. This study aims to elucidate the molecular role of C1orf50 in breast cancer progression. Bioinformatic analyses of the breast cancer dataset of TCGA, and in vitro analyses, reveal the molecular pathways influenced by C1orf50 expression. C1orf50 knockdown suppressed the cell cycle of breast cancer cells and weakened their ability to maintain the undifferentiated state and self-renewal capacity. Interestingly, upregulation of C1orf50 increased sensitivity to CDK4/6 inhibition. In addition, C1orf50 was found to be more abundant in breast cancer cells than in normal breast epithelium, suggesting C1orf50's involvement in breast cancer pathogenesis. Furthermore, the mRNA expression level of C1orf50 was positively correlated with the expression of PD-L1 and its related factors. These results suggest that C1orf50 promotes breast cancer progression through cell cycle upregulation, maintenance of cancer stemness, and immune evasion mechanisms. Our study uncovers the biological functions of C1orf50 in Luminal breast cancer progression, a finding not previously reported in any type of cancer.

DOI： 10.1007/s12282-024-01653-8

Enhanced design of pCMViR-TSC plasmid vector for sustainably high cargo gene expression in mammalian cells. International journal

Masakiyo Sakaguchi, Rie Kinoshita, Nahoko Tomonobu, Yoshihiko Sakaguchi, Junichiro Futami, Akira Yamauchi, Hitoshi Murata, Ken-Ichi Yamamoto, Tetta Takahashi, Yuma Gohara, Toshiki Ochi, Fan Jiang, Ni Luh Gede Yoni Komalasari, Youyi Chen, I Made Winarsa Ruma, I Wayan Sumardika, Jin Zhou, Tomoko Honjo, Futoshi Kuribayashi, Kazumi Sagayama, Shinichi Toyooka, Eisaku Kondo, Yusuke Inoue

In vitro cellular & developmental biology. Animal 2024.11

Language：English Publishing type：Research paper (scientific journal)

The first-generation pCMViR-TSC, implemented through the promoter sandwich rule, yields 10- to 100-fold higher gene expression than the standard plasmid used with the CMV (cytomegalovirus) or CAG promoter. However, the vector's shortcomings limit its utility to transient expression only, as it is not suitable for establishing stable transformants in mammalian cells. To overcome this weakness, we here introduce the improved plasmid vector pSAKA-4B, derived from pCMViR-TSC as a second-generation chromosome-insertable vector. This vector facilitates the linear entry of the expression unit into the TTAA site of DNA universally with transposase assistance. The vector is helpful for the indefinite expression of our target gene. The new vector system is proven here to be efficient in establishing stable transformants with a high likelihood of positive clones that exhibit significantly elevated expression levels of the delivered foreign gene. This system, alongside the first-generation vector, is therefore instrumental for diverse basic research endeavors concerning genes, proteins, cells, and animals, and potentially for clinical applications such as gene therapy.

DOI： 10.1007/s11626-024-00992-2

Expression of SPRED2 in the lung adenocarcinoma. International journal

Yoko Ota, Tong Gao, Masayoshi Fujisawa, I Wayan Sumardika, Masakiyo Sakaguchi, Shinichi Toyooka, Teizo Yoshimura, Akihiro Matsukawa

Pathology, research and practice 265 155721 - 155721 2024.11

Language：English Publishing type：Research paper (scientific journal)

SPRED2 (Sprouty-related, EVH1 domain-containing protein 2), a negative regulator of the ERK1/2 pathway, is downregulated in several cancers; however, the significance of SPRED2 expression in lung adenocarcinoma (LUAD) remains unclear. Here, we investigated the pathological expression of SPRED2 and its relationship with ERK1/2 activation (ERK1/2 phosphorylation), Ki67 index and clinicopathological features in 77 LUAD tissues from clinical patients. Immunohistochemically, SPRED2 expression was decreased in invasive adenocarcinoma (IA) compared to adenocarcinoma in situ (AIS). There was a negative correlation between SPRED2 expression and pERK1/2 levels and a positive correlation between SPRED2 expression and Ki67 index. In the database analysis, the survival probability was higher in patients with higher SPRED2 expression than in those with lower expression. In vitro, SPRED2 deletion increased cell proliferation, migration and invasion of three LUAD cell lines (A549:KRAS mutation, H1993:METamplification, and HCC4006:EGFR mutation), whereas SPRED2 overexpression decreased these responses. Thus, SPRED2 appears to be a regulator of LUAD progression and a potential target for the treatment of LUAD.

DOI： 10.1016/j.prp.2024.155721

Long Short-Term Memory Algorithm for Personalized Tacrolimus Dosing: A Simple and Effective Time Series Forecasting Approach Post-Lung Transplantation. International journal

Haruki Choshi, Kentaroh Miyoshi, Maki Tanioka, Hayato Arai, Shin Tanaka, Kazuhiko Shien, Ken Suzawa, Mikio Okazaki, Seiichiro Sugimoto, Shinichi Toyooka

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2024.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Management of tacrolimus trough levels influences morbidity and mortality after lung transplantation. Several studies have explored pharmacokinetic and artificial intelligence models to monitor tacrolimus levels. However, many models depend on a wide range of variables, some of which, like genetic polymorphisms, are not commonly tested for in regular clinical practice. This study aimed to verify the efficacy of a novel approach simply utilizing time series data of tacrolimus dosing, with the objective of accurately predicting trough levels in the variety of clinical settings. METHODS: Data encompassing 36 clinical variables for each patient were gathered, and a multivariate long short-term memory algorithm was applied to forecast subsequent tacrolimus trough levels based on the selected clinical variables. The tool was developed using a dataset of 87,112 data points from 117 patients and its efficacy was confirmed using six additional cases. RESULTS: Shapley Additive exPlanations revealed a significant correlation between trough levels and prior dose-concentration data. By using simple trend learning of dose, administration route, and previous trough levels of tacrolimus, we could predict values within 30% of the actual values for 88.5% of time points, which facilitated the creation of a tool for simulating tacrolimus trough levels in response to dosage adjustments. The tool exhibited the potential for rectifying clinical misjudgments in a simulation cohort. CONCLUSIONS: Utilizing our time series forecasting tool, precise prediction of trough levels is attainable independently of other clinical variables, through the analysis of historical tacrolimus dose-concentration trends alone.

DOI： 10.1016/j.healun.2024.10.026

Late living-donor kidney transplantation from the same donor after living-donor lobar lung transplantation Reviewed

Tsuyoshi Ryuko, Seiichiro Sugimoto, Shin Tanaka, Kentaroh Miyoshi, Megumi Ishihara, Yuichi Shibuya, Shinichi Toyooka

JHLT Open 2024.11

胸腺上皮性腫瘍:再発治療、周術期治療、新規治療胸腺癌の術式と術後予後に関する多施設共同後ろ向き観察研究胸腺癌に対しての縮小手術は許容されるか

林龍也, 岡崎幹生, 土生智大, 枝園和彦, 諏澤憲, 山本寛斉, 大塚智昭, 渡邉元嗣, 山田英司, 藤原俊哉, 葉山牧夫, 山根正修, 井野川英利, 平見有二, 青江基, 山下素弘, 佐野由文, 中田昌男, 豊岡伸一

日本胸部外科学会定期学術集会 77回 LPD2 - 3 2024.11

Real-World Comparative Analysis of Trastuzumab Originator and Biosimilars: Safety, Efficacy, and Cost Effectiveness. International journal

Tomoka Mamori, Maki Tanioka, Kenji Takada, Hirofumi Hamano, Takahiro Tsukioki, Yuko Takahashi, Tsuguo Iwatani, Tadahiko Shien, Shinichi Toyooka

BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy 2024.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Despite the global use of trastuzumab biosimilars, concerns remain regarding their efficacy and safety. In particular, when used concurrently with pertuzumab, trastuzumab biosimilars lack extensive real-world data and safety information. Additionally, as cancer drug expenditures continue to rise worldwide, cost savings from biosimilars have become increasingly important. OBJECTIVE: This study aims to assess the safety, efficacy, and cost effectiveness of trastuzumab originators and their biosimilars in real-world clinical settings, focusing on a large patient population. METHODS: The analysis included 31,661 patients with HER2-positive breast cancer from the Medical Data Vision Co., Ltd. database in Japan. Additionally, adverse event reports for the trastuzumab originator and its biosimilars were obtained for 58,799 patients from the World Health Organization's VigiBase, the global adverse event reporting database. RESULTS: No significant differences were observed in heart failure hospitalizations, liver dysfunction, or infusion reaction rates in both the Medical Data Vision Co., Ltd. database and the World Health Organization's VigiBase. In the Medical Data Vision Co., Ltd. database, the addition of pertuzumab did not significantly influence the incidence of adverse events, and the use of biosimilars significantly reduced medical costs, with no significant difference in breast cancer recurrence rates. CONCLUSIONS: By analyzing two large and diverse datasets from multiple perspectives, we obtained reliable results that the trastuzumab originator and its biosimilars have similar safety profiles. The concurrent use of pertuzumab was also found to be safe. The use of biosimilars can lead to cost savings. These findings provide crucial insights for the evaluation and adoption of biosimilars in clinical practice.

DOI： 10.1007/s40259-024-00686-x

Loss of Nr4a1 ameliorates endothelial cell injury and vascular leakage in lung transplantation from circulatory-death donor. International journal

Shinichi Kawana, Mikio Okazaki, Tomohisa Sakaue, Kohei Hashimoto, Kentaro Nakata, Haruki Choshi, Shin Tanaka, Kentaroh Miyoshi, Shinji Ohtani, Toshiaki Ohara, Seiichiro Sugimoto, Akihiro Matsukawa, Shinichi Toyooka

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2024.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Ischemia-reperfusion injury (IRI) stands as a major trigger for primary graft dysfunction (PGD) in lung transplantation (LTx). Especially in LTx from donation after cardiac death (DCD), effective control of IRI following warm ischemia (WIRI) is crucial to prevent PGD. This study aimed to identify the key factors affecting WIRI in LTx from DCD. METHODS: Previously reported RNA-sequencing dataset of lung WIRI was reanalyzed to identify nuclear receptor subfamily 4 group A member 1 (NR4A1) as the immediate early gene for WIRI. Dynamics of NR4A1 expression were verified using a mouse hilar clamp model. To investigate the role of NR4A1 in WIRI, a mouse model of LTx from DCD was established using Nr4a1 knockout (Nr4a1-/-) mice. RESULTS: NR4A1 was located around vascular cells, and its protein levels in the lungs increased rapidly and transiently during WIRI. LTｘ from Nr4a1-/- donors significantly improved pulmonary graft function compared to wild-type donors (P < 0.001). Histological analysis showed decreased microvascular endothelial cell death (P = 0.007), neutrophil infiltration (P < 0.001), and albumin leakage (P < 0.001). Evans blue permeability assay demonstrated maintained pulmonary microvascular barrier integrity in grafts from Nr4a1-/- donors, correlating with diminished pulmonary edema (P < 0.001). However, NR4A1 did not significantly affect the inflammatory response during WIRI, and IRI was not suppressed when a wild-type donor lung was transplanted into the Nr4a1-/- recipient. CONCLUSIONS: Donor NR4A1 plays a specialized role in the positive regulation of endothelial cell injury and microvascular hyperpermeability. These findings demonstrate the potential of targeting NR4A1 interventions to alleviate PGD and improve outcomes in LTx from DCD.

DOI： 10.1016/j.healun.2024.09.028

肺癌周術期治療の現在と未来術前導入化学放射線療法の経験に基づく当院の肺がん周術期治療の現状と工夫

枝園和彦, 柳光剛志, 富岡泰章, 田中真, 諏澤憲, 三好健太郎, 岡崎幹生, 杉本誠一郎, 豊岡伸一

日本癌治療学会学術集会抄録集 62回 OSY1 - 5 2024.10

局所進行肺癌に対する治療を再考する切除可能局所進行肺癌に対する導入化学放射線療法の長期成績

諏澤憲, 岡田和大, 柳光剛志, 富岡泰章, 田中真, 枝園和彦, 三好健太郎, 岡崎幹生, 杉本誠一郎, 豊岡伸一

日本癌治療学会学術集会抄録集 62回 OPD5 - 5 2024.10

小児・AYA世代がんのゲノム医療小児・AYA世代の肉腫におけるゲノム医療の意義

中田英二, 遠西大輔, 二宮貴一朗, 冨田秀太, 山本英喜, 岡崎哲也, 平沢晃, 豊岡伸一, 尾崎敏文

日本癌治療学会学術集会抄録集 62回 OSY16 - 2 2024.10

A Case of Single-lung Transplant in a Patient with Mycobacterium avium Pulmonary Disease Successfully Treated with Amikacin Liposome Inhalation Suspension. Reviewed

Taichi Ozeki, Hisao Higo, Hiroki Omori, Shunta Mori, Shin Tanaka, Go Makimoto, Kiichiro Ninomiya, Akihiko Taniguchi, Masanori Fujii, Kentaro Miyoshi, Kammei Rai, Eiki Ichihara, Kadoaki Ohashi, Seiichiro Sugimoto, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Nobuaki Miyahara

Internal medicine (Tokyo, Japan) 2024.9

Language：English Publishing type：Research paper (scientific journal)

A 55-year-old man presented to our hospital with idiopathic pulmonary fibrosis (IPF). He was registered with the Japan Organ Transplant Network the following year due to disease progression. Treatment with clarithromycin, ethambutol, and rifampicin for complications of Mycobacterium avium pulmonary disease was initiated, but sputum conversion could not be achieved. The administration of an amikacin liposome inhalation suspension (ALIS) resulted in sputum conversion, and single-lung transplantation was performed. ALIS therapy was continued after lung transplantation, and no M. avium disease was observed for 15 months. ALIS may cause M. avium pulmonary disease with additional indications for lung transplantation.

DOI： 10.2169/internalmedicine.3854-24

Response to Imatinib in a Patient With Gastric Adenocarcinoma With KIT Q556_K558 In-Frame Deletion: A Case Report. International journal

Kiichiro Ninomiya, Daisuke Ennishi, Kunio Okamoto, Midori Ando, Satoko Nakamura, Shuta Tomida, Yoshiyuki Ayada, Go Makimoto, Eiki Ichihara, Natsuko Okita, Shinichi Toyooka, Yoshinobu Maeda, Masahiro Tabata

JCO precision oncology 8 e2400228 2024.9

The effect of exercise and educational programs for breast cancer patients on the development of breast cancer-related lymphoedema: secondary endpoint from a randomized controlled trial in the Setouchi Breast Project-10. Reviewed

Shogo Nakamoto, Takayuki Iwamoto, Naruto Taira, Yukiko Kajiwara, Kengo Kawada, Daisuke Takabatake, Yuichiro Miyoshi, Shinichiro Kubo, Yoko Suzuki, Mari Yamamoto, Yutaka Ogasawara, Minami Hatono, Seiji Yoshitomi, Kyoko Hara, Asako Sasahara, Shozo Ohsumi, Masahiko Ikeda, Hiroyoshi Doihara, Yuri Mizota, Seiichiro Yamamoto, Tadahiko Shien, Shinichi Toyooka

Breast cancer (Tokyo, Japan) 31 ( 5 ) 969 - 978 2024.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Although the association between higher physical activity and preventive effect on breast-cancer-related lymphoedema (BCRL) has been reported, it is unclear what intervention is optimal. We aimed to investigate the effect of exercise and educational programs on BCRL development. METHODS: This study was a secondary endpoint analysis from a prospective randomized controlled trial. We enrolled patients with stage 0-III breast cancer from March 2016 to March 2020 and randomly assigned them to the control (n = 111), education (n = 115), or exercise (n = 104) group. As secondary endpoint, we assessed the incidence of and preventive effect on BCRL at 12 months post-intervention. RESULTS: There were no significant differences in the incidence of BCRL at 12 months post-intervention between the exercise and control groups (9.8% and 10.8%, P = 0.83) and the education and control groups (11.6% and 10.8%, P = 1.00). There were no significant differences in time to BCRL onset from the day of surgery between the exercise and control groups (event rate at 12 months: 20.7% and 17.2%, log-rank, P = 0.54) and the education and control groups (18.8% and 17.2%, log-rank, P = 0.57). The multivariable analyses indicated that axillary dissection and obesity significantly increased the risk of BCRL [hazard ratio (HR): 2.36, 95% confidence interval (CI) 1.52-3.67 and HR: 1.68, 95% CI 1.07-2.63, respectively]. CONCLUSIONS: The intervention did not decrease the risk of BCRL, and axillary dissection and obesity were the risk factors of BCRL. TRIAL REGISTRATION NUMBER: UMIN000020595 at UMIN Clinical Trial Registry.

DOI： 10.1007/s12282-024-01610-5

両側脳死肺移植後のサイトメガロウイルス感染症の予防にレテルモビルが有効だった一例

俣野貴慶, 杉本誠一郎, 田中真, 柳光剛志, 調枝治樹, 富岡泰章, 堂口佳子, 石原恵, 諏澤憲, 枝園和彦, 三好健太郎, 岡崎幹生, 豊岡伸一

移植 59 ( 総会臨時 ) 373 - 373 2024.9

肺移植後長期管理 Up to date 肺移植後の慢性腎臓病に対する長期管理 up to date

杉本誠一郎, 柳光剛志, 富岡泰章, 田中真, 石原恵, 堂口佳子, 諏澤憲, 枝園和彦, 三好健太郎, 岡崎幹生, 豊岡伸一

移植 59 ( 総会臨時 ) 173 - 173 2024.9

再肺移植後急性期に膵頭部癌による出血性膵炎を繰り返したNightmare case

林龍也, 田中真, 石原恵, 堂口佳子, 梅田将志, 調枝治樹, 柳光剛志, 富岡泰章, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 杉本誠一郎, 豊岡伸一

移植 59 ( 総会臨時 ) 255 - 255 2024.9

臓器移植レシピエントの感染症肺移植レシピエントにおける新型コロナウイルス感染症 5類移行後の現状

妹尾知哉, 杉本誠一郎, 調枝治樹, 柳光剛志, 富岡泰章, 田中真, 石原恵, 堂口佳子, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 豊岡伸一

移植 59 ( 総会臨時 ) 161 - 161 2024.9

脳死片肺移植後の抗体関連型拒絶反応に対する集学的治療の経験

調枝治樹, 杉本誠一郎, 柳光剛志, 富岡泰章, 田中真, 堂口佳子, 石原恵, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 豊岡伸一

移植 59 ( 総会臨時 ) 294 - 294 2024.9

肺移植後の機能性ディスペプシアに対しPEG-J留置が奏功した一例

柳光剛志, 杉本誠一郎, 田中真, 富岡泰章, 石原恵, 堂口佳子, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 豊岡伸一

移植 59 ( 総会臨時 ) 374 - 374 2024.9

肉腫におけるゲノム医療の進歩 C-CATデータを用いた肉腫のゲノム解析

中田英二, 遠西大輔, 二宮貴一朗, 山本英喜, 冨田秀太, 国定俊之, 藤原智洋, 二川摩周, 平沢晃, 豊岡伸一, 尾崎敏文

日本整形外科学会雑誌 98 ( 8 ) S1727 - S1727 2024.9

新たながん遺伝子パネル検査 TruSight Oncology 500(TSO500)の臨床的意義(Clinical relevance of novel comprehensive genomic profiling assay - TruSight Oncology 500(TSO500))

遠西大輔, 冨田秀太, 松井啓隆, 藤野泰輝, 檜井孝夫, 杉本健樹, 川上耕史, 松本光史, 山本弥寿子, 曳野肇, 二宮貴一朗, 山本英喜, 柳井広之, 平沢晃, 豊岡伸一, 豊岡伸一

日本癌学会総会記事 83回 P - 2114 2024.9

臓器移植レシピエントの感染症肺移植レシピエントにおける新型コロナウイルス感染症 5類移行後の現状

妹尾知哉, 杉本誠一郎, 調枝治樹, 柳光剛志, 富岡泰章, 田中真, 石原恵, 堂口佳子, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 豊岡伸一

移植 59 ( 総会臨時 ) 161 - 161 2024.9

肺移植後長期管理 Up to date 肺移植後の慢性腎臓病に対する長期管理 up to date

杉本誠一郎, 柳光剛志, 富岡泰章, 田中真, 石原恵, 堂口佳子, 諏澤憲, 枝園和彦, 三好健太郎, 岡崎幹生, 豊岡伸一

移植 59 ( 総会臨時 ) 173 - 173 2024.9

再肺移植後急性期に膵頭部癌による出血性膵炎を繰り返したNightmare case

林龍也, 田中真, 石原恵, 堂口佳子, 梅田将志, 調枝治樹, 柳光剛志, 富岡泰章, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 杉本誠一郎, 豊岡伸一

移植 59 ( 総会臨時 ) 255 - 255 2024.9

脳死片肺移植後の抗体関連型拒絶反応に対する集学的治療の経験

調枝治樹, 杉本誠一郎, 柳光剛志, 富岡泰章, 田中真, 堂口佳子, 石原恵, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 豊岡伸一

移植 59 ( 総会臨時 ) 294 - 294 2024.9

両側脳死肺移植後のサイトメガロウイルス感染症の予防にレテルモビルが有効だった一例

俣野貴慶, 杉本誠一郎, 田中真, 柳光剛志, 調枝治樹, 富岡泰章, 堂口佳子, 石原恵, 諏澤憲, 枝園和彦, 三好健太郎, 岡崎幹生, 豊岡伸一

移植 59 ( 総会臨時 ) 373 - 373 2024.9

肺移植後の機能性ディスペプシアに対しPEG-J留置が奏功した一例

柳光剛志, 杉本誠一郎, 田中真, 富岡泰章, 石原恵, 堂口佳子, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 豊岡伸一

移植 59 ( 総会臨時 ) 374 - 374 2024.9

Prophylactic effect of tissue flap in the prevention of bronchopleural fistula after surgery for lung cancer. Reviewed

Tomohiro Habu, Hiromasa Yamamoto, Kentaro Nakata, Kohei Hashimoto, Shin Tanaka, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Mikio Okazaki, Seiichiro Sugimoto, Shinichi Toyooka

Surgery today 2024.8

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Bronchopleural fistula (BPF) is a serious complication of lung resection. To avoid BPF, the bronchial stump/anastomotic site is often covered with a flap of surrounding tissue. One risk factor for BPF is radical lung resection after induction chemoradiotherapy for lung cancer. We retrospectively reviewed our database to elucidate the characteristics of tissue flaps that prevent BPF. METHODS: This retrospective study included 152 patients treated between 1999 and 2019. We examined the clinicopathological characteristics, including the type and thickness of the tissue flap used to cover the bronchial stump/anastomotic site, and postoperative complications, including BPF. RESULTS: BPF occurred in 5 patients (3.3%). All 5 patients had complications that could have affected delayed wound healing, such as pneumonia. The covering tissue flap thickness was significantly greater in patients without BPF than in those who developed BPF (p = 0.0290). Additionally, the tissue flap thickness was significantly greater than in those with BPF (p = 0.0077), even in high-risk patients who developed pneumonia or radiation pneumonitis on the operative side within 6 months postoperatively. CONCLUSION: Perioperative management is crucial to avoid complications affecting the healing of the bronchial stump/anastomotic site, and the covering tissue flap thickness may be an important factor in avoiding or minimizing BPF.

DOI： 10.1007/s00595-024-02927-6

Somatic mutations in tumor-infiltrating lymphocytes impact on antitumor immunity. Reviewed International journal

Fumiaki Mukohara, Kazuma Iwata, Takamasa Ishino, Takashi Inozume, Joji Nagasaki, Youki Ueda, Ken Suzawa, Toshihide Ueno, Hideki Ikeda, Katsushige Kawase, Yuka Saeki, Shusuke Kawashima, Kazuo Yamashita, Yu Kawahara, Yasuhiro Nakamura, Akiko Honobe-Tabuchi, Hiroko Watanabe, Hiromichi Dansako, Tatsuyoshi Kawamura, Yutaka Suzuki, Hiroaki Honda, Hiroyuki Mano, Shinichi Toyooka, Masahito Kawazu, Yosuke Togashi

Proceedings of the National Academy of Sciences of the United States of America 121 ( 35 ) e2320189121 2024.8

Language：English Publishing type：Research paper (scientific journal)

Immune checkpoint inhibitors (ICIs) exert clinical efficacy against various types of cancers by reinvigorating exhausted CD8+ T cells that can expand and directly attack cancer cells (cancer-specific T cells) among tumor-infiltrating lymphocytes (TILs). Although some reports have identified somatic mutations in TILs, their effect on antitumor immunity remains unclear. In this study, we successfully established 18 cancer-specific T cell clones, which have an exhaustion phenotype, from the TILs of four patients with melanoma. We conducted whole-genome sequencing for these T cell clones and identified various somatic mutations in them with high clonality. Among the somatic mutations, an SH2D2A loss-of-function frameshift mutation and TNFAIP3 deletion could activate T cell effector functions in vitro. Furthermore, we generated CD8+ T cell-specific Tnfaip3 knockout mice and showed that Tnfaip3 function loss in CD8+ T cell increased antitumor immunity, leading to remarkable response to PD-1 blockade in vivo. In addition, we analyzed bulk CD3+ T cells from TILs in additional 12 patients and identified an SH2D2A mutation in one patient through amplicon sequencing. These findings suggest that somatic mutations in TILs can affect antitumor immunity and suggest unique biomarkers and therapeutic targets.

DOI： 10.1073/pnas.2320189121

Surgically resected sarcomatoid carcinoma of the lung: a nationwide retrospective study in 2010. Reviewed International journal

Kaoru Kaseda, Keisuke Asakura, Yasushi Shintani, Jiro Okami, Shinichi Toyooka, Yukio Sato, Shun-Ichi Watanabe, Masayuki Chida, Hidemi Suzuki, Etsuo Miyaoka, Ichiro Yoshino, Hiroshi Date

BMC cancer 24 ( 1 ) 938 - 938 2024.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Sarcomatoid carcinoma of the lung is a rare histological type of non-small cell lung cancer with a poor prognosis. We aimed to investigate the clinicopathological characteristics and prognostic factors of surgically resected sarcomatoid carcinoma of the lung. METHODS: We retrospectively reviewed 14999 patients who underwent surgical resection for non-small cell lung cancer accumulated by the Japanese Joint Committee of Lung Cancer Registry in 2010. Clinicopathological characteristics and survival were compared between the sarcomatoid carcinoma and other non-small cell cancer groups. The prognostic factors in the sarcomatoid carcinoma group were identified using a multivariate Cox proportional hazard model. RESULTS: Patients with sarcomatoid carcinoma comprised 1.4% of all patients. The sarcomatoid carcinoma group demonstrated a more aggressive pathology with presentation at more advanced stages, requiring more frequent extensive surgical resections. The sarcomatoid carcinoma group had remarkably poorer overall and recurrence-free survival than the other non-small cell lung cancer group. Adjuvant chemotherapy was associated with improved survival for pathological stage II-III sarcomatoid carcinoma cases rather than for pathological stage I disease. In the multivariate analysis, larger tumor size, lymphatic permeation, and no adjuvant chemotherapy were associated with the sarcomatoid carcinoma group's overall and recurrence-free survival. CONCLUSIONS: Surgically resected sarcomatoid carcinoma of the lung has a higher aggressive and metastatic potential and a worse prognosis than other non-small cell lung cancers. Adjuvant chemotherapy, which was associated with enhanced survival in patients with pathological stage II-III of the disease, could be considered for treating patients with pathological stage II-III sarcomatoid carcinoma of the lung.

DOI： 10.1186/s12885-024-12728-2

Increased Oxidative Stress and Decreased Citrulline in Blood Associated with Severe Novel Coronavirus Pneumonia in Adult Patients. Reviewed International journal

Mitsuru Tsuge, Eiki Ichihara, Kou Hasegawa, Kenichiro Kudo, Yasushi Tanimoto, Kazuhiro Nouso, Naohiro Oda, Sho Mitsumune, Goro Kimura, Haruto Yamada, Ichiro Takata, Toshiharu Mitsuhashi, Akihiko Taniguchi, Kohei Tsukahara, Toshiyuki Aokage, Hideharu Hagiya, Shinichi Toyooka, Hirokazu Tsukahara, Yoshinobu Maeda

International journal of molecular sciences 25 ( 15 ) 2024.7

Language：English Publishing type：Research paper (scientific journal)

This study investigated the correlation between oxidative stress and blood amino acids associated with nitric oxide metabolism in adult patients with coronavirus disease (COVID-19) pneumonia. Clinical data and serum samples were prospectively collected from 100 adult patients hospitalized for COVID-19 between July 2020 and August 2021. Patients with COVID-19 were categorized into three groups for analysis based on lung infiltrates, oxygen inhalation upon admission, and the initiation of oxygen therapy after admission. Blood data, oxidative stress-related biomarkers, and serum amino acid levels upon admission were compared in these groups. Patients with lung infiltrations requiring oxygen therapy upon admission or starting oxygen post-admission exhibited higher serum levels of hydroperoxides and lower levels of citrulline compared to the control group. No remarkable differences were observed in nitrite/nitrate, asymmetric dimethylarginine, and arginine levels. Serum citrulline levels correlated significantly with serum lactate dehydrogenase and C-reactive protein levels. A significant negative correlation was found between serum levels of citrulline and hydroperoxides. Levels of hydroperoxides decreased, and citrulline levels increased during the recovery period compared to admission. Patients with COVID-19 with extensive pneumonia or poor oxygenation showed increased oxidative stress and reduced citrulline levels in the blood compared to those with fewer pulmonary complications. These findings suggest that combined oxidative stress and abnormal citrulline metabolism may play a role in the pathogenesis of COVID-19 pneumonia.

DOI： 10.3390/ijms25158370

Augmented humoral response to third and fourth dose of SARS-CoV-2 mRNA vaccines in lung transplant recipients. Reviewed International journal

Shinichi Kawana, Seiichiro Sugimoto, Kei Matsubara, Haruki Choshi, Shin Tanaka, Megumi Ishihara, Tomohiro Habu, Kohei Hashimoto, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Mikio Okazaki, Masanori Nakayama, Shinichi Toyooka

Respiratory investigation 62 ( 5 ) 804 - 810 2024.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Since lung transplant recipients (LTRs) exhibit low immunogenicity after two doses of SARS-CoV-2 mRNA vaccines, optimal vaccine strategies for SARS-CoV-2 are required in LTRs. This study aimed to investigate the efficacy and safety of the third and fourth doses of the SARS-CoV-2 mRNA vaccines in LTRs. METHODS: We conducted a single-center study of 73 LTRs and 23 healthy controls (HCs). Participants received two-to-four doses of SARS-CoV-2 mRNA vaccines. The LTRs were divided into three groups based on the number of vaccine dose. IgG titers against SARS-CoV-2 spike protein were measured, and adverse events were assessed. Factors associated with humoral response were analyzed using univariate and multivariate analyses. RESULTS: The Dose 4 group (n = 27) had a higher humoral response rate (P = 0.018) and higher levels of anti-SARS-CoV-2 IgG antibody (P = 0.04) than the Dose 2 group (n = 14). The Dose 3 group (n = 32) had lower humoral response rates (P = 0.005) and levels of anti-SARS-CoV-2 IgG antibody (P = 0.0005) than the HCs (n = 23) even after the same dose. Systemic adverse events were milder in the LTRs than in the HCs (P < 0.05). Increased number of vaccine dose was identified as a predictor of positive humoral response (P = 0.021). CONCLUSION: Booster doses of SARS-CoV-2 mRNA vaccines may enhance humoral response with mild adverse events in LTRs. Repeated vaccination might be warranted for LTRs to prevent SARS-CoV-2 infection.

DOI： 10.1016/j.resinv.2024.07.004

Treatment patterns and clinical outcomes of resectable clinical stage III non-small cell lung cancer in a Japanese real-world setting: Surgery cohort analysis of the SOLUTION study. Reviewed International journal

Masahiro Tsuboi, Haruyasu Murakami, Hideyuki Harada, Tomotaka Sobue, Tomohiro Kato, Shinji Atagi, Takaaki Tokito, Tadashi Mio, Hirofumi Adachi, Toshiyuki Kozuki, Takashi Sone, Masahiro Seike, Shinichi Toyooka, Hiroshi Kitagawa, Ryo Koto, Satoshi Yamazaki, Hidehito Horinouchi

Thoracic cancer 15 ( 20 ) 1541 - 1552 2024.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: To elucidate the treatment and surgery outcomes with or without perioperative therapies in Japanese patients with clinical stage III non-small cell lung cancer (NSCLC) in real-world settings. METHODS: We performed subset analyses of the SOLUTION study, a multicenter, noninterventional, observational study of Japanese patients diagnosed with clinical stage III NSCLC, for those who started first-line treatment (surgery±perioperative therapy) between January 2013 and December 2014 (study registration: UMIN000031385). Follow-up data were obtained using medical records from diagnosis to March 1, 2018. RESULTS: Of 149 eligible patients, 67 underwent surgery alone (median age 71 years) and 82 underwent surgery+perioperative therapy (median age 63 years). Lung resection was performed in 137 patients and the others underwent exploratory thoracotomy or other procedures. Perioperative therapies included adjuvant therapy only (n = 41), neoadjuvant therapy only (n = 24), and neoadjuvant+adjuvant therapy (n = 17). The median overall survival (OS) and 3-year OS rate were 29.3 months and 44.0%, respectively, in patients who underwent surgery alone, and not reached and 61.1%, respectively, in patients who underwent surgery+perioperative therapy. The 3-year progression-free survival (PFS) and disease-free survival (DFS) rates were 42.4% and 47.1%, respectively, in patients who underwent surgery+perioperative therapy and 28.5% and 28.9%, respectively, in patients who underwent surgery alone. In multivariable Cox regression, perioperative therapy was associated with improved OS (hazard ratio [95% confidence interval] 0.49 [0.29-0.81]), PFS (0.62 [0.39-0.96]), and DFS (0.62 [0.39-0.97]) versus surgery alone. CONCLUSIONS: Our study suggested that perioperative therapy may be associated with better survival among patients undergoing surgical treatment of clinical stage III NSCLC.

DOI： 10.1111/1759-7714.15305

Baseline gut microbiota as a predictive marker for the efficacy of neoadjuvant chemotherapy in patients with early breast cancer: a multicenter prospective cohort study in the Setouchi Breast Project-14. Reviewed International journal

Shogo Nakamoto, Yukiko Kajiwara, Kohei Taniguchi, Akira I Hida, Yuichiro Miyoshi, Takanori Kin, Mari Yamamoto, Daisuke Takabatake, Shinichiro Kubo, Hajime Hikino, Yutaka Ogasawara, Masahiko Ikeda, Hiroyoshi Doihara, Tadahiko Shien, Naruto Taira, Takayuki Iwamoto, Shinichi Toyooka

Breast cancer research and treatment 2024.6

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Various studies have demonstrated the causal relationship between gut microbiota and efficacy of chemotherapy; however, the impact of gut microbiota on breast cancer has not been fully elucidated. This study aimed to evaluate the associations between the gut microbiota before neoadjuvant chemotherapy and its consequent efficacy in breast cancer. METHODS: This prospective observational study included patients who received neoadjuvant chemotherapy for primary early breast cancer at eight institutions between October 1, 2019, and March 31, 2022. We performed 16S rRNA analysis of fecal samples and α and β diversity analyses of the gut microbiota. The primary endpoint was the association between the gut microbiota and pathological complete response (pCR) to neoadjuvant chemotherapy. RESULTS: Among the 183 patients, the pCR rate after neoadjuvant chemotherapy was 36.1% in all patients and 12.9% (9/70), 69.5% (41/59), and 29.6% (16/54) in those with the luminal, human epidermal growth factor receptor 2, and triple-negative types, respectively. The α diversity of the gut microbiota did not significantly differ between patients with pCR and those without pCR. Among the gut microbiota, two species (Victivallales, P = 0.001 and Anaerolineales, P = 0.001) were associated with pCR, and one (Gemellales, P = 0.002) was associated with non-pCR. CONCLUSION: Three species in the gut microbiota had potential associations with neoadjuvant chemotherapy efficacy, but the diversity of the gut microbiota was not associated with response to chemotherapy. Further research is needed to validate our findings.

DOI： 10.1007/s10549-024-07395-7

加速する骨・軟部腫瘍に対するゲノム医療: 現状と課題肉腫におけるゲノム医療の現状と課題

中田英二, 遠西大輔, 二宮貴一朗, 山本英喜, 冨田秀太, 藤原智洋, 国定俊之, 平沢晃, 豊岡伸一, 尾崎敏文

日本整形外科学会雑誌 98 ( 6 ) S1457 - S1457 2024.6

Pulmonary Vein Repair on Extracorporeal Life Support: A Potential Surgical Complication for 2-Staged Lung Transplantation: Case Report. Reviewed International journal

Shin Tanaka, Kentaroh Miyoshi, Seiichiro Sugimoto, Shinichi Toyooka

Transplantation proceedings 2024.5

Language：English Publishing type：Research paper (scientific journal)

Double-lung transplantation (DLT) is favored for enhanced long-term survival despite the risk of major complications, particularly in elderly patients or those with comorbidities. Two-stage contralateral single-lung transplantation (SLT) leading to DLT is considered a valuable option to combine the advantages of less invasive SLT with DLT survival benefits. This study detailed the intraoperative challenges encountered during the procedure. A 54-year-old patient with chronic lung allograft dysfunction after right SLT underwent contralateral (left) SLT because of left lung dysfunction. During surgery, unexpected complications arose from robust adhesions on the right side, a consequence of prior transplantation, causing difficulty in manipulating the heart position. The deep bifurcation of the left pulmonary vein posed challenges, leading to damage to the left atrium, necessitating extracorporeal circulation. Despite these complexities, successful anastomosis was achieved. This case highlights the importance of recognizing potential surgical difficulties in contralateral lung transplantation, particularly in cases with adhesions, and emphasizes the need for caution when managing deep pulmonary veins. This 2-stage approach holds promise for patients with poor health but emphasizes the significance of addressing the potential challenges inherent in the surgical procedure.

DOI： 10.1016/j.transproceed.2024.05.009

Utility of neutrophil-to-lymphocyte ratio as an indicator of tumor immune status in non-small cell lung cancer. Reviewed International journal

Kazuma Iwata, Ken Suzawa, Kohei Hashimoto, Shin Tanaka, Kazuhiko Shien, Kentaroh Miyoshi, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Shinichi Toyooka

Japanese journal of clinical oncology 2024.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic biomarker in non-small cell lung cancer (NSCLC); however, the underlying biological rationale remains unclear. The present study aimed to explore the potential utility of NLR as a surrogate biomarker for immune response to cancer and to elucidate the underlying mechanism. METHODS: This retrospective study included the medical records of 120 patients with NSCLC who underwent surgery at the study institution in 2012. NLR in peripheral blood was determined from blood test within 30 days before surgery. Tumor immune status was evaluated using immunohistochemical staining to identify CD3+, CD8+ and FOXP3+ tumor-infiltrating lymphocytes (TILs), and the relationship of NLR, with clinicopathologic characteristics including 5-year overall survival (OS), and the tumor immune status was investigated. The median values of NLR and TIL count were used as cutoff points. RESULTS: The 5-year OS was significantly better in patients with low NLR (<2.2) than in those with high NLR (≥2.2) (70.1% vs. 56.8%, P = 0.042) and in patients with high CD3+ TIL count (≥242) than in those with low CD3+ TIL count (<242) (70% vs. 56.8%, P = 0.019). Additionally, the CD3+ TIL count was negatively correlated with preoperative NLR (P = 0.005). CONCLUSION: NLR might potentially reflect the immune status of tumor microenvironment, explaining its impact on prognosis of patients with NSCLC.

DOI： 10.1093/jjco/hyae058

Postoperative Complications in Living Donors for Lung Transplantation. Reviewed International journal

Shin Tanaka, Kento Fujii, Megumi Ishihara, Haruki Choshi, Kei Matsubara, Kohei Hashimoto, Shuji Okahara, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Shinichi Toyooka

Transplantation direct 10 ( 5 ) e1617 2024.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Living donor lobar lung transplantation is a life-saving procedure for critically ill patients. This requires 2 healthy donors exposed to risks and without medical benefit. Therefore, the donor's safety and minimal postoperative complications are crucial. This study aimed to investigate the short-term outcomes and identify the risk factors affecting these outcomes. METHODS: The data of 175 living donors enrolled between 1998 and 2022 were analyzed. Donors were divided into era 1 (1998-2009) and era 2 (2010-2022). RESULTS: The overall incidence of postoperative complications was 39%, of which 7% were major complications. Donors who underwent surgery on the right side had a higher incidence of delayed pulmonary fistulae (P = 0.01) and elevated liver enzyme levels (P = 0.028). Living donor surgery on the right side (P = 0.01), era 2 (P = 0.01), and the need for plasty (P = 0.04) were predictors of postoperative complications. CONCLUSIONS: Updated data on complications and their correlation with postoperative quality of life from this study could aid in the selection of potential donors and facilitate informed consent.

DOI： 10.1097/TXD.0000000000001617

Dissection of the signal transduction machinery responsible for the lysyl oxidase-like 4-mediated increase in invasive motility in triple-negative breast cancer cells: mechanistic insight into the integrin-β1-NF-κB-MMP9 axis Reviewed

Fan Jiang, Youyi Chen, Nahoko Tomonobu, Rie Kinoshita, Ni Luh Gede, Yoni Komalasari, Carlos Ichiro, Kasano-Camones, Kazumi Ninomiya, Hitoshi Murata, Ken-ichi Yamamoto, Yuma Gohara, Toshiki Ochi, I Made Winarsa Ruma, I Wayan, Sumardika, Jin Zhou, Tomoko Honjo, Yoshihiko Sakaguchi, Akira Yamauchi, Futoshi Kuribayashi, Junichiro Futami, Eisaku Kondo, Yusuke Inoue, Shinichi Toyooka, Masakiyo Sakaguchi

Front. Oncol. Sec. Molecular and Cellular Oncology. 14 ( 1371307 ) 2024.5

肺癌登録事業報告2024年

鈴木秀海, 吉野一郎, 新谷康, 四倉正也, 渡辺俊一, 川口知哉, 山本信之, 清家正博, 高橋和久, 高山浩一, 豊岡伸一, 佐藤幸夫, 千田雅之, 宮岡悦良, 服部聡, 伊達洋至, 全国肺癌登録合同委員会

気管支学 46 ( Suppl. ) S208 - S208 2024.5

Adrenergic microenvironment driven by cancer-associated Schwann cells contributes to chemoresistance in patients with lung cancer. Reviewed International journal

Yusuke Otani, Haruyoshi Katayama, Yidan Zhu, Rongsheng Huang, Takafumi Shigehira, Kazuhiko Shien, Ken Suzawa, Hiromasa Yamamoto, Tadahiko Shien, Shinichi Toyooka, Atsushi Fujimura

Cancer science 2024.4

Language：English Publishing type：Research paper (scientific journal)

Doublecortin (DCX)-positive neural progenitor-like cells are purported components of the cancer microenvironment. The number of DCX-positive cells in tissues reportedly correlates with cancer progression; however, little is known about the mechanism by which these cells affect cancer progression. Here we demonstrated that DCX-positive cells, which are found in all major histological subtypes of lung cancer, are cancer-associated Schwann cells (CAS) and contribute to the chemoresistance of lung cancer cells by establishing an adrenergic microenvironment. Mechanistically, the activation of the Hippo transducer YAP/TAZ was involved in the acquisition of new traits of CAS and DCX positivity. We further revealed that CAS express catecholamine-synthesizing enzymes and synthesize adrenaline, which potentiates the chemoresistance of lung cancer cells through the activation of YAP/TAZ. Our findings shed light on CAS, which drive the formation of an adrenergic microenvironment by the reciprocal regulation of YAP/TAZ in lung cancer tissues.

DOI： 10.1111/cas.16164

Effective division of the intersegmental plane using a robotic stapler in robotic pulmonary segmentectomy. Reviewed

Mikio Okazaki, Ken Suzawa, Kazuhiko Shien, Kohei Hashimoto, Shin Tanaka, Kentaroh Miyoshi, Hiromasa Yamamoto, Seiichiro Sugimoto, Shinichi Toyooka

Surgery today 2024.4

Language：English Publishing type：Research paper (scientific journal)

PURPOSES: Robot-assisted thoracoscopic (RATS) segmentectomy is becoming increasingly common because of the expanded indications for segmentectomy and the widespread adoption of robotic surgery. The precise division of the intersegmental plane is necessary to ensure oncologic margins from the tumor and to preserve the lung function. In this study, we present a strategy for accurately dividing the intersegmental plane using a robotic stapler and review the surgical outcomes. METHODS: RATS portal segmentectomy was performed using the Da Vinci Xi system and the intersegmental plane was dissected using a robotic stapler. We evaluated the perioperative outcomes in 92 patients who underwent RATS portal segmentectomy between May 2020 and January 2023. These results were compared with those of 82 patients who underwent complete video-assisted thoracoscopic surgery (CVATS) during the same period. RESULTS: The operative and console times were 162 and 97 min, respectively. No intraoperative complications occurred, and postoperative complications were observed in four cases (4.3%). The operative time, blood loss, postoperative complications, and maximum incision size were significantly lower in the RATS group than in the CVATS group. However, RATS requires a significantly higher number of staplers than CVATS. CONCLUSIONS: The division of the intersegmental plane using a robotic stapler in RATS portal segmentectomy was, therefore, found to be safe and effective.

DOI： 10.1007/s00595-024-02840-y

Clinical outcomes of left upper segmentectomy vs. lobectomy for early non-small-cell lung cancer: a nationwide database study in Japan. Reviewed

Shinya Tane, Jiro Okami, Yoshimasa Maniwa, Yasushi Shintani, Hiroyuki Ito, Takashi Ohtsuka, Shinichi Toyooka, Takeshi Mori, Shun-Ichi Watanabe, Masayuki Chida, Shunsuke Endo, Ryoichi Nakanishi, Mitsutaka Kadokura, Hidemi Suzuki, Etsuo Miyaoka, Ichiro Yoshino, Hiroshi Date

Surgery today 2024.4

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Given that left upper lobe and right upper and middle lobes share a similar anatomy, segmentectomy, such as upper division and lingulectomy, should yield identical oncological clearance to left upper lobectomy. We compared the prognosis of segmentectomy with that of lobectomy for early stage non-small-cell lung cancer (NSCLC) in the left upper lobe. METHODS: We retrospectively examined 2115 patients who underwent segmentectomy or lobectomy for c-stage I (TNM 8th edition) NSCLC in the left upper lobe in 2010. We compared the oncological outcomes of segmentectomy (n = 483) and lobectomy (n = 483) using a propensity score matching analysis. RESULTS: The 5-year recurrence-free and overall survival rates in the segmentectomy and lobectomy groups were comparable, irrespective of c-stage IA or IB. Subset analyses according to radiological tumor findings showed that segmentectomy yielded oncological outcomes comparable to those of lobectomy for non-pure solid tumors. In cases where the solid tumor exceeded 20 mm, segmentectomy showed a recurrence-free survival inferior to that of lobectomy (p = 0.028), despite an equivalent overall survival (p = 0.38). CONCLUSION: Segmentectomy may be an acceptable alternative to lobectomy with regard to the overall survival of patients with c-stage I NSCLC in the left upper lobe.

DOI： 10.1007/s00595-024-02844-8

Reconstruction method for massive lateral chest wall sarcoma using titanium plates and mesh: a case report. Reviewed International journal

Shin Tanaka, Eiji Nakata, Toshifumi Ozaki, Shinichi Toyooka

Journal of cardiothoracic surgery 19 ( 1 ) 245 - 245 2024.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Very large chest wall resections can lead to acute thoracic insufficiency syndrome due to the interdependence of lung expansion and thoracic volume. Chest wall tumor surgeries often encounter complications, with the size of the chest wall defect being a significant predictor. Several methods for large chest wall reconstruction have been described, aiming to provide stability, prevent flail chest, and ensure airtight closure. However, no single method fulfills all requirements. Composite chest wall reconstruction using titanium plates and Gore-Tex patches has shown the potential to minimize physiologic abnormalities caused by extensive defects. CASE PRESENTATION: A 42-year-old man with myxofibrosarcoma underwent multiple surgeries, chemotherapies, and radiation therapies due to repeated local recurrences. After right arm amputation and resection of the right third to fifth ribs, a local recurrence was detected. A 30 × 40 cm chest wall defect was resected en bloc, and a titanium plate was used for three-dimensional formability, preventing flail chest and volume loss. The Gore-Tex patch was then reconstructed into an arch shape, allowing lateral thoracic mobility. The patient recovered well and did not experience respiratory dysfunction or local recurrence but later succumbed to distant metastasis. CONCLUSIONS: In this case, the combination of a titanium plate and a Gore-Tex patch proved effective for reconstructing massive lateral chest wall defects. The approach provided stability, preserved thoracic volume, and allowed for lateral mobility. While the patient achieved a successful outcome in terms of local recurrence and respiratory function, distant metastasis remained a challenge for myxofibrosarcoma patients, and its impact on long-term prognosis requires further investigation. Nevertheless, the described procedure offers promise for managing extensive chest wall defects.

DOI： 10.1186/s13019-024-02639-5

Effect of revised organ transplant law in Japan on lung transplantation. Reviewed

Yoshito Imamura, Daisuke Nakajima, Takashi Kanou, Yasushi Shintani, Seiichiro Sugimoto, Shinichi Toyooka, Yasushi Hoshikawa, Keitaro Matsumoto, Takeshi Nagayasu, Hidemi Suzuki, Sumiko Maeda, Masayuki Chida, Takeshi Shiraishi, Toshihiko Sato, Masaaki Sato, Jun Nakajima, Hisashi Oishi, Yoshinori Okada, Hiroshi Date

Surgery today 2024.4

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To investigate how revision of the organ transplant law in Japan affected lung transplantation in this country. METHODS: Lung transplant candidates registered between January, 2000 and December, 2009 were designated as the pre-revision group (n = 396) and those registered between January, 2011 and December, 2020, as the post-revision group (n = 1326). Both groups were analyzed retrospectively using data collected by the Japanese Society of Lung and Heart-Lung Transplantation. RESULTS: The number of patients who underwent brain-dead donor lung transplantation (BDLT) increased significantly after the law amendment (32.2 vs. 13.8%, p < 0.01). The median waiting time for BDLT was significantly reduced (708 days vs. 1163 days, p < 0.01) and the mortality rate while waiting for BDLT improved significantly after the law amendment (33.1 vs. 42.6%, p < 0.01). In the post-revision group, 18 pediatric patients underwent BDLT. The 5-year survival rates after BDLT were comparable between the groups (73.5% in the pre-revision group vs. 73.2% in the post-revision group, p = 0.32). CONCLUSIONS: The organ transplant law revision shortened the waiting time for BDLT significantly and decreased the mortality rate while waiting for BDLT. The posttransplant outcomes in Japan remained favorable throughout the study period.

DOI： 10.1007/s00595-024-02839-5

The BAP1 nuclear deubiquitinase is involved in the nonhomologous end-joining pathway of double-strand DNA repair through interaction with DNA-PK. Reviewed International journal

Hiroki Sato, Tatsuo Ito, Takuo Hayashi, Shigehisa Kitano, Hediye Erdjument-Bromage, Matthew J Bott, Shinichi Toyooka, Marjorie Zauderer, Marc Ladanyi

Oncogene 43 ( 15 ) 1087 - 1097 2024.4

Language：English Publishing type：Research paper (scientific journal)

BRCA1-associated protein 1 (BAP1) has emerged as a major tumor suppressor gene in diverse cancer types, notably in malignant pleural mesothelioma (DPM), and has also been identified as a germline cancer predisposition gene for DPM and other select cancers. However, its role in the response to DNA damage has remained unclear. Here, we show that BAP1 inactivation is associated with increased DNA damage both in Met-5A human mesothelial cells and human DPM cell lines. Through proteomic analyses, we identified PRKDC as an interaction partner of BAP1 protein complexes in DPM cells and 293 T human embryonic kidney cells. PRKDC encodes the catalytic subunit of DNA protein kinase (DNA-PKcs) which functions in the nonhomologous end-joining (NHEJ) pathway of DNA repair. Double-stranded DNA damage resulted in prominent nuclear expression of BAP1 in DPM cells and phosphorylation of BAP1 at serine 395. A plasmid-based NHEJ assay confirmed a significant effect of BAP1 knockdown on cellular NHEJ activity. Combination treatment with X-ray irradiation and gemcitabine (as a radiosensitizer) strongly suppressed the growth of BAP1-deficient cells. Our results suggest reciprocal positive interactions between BAP1 and DNA-PKcs, based on phosphorylation of BAP1 by the latter and deubiquitination of DNA-PKcs by BAP1. Thus, functional interaction of BAP1 with DNA-PKcs supports a role for BAP1 in NHEJ DNA repair and may provide the basis for new therapeutic strategies and new insights into its role as a tumor suppressor.

DOI： 10.1038/s41388-024-02966-w

外科と救急のダブルボード取得を目指した外科救急連携コース

黒田新士, 安井和也, 岡崎幹生, 小谷恭弘, 枝園忠彦, 小林純子, 中尾篤典, 笠原真悟, 豊岡伸一, 藤原俊義

日本外科学会定期学術集会抄録集 124回 SP - 6 2024.4

Lysyl oxidase-like 4 promotes the invasiveness of triple-negative breast cancer cells by orchestrating the invasive machinery formed by annexin A2 and S100A11 on the cell surface Reviewed

Tetta Takahashi, Nahoko Tomonobu, Rie Kinoshita, Ken-ichi Yamamoto, Hitoshi Murata, Ni Luh Gede Yoni Komalasari, Youyi Chen, Fan Jiang, Yuma Gohara, Toshiki Ochi, I Made Winarsa Ruma, I Wayan Sumardika, Jin Zhou, Tomoko Honjo, Yoshihiko Sakaguchi, Akira Yamauchi, Futoshi Kuribayashi, Eisaku Kondo, Yusuke Inoue, Junichiro Futami, Shinichi Toyooka, Yoshito Zamami, Masakiyo Sakaguchi

Frontiers in Oncology 14 2024.3

Publishing type：Research paper (scientific journal) Publisher：Frontiers Media SA

Background

Our earlier research revealed that the secreted lysyl oxidase-like 4 (LOXL4) that is highly elevated in triple-negative breast cancer (TNBC) acts as a catalyst to lock annexin A2 on the cell membrane surface, which accelerates invasive outgrowth of the cancer through the binding of integrin-β1 on the cell surface. However, whether this machinery is subject to the LOXL4-mediated intrusive regulation remains uncertain.

Methods

Cell invasion was assessed using a transwell-based assay, protein–protein interactions by an immunoprecipitation–Western blotting technique and immunocytochemistry, and plasmin activity in the cell membrane by gelatin zymography.

Results

We revealed that cell surface annexin A2 acts as a receptor of plasminogen via interaction with S100A10, a key cell surface annexin A2-binding factor, and S100A11. We found that the cell surface annexin A2/S100A11 complex leads to mature active plasmin from bound plasminogen, which actively stimulates gelatin digestion, followed by increased invasion.

Conclusion

We have refined our understanding of the role of LOXL4 in TNBC cell invasion: namely, LOXL4 mediates the upregulation of annexin A2 at the cell surface, the upregulated annexin 2 binds S100A11 and S100A10, and the resulting annexin A2/S100A11 complex acts as a receptor of plasminogen, readily converting it into active-form plasmin and thereby enhancing invasion.

DOI： 10.3389/fonc.2024.1371342

Impact of the neutrophil-to-lymphocyte ratio on patients with locally advanced non-small cell lung cancer who suffer radiation pneumonitis during the course of induction chemoradiotherapy followed by surgery. Reviewed

Yujiro Kubo, Hiromasa Yamamoto, Kei Matsubara, Kohei Hashimoto, Shin Tanaka, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Mikio Okazaki, Seiichiro Sugimoto, Kuniaki Katsui, Takao Hiraki, Katsuyuki Kiura, Shinichi Toyooka

Surgery today 2024.3

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Radiation pneumonitis (RP) is an obstacle for patients after surgery following induction chemoradiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC). We performed a comparative analysis of the association between clinicopathological factors, including the neutrophil-to-lymphocyte ratio (NLR) and prognosis, in LA-NSCLC patients with or without RP during induction chemoradiotherapy followed by surgery. METHODS: The subjects of this analysis were 168 patients undergoing trimodality therapy for LA-NSCLC between January, 1999 and May, 2019. Patients were divided into two groups: the RP group (n = 41) and the non-RP group (n = 127). We compared the clinicopathological factors including the NLR between the groups and analyzed the association between the NLR and prognosis. RESULTS: The RP group had more patients with tumors located in the lower lobe, more bilobar resections, shorter operative times, no implementation of postoperative adjuvant chemotherapy, and a higher postoperative NLR than the non-RP group. There were no significant differences in serious postoperative complications and the prognosis. Patients with a low postoperative NLR had a significantly better prognosis in the non-RP group, and a trend toward a better prognosis even in the RP group. CONCLUSION: Postoperative NLR may be a useful prognostic factor, even for patients who suffer RP after trimodality therapy for LA-NSCLC.

DOI： 10.1007/s00595-024-02816-y

肺癌登録事業報告2024年

鈴木秀海, 吉野一郎, 新谷康, 四倉正也, 渡辺俊一, 川口知哉, 山本信之, 清家正博, 高橋和久, 高山浩一, 豊岡伸一, 佐藤幸夫, 千田雅之, 宮岡悦良, 服部聡, 伊達洋至, 全国肺癌登録合同委員会

日本呼吸器学会誌 13 ( 増刊 ) 128 - 128 2024.3

Effects of case volume on short- and long-term outcomes following cadaveric lung transplantation in Japan. Reviewed International journal

Masayuki Chida, Takashi Inoue, Takahiro Nakajima, Yoshinori Okada, Hisashi Oishi, Jun Nakajima, Masaaki Sato, Ichiro Yoshino, Hidemi Suzuki, Daisuke Nakajima, Yasushi Shintani, Takashi Kanou, Shinichi Toyooka, Kentaroh Miyoshi, Takeshi Shiraishi, Toshihiko Sato, Keitaro Matsumoto, Takeshi Nagayasu, Yasushi Hoshikawa, Yasushi Matsuda, Sumiko Maeda, Hiroshi Date

Journal of thoracic disease 16 ( 2 ) 1473 - 1479 2024.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Despite the low number of lung transplantations (LTs) in Japan, 10 LT facilities are accredited and good outcomes have been reported. A database review was conducted to clarify the impact of case volume at LT facilities in Japan on short- and long-term outcomes. METHODS: All cadaveric LT cases treated between 2000 and 2021 in Japan were analyzed using the database of the Japanese Society of Lung and Heart-Lung Transplantation (JSLHT). The nine institutions represented were categorized into the low-volume (LV; <80 cumulative LT cases, <8 LTs/year, n=5) and high-volume (HV; ≥80 cumulative LT cases, ≥8 LTs/year, n=4) centers. Ninety-day and 1-year mortality, as well as 5- and 10-year survival data were evaluated. RESULTS: A total of 658 cadaveric LTs were performed at the nine institutions. The 90-day rates of mortality at the HV and LV centers were 3.5% and 3.9%, respectively (P=0.801), while the 1-year mortality rates were 9.2% and 11.5%, respectively (P=0.199). Additionally, log-rank analysis of Kaplan-Meier curves showing case volume did not reveal a significant difference in long-term survival between the HV and LV centers (P=0.272), though the LV centers had wide differences for long-term outcomes (P=0.030). CONCLUSIONS: Case volume did not have effects on short- or long-term outcomes following LT in Japan, while there were large variations in long-term outcomes among the LV centers compared to those of the HV centers.

DOI： 10.21037/jtd-23-90

Plasma concentrations of histidine-rich glycoprotein in primary graft dysfunction after lung transplantation. Reviewed International journal

Toshio Shiotani, Seiichiro Sugimoto, Yasuaki Tomioka, Shin Tanaka, Toshiharu Mitsuhashi, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Hiromasa Yamamoto, Mikio Okazaki, Shinichi Toyooka

Interdisciplinary cardiovascular and thoracic surgery 2024.2

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Histidine-rich glycoprotein has been reported as an anti-inflammatory glycoprotein that inhibits acute lung injury in mice with sepsis and as a prognostic biomarker in patients with sepsis. We investigated the relationship between plasma concentrations of histidine-rich glycoprotein and the risk of occurrence of primary graft dysfunction. METHODS: According to the primary graft dysfunction grade at post-transplant 72 hours, patients who underwent lung transplantation were divided into three groups: non-primary graft dysfunction group (grade 0-1), moderate primary graft dysfunction group (grade 2), and severe primary graft dysfunction group (grade 3). The plasma concentrations of histidine-rich glycoprotein measured daily during the first post-transplant 7 days were compared among the three groups. Appropriate cutoff values of the concentrations were set for survival analyses after lung transplantation. RESULTS: A total of 68 patients were included. The plasma histidine-rich glycoprotein concentration at post-transplant 72 hours was significantly lower in the severe primary graft dysfunction group (n = 7) than in the other two groups (non-primary graft dysfunction group (n = 43), P = 0.042; moderate primary graft dysfunction group (n = 18), P = 0.040). Patients with plasma histidine-rich glycoprotein concentration ≥34.4 µg/mL at post-transplant 72 hours had significantly better chronic lung allograft dysfunction-free survival (P = 0.012) and overall survival (P = 0.037) than those with the concentration <34.4 µg/mL. CONCLUSIONS: Plasma histidine-rich glycoprotein concentrations at post-transplant 72 hours might be associated with the risk of development of primary graft dysfunction.

DOI： 10.1093/icvts/ivae021

Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses. Reviewed International journal

Kouya Shiraishi, Atsushi Takahashi, Yukihide Momozawa, Yataro Daigo, Syuzo Kaneko, Takahisa Kawaguchi, Hideo Kunitoh, Shingo Matsumoto, Hidehito Horinouchi, Akiteru Goto, Takayuki Honda, Kimihiro Shimizu, Masahiro Torasawa, Daisuke Takayanagi, Motonobu Saito, Akira Saito, Yuichiro Ohe, Shun-Ichi Watanabe, Koichi Goto, Masahiro Tsuboi, Katsuya Tsuchihara, Sadaaki Takata, Tomomi Aoi, Atsushi Takano, Masashi Kobayashi, Yohei Miyagi, Kazumi Tanaka, Hiroyuki Suzuki, Daichi Maeda, Takumi Yamaura, Maiko Matsuda, Yoko Shimada, Takaaki Mizuno, Hiromi Sakamoto, Teruhiko Yoshida, Yasushi Goto, Tatsuya Yoshida, Taiki Yamaji, Makoto Sonobe, Shinichi Toyooka, Kazue Yoneda, Katsuhiro Masago, Fumihiro Tanaka, Megumi Hara, Nobuo Fuse, Satoshi S Nishizuka, Noriko Motoi, Norie Sawada, Yuichiro Nishida, Kazuki Kumada, Kenji Takeuchi, Kozo Tanno, Yasushi Yatabe, Kuniko Sunami, Tomoyuki Hishida, Yasunari Miyazaki, Hidemi Ito, Mitsuhiro Amemiya, Hirohiko Totsuka, Haruhiko Nakayama, Tomoyuki Yokose, Kazuyoshi Ishigaki, Toshiteru Nagashima, Yoichi Ohtaki, Kazuhiro Imai, Ken Takasawa, Yoshihiro Minamiya, Kazuma Kobayashi, Kenichi Okubo, Kenji Wakai, Atsushi Shimizu, Masayuki Yamamoto, Motoki Iwasaki, Koichi Matsuda, Johji Inazawa, Yuichi Shiraishi, Hiroyoshi Nishikawa, Yoshinori Murakami, Michiaki Kubo, Fumihiko Matsuda, Yoichiro Kamatani, Ryuji Hamamoto, Keitaro Matsuo, Takashi Kohno

Cancer communications (London, England) 44 ( 2 ) 287 - 293 2024.2

Long-term outcomes of lung transplantation requiring renal replacement therapy: A single-center experience. Reviewed International journal

Yasuaki Tomioka, Seiichiro Sugimoto, Toshio Shiotani, Kei Matsubara, Haruki Choshi, Megumi Ishihara, Shin Tanaka, Kentaroh Miyoshi, Shinji Otani, Shinichi Toyooka

Respiratory investigation 62 ( 2 ) 240 - 246 2024.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Life-long immunosuppressive therapy after lung transplantation (LT) may lead to end-stage renal disease (ESRD), requiring renal replacement therapy (RRT). We aimed to investigate the characteristics and long-term outcomes of patients undergoing LT and requiring RRT. METHODS: This study was a single-center, retrospective cohort study. The patients were divided into the RRT (n = 15) and non-RRT (n = 170) groups. We summarized the clinical features of patients in the RRT group and compared patient characteristics, overall survival, and chronic lung allograft dysfunction (CLAD)-free survival between the two groups. RESULTS: The cumulative incidences of ESRD requiring RRT after LT at 5, 10, and 15 years were 0.8 %, 7.6 %, and 25.2 %, respectively. In the RRT group, all 15 patients underwent hemodialysis but not peritoneal dialysis, and two patients underwent living-donor kidney transplantation. The median follow-up period was longer in the RRT group than in the non-RRT group (P < 0.001). The CLAD-free survival and overall survival did not differ between the two groups. The 5-year survival rate even after the initiation of hemodialysis was 53.3 %, and the leading cause of death in the RRT group was infection. CONCLUSIONS: Favorable long-term outcomes can be achieved by RRT for ESRD after LT.

DOI： 10.1016/j.resinv.2024.01.001

Clinical Features of Patients With Second Primary Lung Cancer After Head and Neck Cancer. Reviewed International journal

Fumiaki Takatsu, Ken Suzawa, Mikio Okazaki, Kazuhiko Shien, Hiromasa Yamamoto, Mototsugu Watanabe, Makio Hayama, Tsuyoshi Ueno, Ryujiro Sugimoto, Yuho Maki, Toshiya Fujiwara, Riki Okita, Hidetoshi Inokawa, Hiroyuki Tao, Yuji Hirami, Eisuke Matsuda, Kazuhiko Kataoka, Motohiro Yamashita, Yoshifumi Sano, Motoki Matsuura, Hisao Mizutani, Shinichi Toyooka

The Annals of thoracic surgery 117 ( 1 ) 181 - 188 2024.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Survivors of head and neck cancer (HNC) often develop second primary lung cancer (SPLC), due to a common risk factor, that is, smoking. Our multicenter experience has been reviewed to evaluate how the history of diagnosis of HNC affects the outcomes of patients undergoing pulmonary resection for SPLC. METHODS: A multicenter retrospective analysis of patients hospitalized between January 2012 and December 2018 has been performed. From a cohort of 4,521 patients undergoing therapeutic pulmonary resection for primary non-small cell lung cancer, 100 patients with previous history of HNC (HNC group) have been identified. They were compared with a control group consisting of 200 patients without HNC history from the same cohort pair-matched with operating facility, age, sex, and pathological stage of lung cancer. RESULTS: At the time of surgery for SPLC, the HNC group showed malnutrition with lower prognostic nutritional index (PNI) compared with the control group (p < 0.001). The HNC group were determined to have postoperative complications more frequently (p = 0.02). The 5-year overall survival rates in the HNC and control groups were 59.0% and 83.2%, respectively (p < 0.001). Statistically, HNC history, lower PNI, squamous cell lung cancer, and TNM stage were identified to be independently associated with poor survival. CONCLUSIONS: Patients with SPLC following primary HNC often present with malnutrition and are predisposed to have postoperative complications and poor survival after pulmonary resection.

DOI： 10.1016/j.athoracsur.2022.04.052

Successful Living-donor Lobar Lung Transplantation With BK Virus-related Hemorrhagic Cystitis Throughout the Perioperative Period. Reviewed International journal

Yasuaki Tomioka, Shinji Otani, Shin Tanaka, Kentaroh Miyoshi, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

Transplantation direct 10 ( 1 ) e1556 2024.1

PAI-1 mediates acquired resistance to MET-targeted therapy in non-small cell lung cancer. Reviewed International journal

Yin Min Thu, Ken Suzawa, Shuta Tomida, Kosuke Ochi, Shimpei Tsudaka, Fumiaki Takatsu, Keiichi Date, Naoki Matsuda, Kazuma Iwata, Kentaro Nakata, Kazuhiko Shien, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Shinichi Toyooka

PloS one 19 ( 5 ) e0300644 2024

Language：English Publishing type：Research paper (scientific journal)

Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma.

DOI： 10.1371/journal.pone.0300644

Predictive Value of PERCIST for Locally Advanced Non-Small Cell Lung Cancer Treated with Preoperative Induction Therapy - A Multicenter Study in Japan. Reviewed International journal

Katsuhiko Shimizu, Masao Nakata, Shinsuke Saisho, Masayuki Inubushi, Norihito Okumura, Tomohiro Murakawa, Motohiro Yamashita, Hiroshige Nakamura, Yoshifumi Sano, Kazuhiko Kataoka, Shinichi Toyooka

Cancer management and research 16 965 - 976 2024

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Induction therapy followed by surgery is recommended as an alternative treatment strategy for locally advanced non-small cell lung cancer (NSCLC). Patients who achieve pathologic response after induction therapy have better outcomes than non-responders; therefore, therapeutic response must be evaluated. Recently, new approaches for monitoring therapeutic responses, which are based on 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET), have been developed. In this study, we evaluated the predictive value of Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST), which uses standardized uptake values corrected for lean body mass (SUL) and total lesion glycolysis (TLG). METHODS: A total of 130 patients in the Setouchi Lung Cancer Group who underwent FDG-PET imaging before and after induction therapy prior to a planned surgical resection for NSCLC between 2007 and 2016 were studied retrospectively. The pathologic responses of the primary lung tumors and metastatic lymph nodes were compared with their responses based on evaluation using PERCIST. RESULTS: Postoperative pathologic studies revealed pathologic complete response (pCR) in 42 (32.3%) patients. PERCIST was significantly correlated with pathologic response (p < 0.001). The sensitivity, specificity, and accuracy of PERCIST for predicting pCR were 16.7% (7/42), 88.6% (78/88), and 65.4% (85/130), respectively. Patients with pCR had significantly higher reduction rates in SULpeak for both primary lung tumors and metastatic lymph nodes and TLG for primary tumors than non-responders. In a multivariate Cox regression analysis, tumor site in upper lobes, reduction rate of TLG in primary tumor, and pathologic N0 were independent predictors of favorable recurrence-free survival (RFS). CONCLUSION: Our study suggested that PERCIST, especially the rate of TLG reduction rate, are useful to predict the pathological response and prognosis after induction therapy. Although improvement is necessary, PERCIST can be a promising method of the post-induction status in lung cancer. Further research is needed to confirm our findings.

DOI： 10.2147/CMAR.S464265

(, 10.32388/74e1v5)

Ayako Chida-Nagai, Naoki Masaki, Kay Maeda, Konosuke Sasaki, Hiroki Sato, Jun Muneuchi, Yoshie Ochiai, Hiroomi Murayama, Masahiro Tahara, Atsuko Shiono, Atsushi Shinozuka, Fumihiko Kono, Daisuke Machida, Shinichi Toyooka, Seiichiro Sugimoto, Kazufumi Nakamura, Satoshi Akagi, Maiko Kondo, Shingo Kasahara, Yasuhiro Kotani, Junichi Koizumi, Katsuhiko Oda, Masako Harada, Daisuke Nakajima, Akira Murata, Hazumu Nagata, Koichi Yatsunami, Tomio Kobayashi, Yoshikiyo Matsunaga, Takahiro Inoue, Hiroyuki Yamagishi, Naomi Nakagawa, Katsuki Ohtani, Masaki Yamamoto, Yushi Ito, Tatsunori Hokosaki, Yuta Kuwahara, Satoshi Masutani, Koji Nomura, Tsutomu Wada, Hirofumi Sawada, Masayuki Abiko, Tatsunori Takahashi, Yuichi Ishikawa, Seigo Okada, Atsushi Naitoh, Takako Toda, Tatsuya Ando, Akihiro Masuzawa, Shinsuke Hoshino, Masaaki Kawada, Yuichi Nomura, Kentaro Ueno, Naoki Ohashi, Tsuyoshi Tachibana, Yuchen Cao, Hideaki Ueda, Sadamitsu Yanagi, Masaaki Koide, Norie Mitsushita, Kouji Higashi, Yoshihiro Minosaki, Tomohiro Hayashi, Takashi Okamoto, Kenji Kuraishi, Eiji Ehara, Hidekazu Ishida, Hitoshi Horigome, Takashi Murakami, Kohta Takei, Taku Ishii, Gen Harada, Yasutaka Hirata, Jun Maeda, Shunsuke Tatebe, Chiharu Ota, Yasunobu Hayabuchi, Hisanori Sakazaki, Takashi Sasaki, Keiichi Hirono, Sayo Suzuki, Masahiro Yasuda, Atsuhito Takeda, Madoka Sawada, Kagami Miyaji, Atsushi Kitagawa, Yosuke Nakai, Nobuyuki Kakimoto, Kouta Agematsu, Atsushi Manabe, Yoshikatsu Saiki

Frontiers in Cardiovascular Medicine 11 2024

Correction to: Periostin secreted by cancer‑associated fibroblasts promotes cancer progression and drug resistance in non‑small cell lung cancer. Reviewed International journal

Fumiaki Takatsu, Ken Suzawa, Shuta Tomida, Yin Min Thu, Masakiyo Sakaguchi, Tomohiro Toji, Masayoshi Ohki, Shimpei Tsudaka, Keiichi Date, Naoki Matsuda, Kazuma Iwata, Yidan Zhu, Kentaro Nakata, Kazuhiko Shien, Hiromasa Yamamoto, Akiko Nakayama, Mikio Okazaki, Seiichiro Sugimoto, Shinichi Toyooka

Journal of molecular medicine (Berlin, Germany) 2023.12

ASO Author Reflections: Tumor-Infiltrating Lymphocytes, Tertiary Lymphoid Structures, and Neutrophil-to-Lymphocyte Ratio are Prognostic Factors in Pulmonary Metastases from Uterine Leiomyosarcoma. Reviewed International journal

Naoki Matsuda, Hiromasa Yamamoto, Tomohiro Habu, Katsuhito Takahashi, Shinichi Toyooka

Annals of surgical oncology 30 ( 13 ) 8757 - 8758 2023.12

The consecutive impact of COVID-19 on thoracic surgical procedures in Japan: an analysis of data from the National Clinical Database. Reviewed

Yukio Sato, Hiroyuki Yamamoto, Norihiko Ikeda, Hiroshi Konishi, Taizo Hibi, Shunsuke Endo, Masayoshi Inoue, Yoshinori Okada, Yashushi Shintani, Shinichi Toyooka, Hiroshige Nakamura, Yasushi Hoshikawa, Toyofumi Fengshi Chen-Yoshikawa, Hidetaka Uramoto, Yoshihiro Tsubochi, Tadao Kakizoe, Masayuki Chida, Ichiro Yoshino

Surgery today 2023.11

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: The current study was designed to analyze the impact of the COVID-19 pandemic on general thoracic surgeries in Japan. METHODS: Changes in surgeries for lung cancer and metastatic lung tumors were evaluated based on National Clinical Database data regarding cancer screening. RESULTS: In 2021, surgeries for primary lung cancer increased by 3.4% compared to 2020, which, given the increase from 2014 to 2019, indicates an overall 11.1% decrease. In contrast, surgeries for metastatic lung tumors in 2021 decreased by 5.8% compared to 2020, which, given the increase from 2014 to 2020, indicates an overall 9.2% decrease. Half of the primary diseases for metastatic lung tumor were cases of colorectal cancer. Low anterior resection procedures in 2020 decreased by 5.5% compared to 2019. Lung and colon cancer screening examinees in 2021 were increased compared to 2020; however, they still showed respective decreases of 11% and 9.0% compared to 2019. CONCLUSIONS: Surgeries for primary lung cancer still decreased substantially during the COVID-19 pandemic. The continued stagnation of screening was responsible for this decrease. Surgeries for metastatic lung tumors decreased profoundly, and the decrease in screening for primary tumors was responsible for this reduction. Our findings emphasize the significance of maintaining cancer screening efforts, even during a pandemic.

DOI： 10.1007/s00595-023-02763-0

EP07.01-12 A Retrospective Study on the Methods of Covering Bronchial Stump/Anastomotic Site to Avoid the Bronchopleural Fistula after Lung Cancer Surgery Reviewed

T. Habu, H. Yamamoto, K. Nakata, K. Hashimoto, S. Tanaka, K. Suzawa, K. Shien, K. Miyoshi, M. Okazaki, S. Sugimoto, S. Toyooka

Journal of Thoracic Oncology 18 ( 11 ) S512 - S513 2023.11

Impact of changes in skeletal muscle mass and quality during the waiting time on outcomes of lung transplantation. Reviewed International journal

Akikazu Hagiyama, Seiichiro Sugimoto, Shin Tanaka, Kei Matsubara, Kentaroh Miyoshi, Yoshimi Katayama, Masanori Hamada, Masuo Senda, Shinichi Toyooka

Clinical transplantation e15169 2023.10

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: The association of changes in skeletal muscle mass and quality during the waiting time with outcomes of lung transplantation (LT) remains unclear. We aimed to examine the association of changes in skeletal muscle mass and quality during the waiting time, as well as preoperative skeletal muscle mass and quality, with outcomes of LT. METHODS: This study included individuals who underwent LT from brain-dead donors. Skeletal muscle mass (cm2 /m2 ) and quality (mean Hounsfield units [HU]) of the erector spinae muscle at the 12th thoracic level were evaluated using computed tomography. Preoperative skeletal muscle mass and quality, and their changes during the waiting time were calculated. We evaluated the associations among mechanical ventilation (MV) duration, intensive care unit (ICU) length of stay (LOS), hospital LOS, 6-minute walk distance at discharge, and 5-year survival after LT. RESULTS: This study included 98 patients. The median waiting time was 594.5 days (interquartile range [IQR], 355.0-913.0). The median changes in skeletal muscle mass and quality were -4.4% (IQR, -13.3-3.1) and -2.9% (IQR, -16.0-4.1), respectively. Severe low skeletal muscle mass at LT was associated with prolonged ICU LOS (B = 8.46, 95% confidence interval [CI]: .51-16.42) and hospital LOS (B = 36.00, 95% CI: 3.23-68.78). Pronounced decrease in skeletal muscle mass during the waiting time was associated with prolonged MV duration (B = 7.85, 95% CI: .89-14.81) and ICU LOS (B = 7.97, 95% CI: .83-15.10). CONCLUSION: Maintaining or increasing skeletal muscle mass during the waiting time would be beneficial to improve the short-term outcomes of LT.

DOI： 10.1111/ctr.15169

NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study. Reviewed International journal

Satoshi Ikeda, Masahiro Tsuboi, Kazuko Sakai, Toshihiro Misumi, Hiroaki Akamatsu, Hiroyasu Shoda, Noriaki Sakakura, Atsushi Nakamura, Yasuhisa Ohde, Hidetoshi Hayashi, Kyoichi Okishio, Morihito Okada, Ichiro Yoshino, Jiro Okami, Kazuhisa Takahashi, Norihiko Ikeda, Masayuki Tanahashi, Yuichi Tambo, Haruhiro Saito, Shinichi Toyooka, Hidetoshi Inokawa, Toyofumi Chen-Yoshikawa, Toshihide Yokoyama, Tatsuro Okamoto, Noriko Yanagitani, Masahide Oki, Makoto Takahama, Kenji Sawa, Hirohito Tada, Kazuhiko Nakagawa, Tetsuya Mitsudomi, Kazuto Nishio

Molecular oncology 2023.10

Language：English Publishing type：Research paper (scientific journal)

The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.

DOI： 10.1002/1878-0261.13542

Conditional blastocyst complementation of a defective Foxa2 lineage efficiently promotes the generation of the whole lung. Reviewed International journal

Akihiro Miura, Hemanta Sarmah, Junichi Tanaka, Youngmin Hwang, Anri Sawada, Yuko Shimamura, Takehiro Otoshi, Yuri Kondo, Yinshan Fang, Dai Shimizu, Zurab Ninish, Jake Le Suer, Nicole C Dubois, Jennifer Davis, Shinichi Toyooka, Jun Wu, Jianwen Que, Finn J Hawkins, Chyuan-Sheng Lin, Munemasa Mori

eLife 12 2023.10

Language：English Publishing type：Research paper (scientific journal)

Millions suffer from incurable lung diseases, and the donor lung shortage hampers organ transplants. Generating the whole organ in conjunction with the thymus is a significant milestone for organ transplantation because the thymus is the central organ to educate immune cells. Using lineage-tracing mice and human pluripotent stem cell (PSC)-derived lung-directed differentiation, we revealed that gastrulating Foxa2 lineage contributed to both lung mesenchyme and epithelium formation. Interestingly, Foxa2 lineage-derived cells in the lung mesenchyme progressively increased and occupied more than half of the mesenchyme niche, including endothelial cells, during lung development. Foxa2 promoter-driven, conditional Fgfr2 gene depletion caused the lung and thymus agenesis phenotype in mice. Wild-type donor mouse PSCs injected into their blastocysts rescued this phenotype by complementing the Fgfr2-defective niche in the lung epithelium and mesenchyme and thymic epithelium. Donor cell is shown to replace the entire lung epithelial and robust mesenchymal niche during lung development, efficiently complementing the nearly entire lung niche. Importantly, those mice survived until adulthood with normal lung function. These results suggest that our Foxa2 lineage-based model is unique for the progressive mobilization of donor cells into both epithelial and mesenchymal lung niches and thymus generation, which can provide critical insights into studying lung transplantation post-transplantation shortly.

DOI： 10.7554/eLife.86105

In vivo lung perfusion for prompt recovery from primary graft dysfunction after lung transplantation. Reviewed International journal

Kei Matsubara, Kentaroh Miyoshi, Shinichi Kawana, Yujiro Kubo, Dai Shimizu, Yasuaki Tomioka, Toshio Shiotani, Haruchika Yamamoto, Shin Tanaka, Takeshi Kurosaki, Toshiaki Ohara, Mikio Okazaki, Seiichiro Sugimoto, Akihiro Matsukawa, Shinichi Toyooka

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2023.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: No proven treatment after the development of primary graft dysfunction (PGD) is currently available. Here we established a novel strategy of in vivo lung perfusion (IVLP) for the treatment of PGD. IVLP involves the application of an in vivo isolated perfusion circuit to an implanted lung. This study aimed to explore the effectiveness of IVLP versus conventional post-lung transplant (LTx) extracorporeal membrane oxygenation (ECMO) treatment using an experimental swine LTx PGD model. METHODS: After 1.5-h warm ischemia of the donor lungs, a left LTx was performed. Following the confirmation of PGD development, pigs were divided into three groups (n = 5 each): control (no intervention), ECMO, and IVLP. After 2 h of treatment, a 4-h functional assessment was conducted and samples obtained. RESULTS: Significantly better oxygenation were achieved in the IVLP group (p ≤ 0.001). Recovery was confirmed immediately and maintained during the following 4-h observation. The IVLP group also demonstrated better lung compliance than the control group (p = 0.045). A histological evaluation showed that the lung injury score and terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed significantly fewer injuries and a better result in the wet-to-dry weight ratio in the IVLP group. CONCLUSIONS: A two-hour IVLP is technically feasible and allows for prompt recovery from PGD after LTx. The posttransplant short-duration IVLP strategy can complement or overcome the limitations of the current practice for donor assessment and PGD management.

DOI： 10.1016/j.healun.2023.10.011

Periostin secreted by cancer-associated fibroblasts promotes cancer progression and drug resistance in non-small cell lung cancer. Reviewed International journal

Fumiaki Takatsu, Ken Suzawa, Shuta Tomida, Yin Min Thu, Masakiyo Sakaguchi, Tomohiro Toji, Masayoshi Ohki, Shimpei Tsudaka, Keiichi Date, Naoki Matsuda, Kazuma Iwata, Yidan Zhu, Kentaro Nakata, Kazuhiko Shien, Hiromasa Yamamoto, Akiko Nakayama, Mikio Okazaki, Seiichiro Sugimoto, Shinichi Toyooka

Journal of molecular medicine (Berlin, Germany) 2023.10

Language：English Publishing type：Research paper (scientific journal)

Cancer-associated fibroblasts (CAFs) are important components in the tumor microenvironment, and we sought to identify effective therapeutic targets in CAFs for non-small cell lung cancer (NSCLC). In this study, we established fibroblast cell lines from the cancerous and non-cancerous parts of surgical lung specimens from patients with NSCLC and evaluated the differences in behaviors towards NSCLC cells. RNA sequencing analysis was performed to investigate the differentially expressed genes between normal fibroblasts (NFs) and CAFs, and we identified that the expression of periostin (POSTN), which is known to be overexpressed in various solid tumors and promote cancer progression, was significantly higher in CAFs than in NFs. POSTN increased cell proliferation via NSCLC cells' ERK pathway activation and induced epithelial-mesenchymal transition (EMT), which improved migration in vitro. In addition, POSTN knockdown in CAFs suppressed these effects, and in vivo experiments demonstrated that the POSTN knockdown improved the sensitivity of EGFR-mutant NSCLC cells for osimertinib treatment. Collectively, our results showed that CAF-derived POSTN is involved in tumor growth, migration, EMT induction, and drug resistance in NSCLC. Targeting CAF-secreted POSTN could be a potential therapeutic strategy for NSCLC. KEY MESSAGES: • POSTN is significantly upregulated in CAFs compared to normal fibroblasts in NCSLC. • POSTN increases cell proliferation via activation of the NSCLC cells' ERK pathway. • POSTN induces EMT in NSCLC cells and improves the migration ability. • POSTN knockdown improves the sensitivity for osimertinib in EGFR-mutant NSCLC cells.

DOI： 10.1007/s00109-023-02384-7

Connective tissue mast cells store and release noradrenaline. Reviewed

Yusuke Otani, Soichiro Yoshikawa, Kei Nagao, Takehiro Tanaka, Shinichi Toyooka, Atsushi Fujimura

The journal of physiological sciences : JPS 73 ( 1 ) 24 - 24 2023.10

Language：English Publishing type：Research paper (scientific journal)

Mast cells are present in mucosal and connective tissues throughout the body. They synthesize and release a wide variety of bioactive molecules, such as histamine, proteases, and cytokines. In this study, we found that a population of connective tissue mast cells (CTMCs) stores and releases noradrenaline, originating from sympathetic nerves. Noradrenaline-storing cells, not neuronal fibers, were predominantly identified in the connective tissues of the skin, mammary gland, gastrointestinal tract, bronchus, thymus, and pancreas in wild-type mice but were absent in mast cell-deficient W-sash c-kit mutant KitW-sh/W-sh mice. In vitro studies using bone marrow-derived mast cells revealed that extracellular noradrenaline was taken up but not synthesized. Upon ionomycin stimulation, noradrenaline was released. Electron microscopy analyses further suggested that noradrenaline is stored in and released from the secretory granules of mast cells. Finally, we found that noradrenaline-storing CTMCs express organic cation transporter 3 (Oct3), which is also known as an extraneuronal monoamine transporter, SLC22A3. Our findings indicate that mast cells may play a role in regulating noradrenaline concentration by storing and releasing it in somatic tissues.

DOI： 10.1186/s12576-023-00883-3

Author Correction: Identification of genetic loci associated with renal dysfunction after lung transplantation using an ethnic-specific single-nucleotide polymorphism array. Reviewed International journal

Yasuaki Tomioka, Seiichiro Sugimoto, Haruchika Yamamoto, Shuta Tomida, Toshio Shiotani, Shin Tanaka, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Mikio Okazaki, Masaomi Yamane, Shinichi Toyooka

Scientific reports 13 ( 1 ) 16721 - 16721 2023.10

完全切除後II-III期のEGFR変異陽性非小細胞肺癌に対する第III相IMPACT試験における付随バイオマーカー研究

庄田浩康, 池田慧, 坪井正博, 坂井和子, 三角俊裕, 赤松弘朗, 棚橋雅幸, 丹保裕一, 齋藤春洋, 豊岡伸一, 井野川英利, 芳川豊史, 横山俊秀, 岡本龍郎, 柳谷典子, 沖昌英, 光冨徹哉, 多田弘人, 中川和彦, 西尾和人

肺癌 63 ( 5 ) 499 - 499 2023.10

ライフイベント時に本当に必要な支援とは? 高いチーム力でダイバーシティとインクルージョンを目指す当院のキャリア支援

小林純子, 竹原裕子, 溝尾妙子, 菊地覚次, 三好健太郎, 黒田新士, 田邊俊介, 楳田祐三, 小谷恭弘, 杉本誠一郎, 岡崎幹生, 枝園忠彦, 豊岡伸一, 藤原俊義, 笠原真悟

日本臨床外科学会雑誌 84 ( 増刊 ) S73 - S73 2023.10

Long-term management and outcome of lung transplantation in Japan. Reviewed International journal

Seiichiro Sugimoto, Kei Matsubara, Shin Tanaka, Kentaroh Miyoshi, Megumi Ishihara, Shinichi Toyooka

Journal of thoracic disease 15 ( 9 ) 5182 - 5194 2023.9

Language：English Publishing type：Research paper (scientific journal)

The long-term survival after lung transplantation (LT) is favorable in Japan. However, long-term survivors after LT are subject to late complications, including chronic lung allograft dysfunction (CLAD), malignancy, infection, and chronic kidney disease (CKD) because of the need for lifelong immunosuppression. The rates of single cadaveric LT (CLT) and living-donor lobar LT (LDLLT) are higher than that of bilateral CLT in Japan. Here, we will describe the management of late complications and long-term outcome after LT in Japan. Attention should be paid to not only the phenotype of CLAD but also the difference in CLAD after CLT and after LDLLT as well as the timing of lung re-transplantation for advanced CLAD, especially after single CLT. Since post-transplant lymphoproliferative disorder is the most common malignancy after LT, infection monitoring for infection-related malignancies and appropriate screening are keys to the early diagnosis and treatment of malignancy after LT. The long-term management of infection after LT is also important, especially with regard to community-acquired pathogens, Aspergillus, and cytomegalovirus. When providing long-term care after LT, physicians should be aware of CKD and the timing of renal replacement therapy in cases with severe CKD. The widespread use of computed tomography and dialysis in Japan are beneficial for long-term survivors of LT. The similar survival outcomes of single CLT and LDLLT, compared with bilateral CLT, might contribute to improved long-term survival in Japan. Pulmonologists are encouraged to become further involved in long-term management after LT in Japan.

DOI： 10.21037/jtd-22-1679

ASO Visual Abstract: Prognostic Impact of Tumor-Infiltrating Lymphocytes, Tertiary Lymphoid Structures, and Neutrophil-to-Lymphocyte Ratio in Pulmonary Metastases from Uterine Leiomyosarcoma. Reviewed International journal

Naoki Matsuda, Hiromasa Yamamoto, Tomohiro Habu, Kazuma Iwata, Kei Matsubara, Shin Tanaka, Kohei Hashimoto, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Tomohiro Toji, Mikio Okazaki, Seiichiro Sugimoto, Katsuhito Takahashi, Shinichi Toyooka

Annals of surgical oncology 2023.9

Successful management of temporary veno-venous extracorporeal membrane oxygenation for a pediatric lung transplant recipient with bronchiolitis obliterans syndrome awaiting lung re-transplantation: a case report. Reviewed International journal

Yasuaki Tomioka, Kentaroh Miyoshi, Shin Tanaka, Seiichiro Sugimoto, Rie Kanai, Tetsuro Nikai, Shinichi Toyooka, Masaomi Yamane

Surgical case reports 9 ( 1 ) 163 - 163 2023.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation is an uncommon strategy in Japan owing to the severe donor shortage and absence of urgent allocation policy. Moreover, the use of veno-venous (VV) ECMO for immunosuppressed patients is controversial; thus, applying ECMO to patients who await lung re-transplantation is challenging. CASE PRESENTATION: A 16-year-old lung transplant recipient with grade 3 bronchiolitis obliterans syndrome was waitlisted for lung re-transplantation. Eleven months later, he fell into severe respiratory acidosis with hypercapnia, which were not resolved with mechanical ventilation. VV ECMO was introduced to minimize lung stress and strain. Tracheostomy was additionally performed on day 5 after the start of ECMO, and respiratory condition swiftly improved; hence, the weaning process from VV ECMO began on day 9. Rehabilitation became implementable, and bilateral re-lung transplantation was successfully performed 6 months after the ECMO treatment. No critical complication related to the precedent use of ECMO was noted. CONCLUSIONS: VV ECMO can be a feasible treatment option even for lung transplant candidates awaiting re-transplantation for a prolonged period. Introduction of ECMO and tracheostomy in the early deterioration stage may be crucial to successful subsequent patient management.

DOI： 10.1186/s40792-023-01742-4

Prognostic Impact of Tumor-Infiltrating Lymphocytes, Tertiary Lymphoid Structures, and Neutrophil-to-Lymphocyte Ratio in Pulmonary Metastases from Uterine Leiomyosarcoma. Reviewed International journal

Naoki Matsuda, Hiromasa Yamamoto, Tomohiro Habu, Kazuma Iwata, Kei Matsubara, Shin Tanaka, Kohei Hashimoto, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Tomohiro Toji, Mikio Okazaki, Seiichiro Sugimoto, Katsuhito Takahashi, Shinichi Toyooka

Annals of surgical oncology 2023.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The presence of tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) in tumor tissue has been related to the prognosis in various malignancies. Meanwhile, neutrophil-to-lymphocyte ratio (NLR) as a systemic inflammation marker also has been associated with the prognosis in them. However, few reports have investigated the relationship between pulmonary metastases from sarcoma and these biomarkers. METHODS: We retrospectively recruited 102 patients undergoing metastasectomy for pulmonary metastases from uterine leiomyosarcoma at Okayama University Hospital from January 2006 to December 2019. TILs and TLSs were evaluated by immunohistochemical staining of surgically resected specimens of pulmonary metastases using anti-CD3/CD8/CD103/Foxp3/CD20 antibodies. NLR was calculated from the blood examination immediately before the most recent pulmonary metastasectomy. We elucidated the relationship between the prognosis and these factors. Because we considered that the status of tumor tissue and systemic inflammation were equally valuable, we also assessed the impact of the combination of TILs or TLSs and NLR on the prognosis. RESULTS: As for TILs, CD3-positive cells and CD8-positive cells were correlated with the prognosis. The prognosis was significantly better in patients with CD3-high group, CD8-high group, TLSs-high group, and NLR-low group, respectively. The prognosis of CD8-high/NLR-low group and TLSs-high/NLR-low group was significantly better than that of CD8-low/NLR-high group and TLSs-low/NLR-high group, respectively. CONCLUSIONS: CD3-positive TILs, CD8-positive TILs, TLSs, and NLR are correlated with the prognosis, respectively. The combination of CD8-positive TILs or TLSs and NLR may be the indicators to predict the prognosis of patients with pulmonary metastases from uterine leiomyosarcoma.

DOI： 10.1245/s10434-023-14176-x

Five-Year Overall Survival Analysis of the JIPANG Study: Pemetrexed or Vinorelbine Plus Cisplatin for Resected Stage II-IIIA Nonsquamous Non-Small-Cell Lung Cancer. Reviewed International journal

Hirotsugu Kenmotsu, Nobuyuki Yamamoto, Toshihiro Misumi, Kiyotaka Yoh, Haruhiro Saito, Shunichi Sugawara, Koji Yamazaki, Kazuhiko Nakagawa, Kenji Sugio, Takashi Seto, Shinichi Toyooka, Hiroshi Date, Tetsuya Mitsudomi, Isamu Okamoto, Kohei Yokoi, Hideo Saka, Hiroaki Okamoto, Yuichi Takiguchi, Toshiaki Takahashi, Masahiro Tsuboi

Journal of clinical oncology : official journal of the American Society of Clinical Oncology JCO2300179 2023.9

Language：English Publishing type：Research paper (scientific journal)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The JIPANG study is an open-label phase III trial evaluating the efficacy of pemetrexed plus cisplatin (PemP) versus vinorelbine plus cisplatin (NP) as adjuvant chemotherapy in patients with stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC). Here, we report the long follow-up overall survival (OS) data. Eligible patients were randomly assigned to receive either PemP or NP. The primary end point was recurrence-free survival (RFS), and the secondary end point included OS. This analysis was performed using data collected 5 years after the last patient enrollment. Among 804 patients enrolled, 783 patients were eligible (384 for NP and 389 for PemP). The updated median RFS was 37.5 months in the NP arm and 43.4 months in the PemP arm with a hazard ratio of 0.95 (95% CI, 0.79 to 1.14). At a median follow-up of 77.3 months, the OS rates at 3 and 5 years were 84.1% and 75.6% versus 87.0% and 75.0% with a hazard ratio of 1.04 (95% CI, 0.81 to 1.34). This long-term follow-up analysis showed that PemP had similar efficacy to NP in both RFS and OS for this population, with one of the longest OS data compared with the historical data.

DOI： 10.1200/JCO.23.00179

[Perioperative Management for Patients with Metabolic and Endocrine Disorders]. Reviewed

Ken Suzawa, Shinichi Toyooka

Kyobu geka. The Japanese journal of thoracic surgery 76 ( 10 ) 844 - 848 2023.9

Language：Japanese Publishing type：Research paper (scientific journal)

In recent years, the number of surgical cases involving patients with comorbidities has been increasing due to the aging society. Such patients may have a higher risk of postoperative morbidity or mortality. Therefore, surgeons are required to evaluate the current control status of the comorbidity, and perform appropriate perioperative management to decrease perioperative risk. This article focuses on the preoperative evaluation and management, as well as intraoperative and postoperative management of diabetes mellitus, thyroid dysfunction, which are frequently encountered among patients with metabolic and endocrine disorders, and paraganglioma, which is a rare disease but requires special attention in the field of thoracic surgery.

Restrictive allograft dysfunction rather than bronchiolitis obliterans syndrome had a major impact on the overall survival after living-donor lobar lung transplantation. Reviewed

Kei Matsubara, Shinji Otani, Haruchika Yamamoto, Kohei Hashimoto, Shin Tanaka, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Shinichi Toyooka

Surgery today 2023.7

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Chronic lung allograft dysfunction (CLAD) is a known long-term fatal disorder after lung transplantation. In this study, we evaluated the CLAD classification of the International Society for Heart and Lung Transplantation (ISHLT) for living-donor lobar lung transplantation (LDLLT). METHODS: We conducted a single-center retrospective review of data from 73 patients who underwent bilateral LDLLT between 1998 and 2019. Factors related to opacity on computed tomography (CT) and restriction on pulmonary function tests (PFTs) were also analyzed. RESULTS: Overall, 26 (36%) patients were diagnosed with CLAD, including restrictive allograft syndrome (RAS), n = 10 (38.5%); bronchiolitis obliterans syndrome (BOS), n = 8 (30.8%); mixed, n = 1 (3.8%); undefined, n = 2 (7.7%); and unclassified, n = 5 (19.2%). The 5-year survival rate after the CLAD onset was 60.7%. The survival of patients with BOS was significantly better than that of patients with RAS (p = 0.012). In particular, patients with restriction on PFT had a significantly worse survival than those without restriction (p = 0.001). CONCLUSIONS: CLAD after bilateral LDLLT does not have a major impact on the recipient survival, especially in patients with BOS. Restriction on PFT may predict a particularly poor prognosis in patients with CLAD after bilateral LDLLT.

DOI： 10.1007/s00595-023-02729-2

ASO Visual Abstract: EGFR Mutation is a Prognostic Factor in Lung Cancer Patients with Pleural Dissemination Detected During or After Surgery. Reviewed International journal

Toshiya Fujiwara, Kazuhiko Shien, Motoki Matsuura, Junichi Soh, Hiromasa Yamamoto, Soshi Takao, Yuho Maki, Tsuyoshi Ueno, Ryujiro Sugimoto, Ken Suzawa, Mikio Okazaki, Hiroyuki Tao, Makio Hayama, Masafumi Kataoka, Yoshifumi Sano, Hidetoshi Inokawa, Motohiro Yamashita, Osamu Kawamata, Kazuhiko Kataoka, Shinichi Toyooka

Annals of surgical oncology 2023.7

Long-term outcomes following surgical treatment for thymic epithelial tumor in Japan and an analysis of prognostic factors based on the Japanese Association for Research on the Thymus nationwide database. Reviewed

Meinoshin Okumura, Ichiro Yoshino, Soichiro Funaki, Katsuhiro Okuda, Shun-Ichi Watanabe, Masahiro Tsuboi, Kimihiro Shimizu, Hiroshi Date, Toyofumi F Chen-Yoshikawa, Jun Nakajima, Shinichi Toyooka, Hisao Asamura

Surgery today 2023.7

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Patients with a thymic epithelial tumor (TET), comprising thymoma, thymic carcinoma (TC), and thymic neuroendocrine neoplasm (TNEN), are rarely encountered. The present study was conducted to determine the recent outcomes of surgical treatment for TET in Japan and clarify the significance of prognostic factors by analyzing a nationwide database created by the Japanese Association for Research on the Thymus (JART). METHODS: The JART database includes records of 2471 thymoma, 285 TC, and 56 TNEN cases surgically treated between 1991 and 2010. At the time of the final follow-up examination, 439 patients had died, with tumor the cause of death in 188. The disease-specific survival was examined using the Kaplan-Meier method, with Cox's proportional hazards model utilized to determine independent prognostic factors. RESULTS: The 10-year survival rate according to TNM-based Stage I, II, IIIA, IIIB, IVA, and IVB classification was 98.7%, 76.8%, 85.0%, 68.9%, 66.2%, and 59.8%, respectively. The T factor, M factor, and tumor size were independent prognostic factors in both thymoma and thymic carcinoma cases, while the N factor had tendency to be a prognostic factor in thymoma but not in thymic carcinoma cases. The WHO histological type was an independent factor in thymoma cases. CONCLUSION: The significance of pathology and TNM classification as prognostic factors was confirmed.

DOI： 10.1007/s00595-023-02705-w

Development and validation of a symptom illustration scale from the patient-reported outcome common terminology criteria for adverse events for patients with breast cancer. Reviewed

Yoko Suzuki, Takayuki Iwamoto, Maya Uno, Minami Hatono, Yukiko Kajiwara, Yuko Takahashi, Mariko Kochi, Tadahiko Shien, Yuichiro Kikawa, Yukari Uemura, Yasuhiro Hagiwara, Seiichiro Yamamoto, Naruto Taira, Hiroyoshi Doihara, Shinichi Toyooka

Breast cancer (Tokyo, Japan) 30 ( 5 ) 856 - 868 2023.7

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Emojis are commonly used for daily communication and may be useful in assessing patient-reported outcomes (PROs) in breast cancer. The purpose of this study is to develop and validate a Symptom Illustration Scale (SIS) as a new PRO measurement. METHODS: Eighteen original SIS items were developed from the PRO-CTCAE. In cohort one, the SIS validity and reliability were examined in patients with breast cancer, using a semi-structured five-question survey to investigate content validity. PROs with PRO-CTCAE and SIS were examined twice to determine criteria validity and test-retest reliability. In cohort two, the responsiveness of the scales were examined in patients treated with anthracycline, docetaxel, paclitaxel, and endocrine therapy. PROs with PRO-CTCAE and SIS were investigated two or three times, depending on the therapy. RESULTS: Patients were enrolled from August 2019 to October 2020. In cohort one (n = 70), most patients had no difficulties with the SIS, but 16 patients indicated that it was difficult to understand severities in the SIS. For criterion validity, Spearman rank correlation coefficients (rs) between PRO-CTCAE and SIS items were ≥ 0.41, except for "Decreased appetite." For test-retest reliability, κ coefficients of the SIS were ≥ 0.41 for 16/18 items (88.9%). Response time was significantly shorter for the SIS than for PRO-CTCAE (p < 0.001). In cohort two (n = 106), score changes between PRO-CTCAE and SIS for relevant symptoms all had correlations with rs ≥ 0.41. CONCLUSION: An original SIS from the PRO-CTCAE for patients with breast cancer were verified the validity, reliability, and responsiveness. Further studies to improve and validate the SIS are needed.

DOI： 10.1007/s12282-023-01480-3

ASO Author Reflections: Prognostic Impact of the Primary Tumor Resection for Lung Cancer Patients Diagnosed with Pleural Dissemination in the Perioperative Period-Importance of Biomarker-Based Treatment Decision Making. Reviewed International journal

Kazuhiko Shien, Toshiya Fujiwara, Shinichi Toyooka

Annals of surgical oncology 2023.6

EGFR Mutation is a Prognostic Factor in Lung Cancer Patients with Pleural Dissemination Detected During or After Surgery. Reviewed International journal

Toshiya Fujiwara, Kazuhiko Shien, Motoki Matsuura, Junichi Soh, Hiromasa Yamamoto, Soshi Takao, Yuho Maki, Tsuyoshi Ueno, Ryujiro Sugimoto, Ken Suzawa, Mikio Okazaki, Hiroyuki Tao, Makio Hayama, Masafumi Kataoka, Yoshifumi Sano, Hidetoshi Inokawa, Motohiro Yamashita, Osamu Kawamata, Kazuhiko Kataoka, Shinichi Toyooka

Annals of surgical oncology 2023.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Primary lung tumors are sometimes resected when either pleural dissemination (PD) or malignant pleural effusion (MPE) exists. This study clarified the prognostic factors for non-small cell lung cancer (NSCLC) with either PD and MPE, or both, detected during or after surgery. PATIENTS AND METHODS: We examined patients with NSCLC from a multicenter database who had either PD, MPE, or both, detected during or after surgery between 2005 and 2015. Hazard ratios and 95% confidence intervals were estimated using the Cox proportional hazards model adjusted for potential confounding factors. RESULTS: Among 9463 registered patients, PD, MPE, or both, were found in 114 patients with NSCLC during or after surgery. Primary tumor resection and exploratory thoracotomy were performed in 65 and 49 patients, respectively. In univariate analysis, adenocarcinoma, clinically undetected lymph node metastasis (c-N0 or unknown), EGFR mutation, and combination of chemotherapy or tyrosine kinase inhibitors after surgery were better prognostic factors for overall survival (OS), whereas in the multivariate analysis, adenocarcinoma, clinically undetected lymph node metastasis, and EGFR mutation were favorable independent prognostic factors in OS. Additionally, limited to patients with EGFR mutation, patients with primary lung tumor resection showed a significantly better 5-year OS than those with exploratory thoracotomy (86.4 vs. 44.8%; p < 0.001). CONCLUSION: Our findings show that surgical resection of primary tumors could improve the prognosis of patients with PD, MPE, or both, detected during or after surgery when the tumors harbor an EGFR mutation.

DOI： 10.1245/s10434-023-13791-y

Elderly lung transplant recipients show acceptable long-term outcomes for lung transplantation: A propensity score-matched analysis. Reviewed

Yasuaki Tomioka, Shin Tanaka, Shinji Otani, Toshio Shiotani, Haruchika Yamamoto, Kentaroh Miyoshi, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

Surgery today 2023.6

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Although the performance lung transplantation (LTx) in the elderly (≥ 60 years) has increased globally, the situation in Japan remains quite different, because the age limit at registration for cadaveric transplantation is 60 years. We investigated the long-term outcomes of LTx in the elderly in Japan. METHODS: This was a single-center retrospective study. We divided the patients into two groups according to age: the younger group (< 60 years; Y group; n = 194) and the elderly group (≥ 60 years; E group; n = 10). We performed three-to-one propensity score matching to compare the long-term survival between the E and Y groups. RESULTS: In the E group, the survival rate was significantly worse (p = 0.003), and single-LTx was more frequent (p = 0.036). There was a significant difference in the indications for LTx between the two groups (p < 0.001). The 5-year survival rate after single-LTx in the E group was significantly lower than that in the Y group (p = 0.006). After propensity score matching, the 5-year survival rates of the two groups were comparable (p = 0.55). However, the 5-year survival rate after single-LTx in the E group was significantly lower than that in the Y group (p = 0.007). CONCLUSION: Elderly patients showed acceptable long-term survival after LTx.

DOI： 10.1007/s00595-023-02699-5

Identification of genetic loci associated with renal dysfunction after lung transplantation using an ethnic-specific single-nucleotide polymorphism array. Reviewed International journal

Yasuaki Tomioka, Seiichiro Sugimoto, Haruchika Yamamoto, Shuta Tomida, Toshio Shiotani, Shin Tanaka, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Mikio Okazaki, Masaomi Yamane, Shinichi Toyooka

Scientific reports 13 ( 1 ) 8912 - 8912 2023.6

Language：English Publishing type：Research paper (scientific journal)

Renal dysfunction is a long-term complication associated with an increased mortality after lung transplantation (LT). We investigated the association of single-nucleotide polymorphisms (SNPs) with the development of renal dysfunction after LT using a Japanese-specific SNP array. First, eligible samples of 34 LT recipients were genotyped using the SNP array and divided into two groups, according to the presence of homozygous and heterozygous combinations of mutant alleles of the 162 renal-related SNPs. To identify candidate SNPs, the renal function tests were compared between the two groups for each SNP. Next, we investigated the association between the candidate SNPs and the time course of changes of the estimated glomerular filtration rate (eGFR) in the 99 recipients until 10 years after the LT. ΔeGFR was defined as the difference between the postoperative and preoperative eGFR values. Eight SNPs were identified as the candidate SNPs in the 34 recipients. Validation analysis of these 8 candidate SNPs in all the 99 recipients showed that three SNPs, namely, rs10277115, rs4690095, and rs792064, were associated with significant changes of the ΔeGFR. Pre-transplant identification of high-risk patients for the development of renal dysfunction after LT based on the presence of these SNPs might contribute to providing personalized medicine.

DOI： 10.1038/s41598-023-36143-y

Pulmonary alveolar proteinosis after lung transplantation: Two case reports and literature review. Reviewed International journal

Shinichi Kawana, Kentaroh Miyoshi, Shin Tanaka, Seiichiro Sugimoto, Dai Shimizu, Kei Matsubara, Mikio Okazaki, Noboru Hattori, Shinichi Toyooka

Respirology case reports 11 ( 6 ) e01160 2023.6

Language：English

Pulmonary alveolar proteinosis (PAP) affecting transplanted lungs is not well recognized. Herein, we report two cases of PAP after lung transplantation (LTx). The first case was a 4-year-old boy with hereditary pulmonary fibrosis who underwent bilateral LTx and presented with respiratory distress on postoperative day (POD) 23. He was initially treated for acute rejection, died due to infection on POD 248, and was diagnosed with PAP at autopsy. The second case involved a 52-year-old man with idiopathic pulmonary fibrosis who underwent bilateral LTx. On POD 99, chest computed tomography revealed ground-glass opacities. Bronchoalveolar lavage and transbronchial biopsy led to a diagnosis of PAP. Follow-up with immunosuppression tapering resulted in clinical and radiological improvement. PAP after lung transplantation mimics common acute rejection; however, is potentially transient or resolved with tapering immunosuppression, as observed in the second case. Transplant physicians should be aware of this rare complication to avoid misconducting immunosuppressive management.

DOI： 10.1002/rcr2.1160

Endobronchial Metastasis with Bloody Sputum 20 Years after Complete Resection of type A Non-Invasive Thymoma. Reviewed

Mototsugu Watanabe, Hiromasa Yamamoto, Kentaroh Miyoshi, Seiichiro Sugimoto, Shinichi Toyooka

Acta medica Okayama 77 ( 3 ) 331 - 334 2023.6

Language：English

Masaoka stage I type A thymomas rarely recur. We report the case of an 82-year-old man who developed endobronchial metastasis after thymothymectomy for Masaoka stage I type A thymoma. Twenty years after surgery, the patient developed bloody sputum, and chest computed tomography revealed a neoplasm obstructing the right upper lobe bronchus of the lung with enlarged mediastinal lymph nodes. He underwent right upper lobectomy and mediastinal lymph node dissection. Although preoperative pathological diagnosis was squamous cell carcinoma of the lung, postoperative histopathology revealed endobronchial metastasis of the thymoma. Nine years later, at age 89, the patient is alive and well.

DOI： 10.18926/AMO/65503

The impact of prognostic nutrition index on the waitlist mortality of lung transplantation. Reviewed

Kei Matsubara, Shinji Otani, Haruchika Yamamoto, Yasuaki Tomioka, Toshio Shiotani, Kentaroh Miyoshi, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

General thoracic and cardiovascular surgery 71 ( 5 ) 306 - 312 2023.5

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: The prognostic nutrition index (PNI), calculated using serum albumin and total lymphocyte count, is a recent topical index related to inflammation. Preoperative PNI is regarded as a new preoperative prognostic score in lung transplantation (LTx). This study aimed to investigate the impact of PNI at the time of registration as a prognostic parameter of mortality on the waiting list for LTx. METHODS: A retrospective review was conducted on the data of 132 adult patients registered for LTx in our department between January 2013 and June 2020. Patients who finally received LTx were analyzed as censored data. The overall survival was evaluated using the Kaplan-Meier method for pre-registered clinical factors including the PNI at the time of registration. Overall survival was calculated from the date of listing to the Japan Organ Transplant Network to the date of death. RESULTS: The low-PNI group had a significantly worse prognosis. Multivariate analysis demonstrated that age (p = 0.023), idiopathic interstitial pneumonia (p < 0.001), lung allocation score (LAS) (p < 0.001), and PNI (p < 0.001) were independent prognostic factors for waitlist mortality. CONCLUSIONS: PNI at the time of registration can be an independent prognostic parameter in registered candidates for LTx.

DOI： 10.1007/s11748-022-01895-3

S100A8/A9 as a prognostic biomarker in lung transplantation. Reviewed International journal

Kentaro Nakata, Mikio Okazaki, Shinichi Kawana, Yujiro Kubo, Dai Shimizu, Shin Tanaka, Kohei Hashimoto, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Hiromasa Yamamoto, Seiichiro Sugimoto, Shinichi Toyooka

Clinical transplantation e15006 2023.4

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: S100A8/A9 is a damage-associated molecule that augments systemic inflammation. However, its role in the acute phase after lung transplantation (LTx) remains elusive. This study aimed to determine S100A8/A9 levels after lung transplantation (LTx) and evaluate their impact on overall survival (OS) and chronic lung allograft dysfunction (CLAD)-free survival. METHODS: Sixty patients were enrolled in this study, and their plasma S100A8/A9 levels were measured on days 0, 1, 2, and 3 after LTx. The association of S100A8/A9 levels with OS and CLAD-free survival was assessed using univariate and multivariate Cox regression analyses. RESULTS: S100A8/A9 levels were elevated in a time-dependent manner until 3 days after LTx. Ischemic time was significantly longer in the high S100A8/9 group than in the low S100A8/A9 group (p = .017). Patients with high S100A8/A9 levels (> 2844 ng/mL) had worse prognosis (p = .031) and shorter CLAD-free survival (p = .045) in the Kaplan-Meier survival analysis than those with low levels. Furthermore, multivariate Cox regression analysis showed that high S100A8/A9 levels were a determinant of poor OS (hazard ratio [HR]: 3.7; 95% confidence interval [CI]: 1.2-12; p = .028) and poor CLAD-free survival (HR: 4.1; 95% CI: 1.1-15; p = .03). In patients with a low primary graft dysfunction grade (0-2), a high level of S100A8/A9 was also a poor prognostic factor. CONCLUSIONS: Our study provided novel insights into the role of S100A8/A9 as a prognostic biomarker and a potential therapeutic target for LTx.

DOI： 10.1111/ctr.15006

Prognostic factors for lung transplant recipients focusing on age and gender: the Japanese lung transplantation report 2022. Reviewed

Hisashi Oishi, Yoshinori Okada, Masaaki Sato, Jun Nakajima, Daisuke Nakajima, Takeshi Shiraishi, Toshihiko Sato, Takashi Kanou, Yasushi Shintani, Kentaroh Miyoshi, Shinichi Toyooka, Sumiko Maeda, Masayuki Chida, Keitaro Matsumoto, Takeshi Nagayasu, Hidemi Suzuki, Ichiro Yoshino, Yasushi Matsuda, Yasushi Hoshikawa, Hiroshi Date

Surgery today 2023.4

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To clarify the impact of donor and recipient characteristics on the survival of recipients before and after lung transplantation in the Japanese population. METHODS: Patients' data were collected for retrospective analysis from all authorized lung transplant centers in Japan. We included 1963 patients listed for lung transplantation by the end of December 2021, comprised of 658 deceased-donor and 270 living-donor lung transplants. RESULTS: Primary disease had a significant impact on the mortality of patients waiting for transplantation. The indications for transplant significantly affected the post-transplant survival rate of deceased-donor lung transplant recipients. The recipient's age also significantly affected the post-transplant survival rate of the deceased-donor and living-donor lung transplant recipients. The recipients of grafts transplanted from donors aged 61 years or older showed a worse post-transplant survival rate (≧60 years old). The survival rate for the combination of a female donor to a male recipient among the deceased-donor lung transplant recipients was the worst among the four combinations. CONCLUSION: The donor and recipient characteristics significantly impacted the survival of recipients after lung transplantation. The underlying mechanism of the negative impact of the gender mismatch of female donor to male recipient on post-transplant survival needs to be investigated further.

DOI： 10.1007/s00595-023-02686-w

Diagnostic value of circulating microRNA-21 in chronic lung allograft dysfunction after bilateral cadaveric and living-donor lobar lung transplantation. Reviewed International journal

Toshio Shiotani, Seiichiro Sugimoto, Yasuaki Tomioka, Haruchika Yamamoto, Shin Tanaka, Kentaroh Miyoshi, Ken Suzawa, Kazuhiko Shien, Hiromasa Yamamoto, Mikio Okazaki, Shinichi Toyooka

Heliyon 9 ( 4 ) e14903 2023.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: MicroRNAs (miRNAs) involved in the pathogenesis of pulmonary fibrosis have been shown to be associated with the development of chronic lung allograft dysfunction (CLAD) after lung transplantation (LT). We investigated the role of circulating miRNAs in the diagnosis of CLAD after bilateral LT, including cadaveric LT (CLT) and living-donor lobar LT (LDLLT). METHODS: The subjects of this retrospective study were 37 recipients of bilateral CLT (n = 23) and LDLLT (n = 14), and they were divided into a non-CLAD group (n = 24) and a CLAD group (n = 13). The plasma miRNA levels of the two groups were compared, and correlations between their miRNAs levels and percent baseline forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and total lung capacity (TLC) values were calculated from one year before to one year after the diagnosis of CLAD. RESULTS: The plasma levels of both miR-21 and miR-155 at the time of the diagnosis of CLAD were significantly higher in the CLAD group than in the non-CLAD group (miR-21, P = 0.0013; miR-155, P = 0.042). The miR-21 levels were significantly correlated with the percent baseline FEV1, FVC, and TLC value of one year before and at the time of diagnosis of CLAD (P < 0.05). A receiver operating characteristic curve analysis of the performance of miR-21 levels in the diagnosis of CLAD yielded an area under the curve of 0.89. CONCLUSION: Circulating miR-21 appears to be of potential value in diagnosing CLAD after bilateral LT.

DOI： 10.1016/j.heliyon.2023.e14903

(1068) Successful Lung Re-Transplantation with Perioperative Desensitization for Sensitized Recipient with Donor Specific DQ Antibody Reviewed

H. Choshi, K. Miyoshi, H. Ujike, S. Kawana, Y. Kubo, D. Shimizu, K. Matsubara, K. Hashimoto, S. Tanaka, K. Shien, K. Suzawa, H. Yamamoto, M. Okazaki, S. Sugimoto, S. Toyooka

The Journal of Heart and Lung Transplantation 42 ( 4 ) S461 - S462 2023.4

(78) Indication and Long-Term Outcome of Pediatric Lung Transplantation in Japan; A Multicenter, Retrospective Study Reviewed

Y. Morimura, S. Tanaka, K. Matsubara, S. Tanaka, T. Kanou, Y. Yamada, Y. Yutaka, A. Ohsumi, D. Nakajima, M. Hamaji, Y. Shintani, S. Sugimoto, S. Toyooka, H. Date

The Journal of Heart and Lung Transplantation 42 ( 4 ) S44 - S45 2023.4

(875) A Novel Strategy In Vivo Lung Recovery for Prompt Recovery from Primary Graft Dysfunction after Lung Transplantation Reviewed

K. Matsubara, K. Miyoshi, K. Takeshi, S. Kawana, Y. Kubo, D. Shimizu, K. Hashimoto, S. Tanaka, M. Okazaki, S. Sugimoto, S. Toyooka

The Journal of Heart and Lung Transplantation 42 ( 4 ) 2023.4

(891) Bilateral Lung Transplantation from Living Donors in a 67-Year-Old Patient Reviewed

H. Ujike, S. Tanaka, H. Choshi, S. Kawana, Y. Kubo, D. Shimizu, K. Matsubara, K. Hashimoto, K. Shien, K. Suzawa, K. Miyoshi, H. Yamamoto, M. Okazaki, S. Sugimoto, S. Toyooka

The Journal of Heart and Lung Transplantation 42 ( 4 ) 2023.4

(347) Augmented Humoral Response to a Third And Fourth Dose of Mrna Sars-Cov-2 Vaccines in Lung Transplant Recipients Reviewed

S. Kawana, S. Sugimoto, K. Matsubara, S. Tanaka, K. Miyoshi, H. Choshi, H. Ujike, Y. Kubo, D. Shimizu, K. Hashimoto, K. Shien, K. Suzawa, H. Yamamoto, M. Okazaki, S. Toyooka

The Journal of Heart and Lung Transplantation 42 ( 4 ) S164 - S165 2023.4

(258) Histidine-Rich Glycoprotein Ameliorates Lung Ischemia-Reperfusion Injury in a Mouse Reviewed

Y. Kubo, S. Sugimoto, H. Choshi, H. Ujike, S. Kawana, D. Shimizu, K. Matsubara, K. Hashimoto, S. Tanaka, K. Shien, K. Suzawa, K. Miyoshi, H. Yamamoto, M. Okazaki, S. Toyooka

The Journal of Heart and Lung Transplantation 42 ( 4 ) S124 - S125 2023.4

[Ⅲ. The Role of Comprehensive Genomic Profiling in Sarcoma]. Reviewed

Eiji Nakata, Tomohiro Fujiwara, Toshiyuki Kunisada, Toshifumi Ozaki, Shinichi Toyooka, Daisuke Ennishi, Hideki Yamamoto, Kiichiro Ninomiya, Shuta Tomida, Akira Hirasawa, Mashu Futagawa, Masahiro Tabata

Gan to kagaku ryoho. Cancer & chemotherapy 50 ( 3 ) 314 - 320 2023.3

LOXL1 and LOXL4 are novel target genes of the Zn2+-bound form of ZEB1 and play a crucial role in the acceleration of invasive events in triple-negative breast cancer cells Reviewed

Daisuke Hirabayashi, Ken-ichi Yamamoto, Akihiro Maruyama, Nahoko Tomonobu, Rie Kinoshita, Youyi Chen, Ni Luh Gede Yoni Komalasari, Hitoshi Murata, Yuma Gohara, Fan Jiang, Jin Zhou, I Made Winarsa Ruma, I Wayan Sumardika, Akira Yamauchi, Futoshi Kuribayashi, Shinichi Toyooka, Yusuke Inoue, Masakiyo Sakaguchi

Frontiers in Oncology 13 2023.2

Publishing type：Research paper (scientific journal) Publisher：Frontiers Media SA

Background

EMT has been proposed to be a crucial early event in cancer metastasis. EMT is rigidly regulated by the action of several EMT-core transcription factors, particularly ZEB1. We previously revealed an unusual role of ZEB1 in the S100A8/A9-mediated metastasis in breast cancer cells that expressed ZEB1 at a significant level and showed that the ZEB1 was activated on the MCAM-downstream pathway upon S100A8/A9 binding. ZEB1 is well known to require Zn²⁺ for its activation based on the presence of several Zn-finger motifs in the transcription factor. However, how Zn²⁺-binding works on the pleiotropic role of ZEB1 through cancer progression has not been fully elucidated.

Methods

We established the engineered cells, MDA-MB-231 MutZEB1 (MDA-MutZEB1), that stably express MutZEB1 (ΔZn). The cells were then evaluated in vitro for their invasion activities. Finally, an RNA-Seq analysis was performed to compare the gene alteration profiles of the established cells comprehensively.

Results

MDA-MutZEB1 showed a significant loss of the EMT, ultimately stalling the invasion. Inclusive analysis of the transcription changes after the expression of MutZEB1 (ΔZn) in MDA-MB-231 cells revealed the significant downregulation of LOX family genes, which are known to play a critical role in cancer metastasis. We found that LOXL1 and LOXL4 remarkably enhanced cancer invasiveness among the LOX family genes with altered expression.

Conclusions

These findings indicate that ZEB1 potentiates Zn²⁺-mediated transcription of plural EMT-relevant factors, including LOXL1 and LOXL4, whose upregulation plays a critical role in the invasive dissemination of breast cancer cells.

DOI： 10.3389/fonc.2023.1142886

Surgical outcome of ipsilateral anatomical resection for lung cancer after pulmonary lobectomy. Reviewed International journal

Mikio Okazaki, Ken Suzawa, Kazuhiko Shien, Hiromasa Yamamoto, Kota Araki, Mototsugu Watanabe, Masanori Okada, Yuho Maki, Tsuyoshi Ueno, Shinji Otani, Ryujiro Sugimoto, Hitoshi Nishikawa, Riki Okita, Makio Hayama, Hiroyuki Tao, Toshiya Fujiwara, Hidetoshi Inokawa, Yuji Hirami, Yoshifumi Sano, Motohiro Yamashita, Osamu Kawamata, Motoki Matsuura, Shinichi Toyooka

European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 63 ( 3 ) 2023.2

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Ipsilateral reoperation after pulmonary lobectomy is often challenging because of adhesions from the previous surgery. In this study, we retrospectively examined the surgical outcome and prognosis of ipsilateral anatomical resection for lung cancer after pulmonary lobectomy using a multicentre database. METHODS: We evaluated the perioperative outcomes and overall survival of 51 patients who underwent pulmonary lobectomy followed by ipsilateral anatomical resection for lung cancer between January 2012 and December 2018. In addition, patients with stage I non-small cell lung cancer (NSCLC) were compared with 3411 patients with stage I lung cancer who underwent pulmonary resection without prior ipsilateral lobectomy. RESULTS: Ipsilateral anatomical resections included 10 completion pneumonectomies, 19 pulmonary lobectomies and 22 pulmonary segmentectomies. Operative time was 312.2 ± 134.5 min and intraoperative bleeding was 522.2 ± 797.5 ml. Intraoperative and postoperative complications occurred in 9 and 15 patients, respectively. However, the 5-year overall survival rate after anatomical resection followed by ipsilateral lobectomy was 83.5%. Furthermore, in patients with c-stage I NSCLC, anatomical resection followed by ipsilateral lobectomy was not associated with worse survival than anatomical resection without prior ipsilateral lobectomy. CONCLUSIONS: Anatomical resection following ipsilateral lobectomy is associated with a high frequency of intraoperative and postoperative complications. However, the 5-year overall survival in patients with c-stage I NSCLC who underwent ipsilateral anatomical resection after pulmonary lobectomy is comparable to that in patients who underwent anatomical resection without prior pulmonary lobectomy.

DOI： 10.1093/ejcts/ezad048

Donor's long-term quality of life following living-donor lobar lung transplantation. Reviewed International journal

Kento Fujii, Shin Tanaka, Megumi Ishihara, Kei Matsubara, Kohei Hashimoto, Shuji Okahara, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

Clinical transplantation 37 ( 4 ) e14927 2023.2

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Living-donor lobar lung transplantation is an alternative procedure to deceased donation lung transplantation. It involves graft donation from healthy donors; however, only a few reports have discussed its long-term prognosis in living lung donors and their associated health-related quality of life. This study aimed to examine living lung donors' health-related quality of life. METHODS: In our cross-sectional survey of living lung donors, we assessed health-related quality of life based on three key aspects (physical, mental, and social health) using the 36-Item Short Form Health Survey. We also evaluated chronic postoperative pain and postoperative breathlessness using the numeric rating scale and the modified Medical Research Council Dyspnea scale, respectively. RESULTS: We obtained consent from 117 of 174 living lung donors. The average scores of the living lung donors on the 36-Item Short Form Health Survey were higher than the national average. However, some donors had poorer physical, mental, and social health, with lower summary scores than the national averages. Low mental component summary predictors included donor age (<40 years; odds ratio = 10.2; p<.001) and recipient age (<18 years; odds ratio = 2.73; p<.032). Low role-social component summary predictors included high lung allocation score (≥50; odds ratio = 3.94, p<.002) and recipient death (odds ratio = 3.64; p = .005). There were no predictors for physical component summary. Additionally, many donors did not complain of pain or dyspnea. CONCLUSIONS: Living lung donors maintained acceptable long-term health-related quality of life after surgery. Potential donors should be informed of relevant risk factors, and high-risk donors should receive appropriate support. This article is protected by copyright. All rights reserved.

DOI： 10.1111/ctr.14927

Lysyl oxidase-like 4 exerts an atypical role in breast cancer progression that is dependent on the enzymatic activity that targets the cell-surface annexin A2. Reviewed International journal

Ni Luh Gede Yoni Komalasari, Nahoko Tomonobu, Rie Kinoshita, Youyi Chen, Yoshihiko Sakaguchi, Yuma Gohara, Fan Jiang, Ken-Ich Yamamoto, Hitoshi Murata, I Made Winarsa Ruma, I Wayan Sumardika, Jin Zhou, Akira Yamauchi, Futoshi Kuribayashi, Yusuke Inoue, Shinichi Toyooka, Masakiyo Sakaguchi

Frontiers in oncology 13 1142907 - 1142907 2023

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: LOX family members are reported to play pivotal roles in cancer. Unlike their enzymatic activities in collagen cross-linking, their precise cancer functions are unclear. We revealed that LOXL4 is highly upregulated in breast cancer cells, and we thus sought to define an unidentified role of LOXL4 in breast cancer. METHODS: We established the MDA-MB-231 sublines MDA-MB-231-LOXL4 mutCA and -LOXL4 KO, which stably overexpress mutant LOXL4 that loses its catalytic activity and genetically ablates the intrinsic LOXL4 gene, respectively. In vitro and in vivo evaluations of these cells' activities of cancer outgrowth were conducted by cell-based assays in cultures and an orthotopic xenograft model, respectively. The new target (s) of LOXL4 were explored by the MS/MS analytic approach. RESULTS: Our in vitro results revealed that both the overexpression of mutCA and the KO of LOXL4 in cells resulted in a marked reduction of cell growth and invasion. Interestingly, the lowered cellular activities observed in the engineered cells were also reflected in the mouse model. We identified a novel binding partner of LOXL4, i.e., annexin A2. LOXL4 catalyzes cell surface annexin A2 to achieve a cross-linked multimerization of annexin A2, which in turn prevents the internalization of integrin β-1, resulting in the locking of integrin β-1 on the cell surface. These events enhance the promotion of cancer cell outgrowth. CONCLUSIONS: LOXL4 has a new role in breast cancer progression that occurs via an interaction with annexin A2 and integrin β-1 on the cell surface.

DOI： 10.3389/fonc.2023.1142907

Randomized phase II study of daily versus alternate-day administrations of S-1 for the elderly patients with completely resected pathological stage IA (tumor diameter > 2 cm)-IIIA of non-small cell lung cancer: Setouchi Lung Cancer Group Study 1201. Reviewed International journal

Hiromasa Yamamoto, Junichi Soh, Norihito Okumura, Hiroyuki Suzuki, Masao Nakata, Toshiya Fujiwara, Kenichi Gemba, Isao Sano, Takuji Fujinaga, Masafumi Kataoka, Yasuhiro Terazaki, Nobukazu Fujimoto, Kazuhiko Kataoka, Shinji Kosaka, Motohiro Yamashita, Hidetoshi Inokawa, Masaaki Inoue, Hiroshige Nakamura, Yoshinori Yamashita, Katsuyuki Hotta, Hiroshige Yoshioka, Satoshi Morita, Keitaro Matsuo, Junichi Sakamoto, Hiroshi Date, Shinichi Toyooka

PloS one 18 ( 5 ) e0285273 2023

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: It is shown that the postoperative adjuvant chemotherapy for non-small cell lung cancer (NSCLC) was associated with survival benefit in an elderly population. We aimed to analyze the feasibility and efficacy of alternate-day S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in elderly patients with completely resected pathological stage IA (tumor diameter > 2 cm) to IIIA (UICC TNM Classification of Malignant Tumours, 7th edition) NSCLC. METHODS: Elderly patients were randomly assigned to receive adjuvant chemotherapy for one year consisting of either alternate-day oral administration of S-1 (80 mg/m2/day) for 4 days a week (Arm A) or a daily oral administration of S-1 (80 mg/m2/day) for 14 consecutive days followed by 7-day rest (Arm B). The primary endpoint was feasibility (treatment completion rate), which was defined as the proportion of patients who completed the allocated intervention for 6 months with a relative dose intensity (RDI) of 70% or more. RESULTS: We enrolled 101 patients in which 97 patients received S-1 treatment. The treatment completion rate at 6 months was 69.4% in Arm A and 64.6% in Arm B (p = 0.67). Treatment completion rate in Arm B tended to be lower compared to Arm A, as the treatment period becomes longer (at 9 and 12 months). RDI of S-1 at 12 months and completion of S-1 administration without dose reduction or postponement at 12 months was significantly better in Arm A than in Arm B (p = 0.026 and p < 0.001, respectively). Among adverse events, anorexia, skin symptoms and lacrimation of any grade were significantly more frequent in Arm B compared with Arm A (p = 0.0036, 0.023 and 0.031, respectively). The 5-year recurrence-free survival rates were 56.9% and 65.7% for Arm A and B, respectively (p = 0.22). The 5-year overall survival rates were 68.6% and 82.0% for Arm A and B, respectively (p = 0.11). CONCLUSION: Although several adverse effects were less frequent in Arm A, both alternate-day and daily oral administrations of S-1 were demonstrated to be feasible in elderly patients with completely resected NSCLC. TRIAL REGISTRATION: Unique ID issued by UMIN: UMIN000007819 (Date of registration: Apr 25, 2012) https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009128. Trial ID issued by jRCT: jRCTs061180089 (Date of registration: Mar 22, 2019, for a shift toward a "specified clinical trial" based on Clinical Trials Act in Japan) https://jrct.niph.go.jp/en-latest-detail/jRCTs061180089.

DOI： 10.1371/journal.pone.0285273

A randomized controlled trial of teprenone in terms of preventing worsening of COVID-19 infection. Reviewed International journal

Eiki Ichihara, Kou Hasegawa, Kenichiro Kudo, Yasushi Tanimoto, Kazuhiro Nouso, Naohiro Oda, Sho Mitsumune, Haruto Yamada, Ichiro Takata, Hideharu Hagiya, Toshiharu Mitsuhashi, Akihiko Taniguchi, Shinichi Toyooka, Kohei Tsukahara, Toshiyuki Aokage, Hirokazu Tsukahara, Katsuyuki Kiura, Yoshinobu Maeda

PloS one 18 ( 10 ) e0287501 2023

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Some COVID-19 patients develop life-threatening disease accompanied by severe pneumonitis. Teprenone induces expression of heat-shock proteins (HSPs) that protect against interstitial pneumonia in preclinical models. We explored whether teprenone prevented worsening of COVID-19 infections. METHODS: This open-label, randomized, pilot phase 2 clinical trial was conducted at five institutions in Japan. We randomized patients hospitalized for COVID-19 with fever to teprenone or no-teprenone groups in a 1:1 ratio. We stratified patients by sex, age < and ≥ 70 years and the existence (or not) of complications (hypertension, diabetes, ischemic heart disease, chronic pulmonary disease and active cancer). No limitation was imposed on other COVID-19 treatments. The primary endpoint was the intubation rate. RESULTS: One hundred patients were included, 51 in the teprenone and 49 in the no- teprenone groups. The intubation rate did not differ significantly between the two groups: 9.8% (5/51) vs. 2.0% (1/49) (sub-hazard ratio [SHR] 4.99, 95% confidence interval [CI]: 0.59-42.1; p = 0.140). The rates of intra-hospital mortality and intensive care unit (ICU) admission did not differ significantly between the two groups: intra-hospital mortality 3.9% (2/51) vs. 4.1% (2/49) (hazard ratio [HR] 0.78, 95%CI: 0.11-5.62; p = 0.809); ICU admission 11.8% (6/51) vs. 6.1% (3/49) (SHR 1.99, 95%CI: 0.51-7.80; p = 0.325). CONCLUSION: Teprenone afforded no clinical benefit. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs061200002 (registered on 20/May/2020).

DOI： 10.1371/journal.pone.0287501

Use of the index of pulmonary vascular disease for predicting long-term outcome of pulmonary arterial hypertension associated with congenital heart disease. Reviewed International journal

Ayako Chida-Nagai, Naoki Masaki, Kay Maeda, Konosuke Sasaki, Hiroki Sato, Jun Muneuchi, Yoshie Ochiai, Hiroomi Murayama, Masahiro Tahara, Atsuko Shiono, Atsushi Shinozuka, Fumihiko Kono, Daisuke Machida, Shinichi Toyooka, Seiichiro Sugimoto, Kazufumi Nakamura, Satoshi Akagi, Maiko Kondo, Shingo Kasahara, Yasuhiro Kotani, Junichi Koizumi, Katsuhiko Oda, Masako Harada, Daisuke Nakajima, Akira Murata, Hazumu Nagata, Koichi Yatsunami, Tomio Kobayashi, Yoshikiyo Matsunaga, Takahiro Inoue, Hiroyuki Yamagishi, Naomi Nakagawa, Katsuki Ohtani, Masaki Yamamoto, Yushi Ito, Tatsunori Hokosaki, Yuta Kuwahara, Satoshi Masutani, Koji Nomura, Tsutomu Wada, Hirofumi Sawada, Masayuki Abiko, Tatsunori Takahashi, Yuichi Ishikawa, Seigo Okada, Atsushi Naitoh, Takako Toda, Tatsuya Ando, Akihiro Masuzawa, Shinsuke Hoshino, Masaaki Kawada, Yuichi Nomura, Kentaro Ueno, Naoki Ohashi, Tsuyoshi Tachibana, Yuchen Cao, Hideaki Ueda, Sadamitsu Yanagi, Masaaki Koide, Norie Mitsushita, Kouji Higashi, Yoshihiro Minosaki, Tomohiro Hayashi, Takashi Okamoto, Kenji Kuraishi, Eiji Ehara, Hidekazu Ishida, Hitoshi Horigome, Takashi Murakami, Kohta Takei, Taku Ishii, Gen Harada, Yasutaka Hirata, Jun Maeda, Shunsuke Tatebe, Chiharu Ota, Yasunobu Hayabuchi, Hisanori Sakazaki, Takashi Sasaki, Keiichi Hirono, Sayo Suzuki, Masahiro Yasuda, Atsuhito Takeda, Madoka Sawai, Kagami Miyaji, Atsushi Kitagawa, Yosuke Nakai, Nobuyuki Kakimoto, Kouta Agematsu, Atsushi Manabe, Yoshikatsu Saiki

Frontiers in cardiovascular medicine 10 1212882 - 1212882 2023

Language：English Publishing type：Research paper (scientific journal)

AIMS: Limited data exist on risk factors for the long-term outcome of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD-PAH). We focused on the index of pulmonary vascular disease (IPVD), an assessment system for pulmonary artery pathology specimens. The IPVD classifies pulmonary vascular lesions into four categories based on severity: (1) no intimal thickening, (2) cellular thickening of the intima, (3) fibrous thickening of the intima, and (4) destruction of the tunica media, with the overall grade expressed as an additive mean of these scores. This study aimed to investigate the relationship between IPVD and the long-term outcome of CHD-PAH. METHODS: This retrospective study examined lung pathology images of 764 patients with CHD-PAH aged <20 years whose lung specimens were submitted to the Japanese Research Institute of Pulmonary Vasculature for pulmonary pathological review between 2001 and 2020. Clinical information was collected retrospectively by each attending physician. The primary endpoint was cardiovascular death. RESULTS: The 5-year, 10-year, 15-year, and 20-year cardiovascular death-free survival rates for all patients were 92.0%, 90.4%, 87.3%, and 86.1%, respectively. The group with an IPVD of ≥2.0 had significantly poorer survival than the group with an IPVD <2.0 (P = .037). The Cox proportional hazards model adjusted for the presence of congenital anomaly syndromes associated with pulmonary hypertension, and age at lung biopsy showed similar results (hazard ratio 4.46; 95% confidence interval: 1.45-13.73; P = .009). CONCLUSIONS: The IPVD scoring system is useful for predicting the long-term outcome of CHD-PAH. For patients with an IPVD of ≥2.0, treatment strategies, including choosing palliative procedures such as pulmonary artery banding to restrict pulmonary blood flow and postponement of intracardiac repair, should be more carefully considered.

DOI： 10.3389/fcvm.2023.1212882

Toll-like receptor 4 promotes bladder cancer progression upon S100A8/A9 binding, which requires TIRAP-mediated TPL2 activation. Reviewed International journal

Acosta Gonzalez Herik Rodrigo, Nahoko Tomonobu, Haruka Yoneda, Rie Kinoshita, Yosuke Mitsui, Takuya Sadahira, Shin-Ichi Terawaki, Yuma Gohara, Ni Luh Gede Yoni Komalasari, Fan Jiang, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Akira Yamauchi, Futoshi Kuribayashi, Yusuke Inoue, Eisaku Kondo, Shinichi Toyooka, Masahiro Nishibori, Masami Watanabe, Yasutomo Nasu, Masakiyo Sakaguchi

Biochemical and biophysical research communications 634 83 - 91 2022.12

Language：English Publishing type：Research paper (scientific journal)

Bladder cancer is an often widely disseminated and deadly cancer. To block the malignant outgrowth of bladder cancer, we must elucidate the molecular-level characteristics of not only bladder cancer cells but also their surrounding milieu. As part of this effort, we have long been studying extracellular S100A8/A9, which is elevated by the inflammation associated with certain cancers. Extracellularly enriched S100A8/A9 can hasten a shift to metastatic transition in multiple types of cancer cells. Intriguingly, high-level S100A8/A9 has been detected in the urine of bladder-cancer patients, and the level increases with the stage of malignancy. Nonetheless, S100A8/A9 has been investigated mainly as a potential biomarker of bladder cancers, and there have been no investigations of its role in bladder-cancer growth and metastasis. We herein report that extracellular S100A8/A9 induces upregulation of growth, migration and invasion in bladder cancer cells through its binding with cell-surface Toll-like receptor 4 (TLR4). Our molecular analysis revealed the TLR4 downstream signal that accelerates such cancer cell events. Tumor progression locus 2 (TPL2) was a key factor facilitating the aggressiveness of cancer cells. Upon binding of S100A8/A9 with TLR4, TPL2 activation was enhanced by an action with a TLR4 adaptor molecule, TIR domain-containing adaptor protein (TIRAP), which in turn led to activation of the mitogen-activated protein kinase (MAPK) cascade of TPL2. Finally, we showed that sustained inhibition of TLR4 in cancer cells effectively dampened cancer survival in vivo. Collectively, our results indicate that the S100A8/A9-TLR4-TPL2 axis influences the growth, survival, and invasive motility of bladder cancer cells.

DOI： 10.1016/j.bbrc.2022.09.116

Association of Genetic Polymorphism with Taxane-induced Peripheral Neuropathy: Sub-analysis of a Randomized Phase II Study to Determine the Optimal Dose of 3-week Cycle Nab-Paclitaxel in Metastatic Breast Cancer Patients. Reviewed

Yuko Abe, Naruto Taira, Kosuke Kashiwabara, Junji Tsurutani, Masahiro Kitada, Masato Takahashi, Hiroaki Kato, Yuichiro Kikawa, Eiko Sakata, Yoichi Naito, Yoshie Hasegawa, Tsuyoshi Saito, Tsutomu Iwasa, Tsutomu Takashima, Tomohiko Aihara, Hirofumi Mukai, Fumikata Hara, Tadahiko Shien, Hiroyoshi Doihara, Shinichi Toyooka

Acta medica Okayama 76 ( 6 ) 661 - 671 2022.12

Language：English Publishing type：Research paper (scientific journal)

Chemotherapy-induced peripheral neuropathy (CIPN) is an important clinical challenge that threatens patients' quality of life. This sub-study of the ABROAD trial investigated the influence of single nucleotide polymorphisms (SNPs) on CIPN, using genotype data from a randomized study to determine the optimal dose of a 3-week-cycle regimen of nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). Patients with HER2-negative MBC were randomly assigned to three doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2). Five SNPs (EPHA4-rs17348202, EPHA5-rs7349683, EPHA6-rs301927, LIMK2-rs5749248, and XKR4-rs4737264) were analyzed based on the results of a previous genome-wide association study. Per-allele SNP associations were assessed by a Cox regression to model the cumulative dose of nab-PTX up to the onset of severe or worsening sensory neuropathy. A total of 141 patients were enrolled in the parent study; 91(65%) were included in this sub-study. Worsening of CIPN was significantly greater in the cases with XKR4 AC compared to those with a homozygote AA (HR 1.86, 95%CI: 1.00001-3.46, p=0.049). There was no significant correlation of CIPN with any other SNP. A multivariate analysis showed that the cumulative dose of nab-PTX was most strongly correlated with CIPN (p<0.01).

DOI： 10.18926/AMO/64116

Early-stage antibody kinetics after the third dose of BNT162b2 mRNA COVID-19 vaccination measured by a point-of-care fingertip whole blood testing Reviewed

Hideharu Hagiya, Yasuhiro Nakano, Masanori Furukawa, Naruhiko Sunada, Toru Hasegawa, Yasue Sakurada, Kou Hasegawa, Koichiro Yamamoto, Hiroko Ogawa, Takafumi Obara, Kouhei Ageta, Naomi Matsumoto, Rumi Matsuo, Tomoka Kadowaki, Akihito Higashikage, Takao Hikita, Takashi Yorifuji, Shinichi Toyooka, Yoshinobu Maeda, Yoshinori Yokokura, Fumio Otsuka, Masanori Nakayama

Scientific Reports 12 ( 1 ) 2022.11

Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Amid the Coronavirus Disease 2019 pandemic, we aimed to demonstrate the accuracy of the fingertip whole blood sampling test (FWT) in measuring the antibody titer and uncovering its dynamics shortly after booster vaccination. Mokobio SARS-CoV-2 IgM & IgG Quantum Dot immunoassay (Mokobio Biotechnology R&D Center Inc., MD, USA) was used as a point-of-care FWT in 226 health care workers (HCWs) who had received two doses of the BNT162b2 mRNA vaccine (Pfizer-BioNTech) at least 8 months prior. Each participant tested their antibody titers before and after the third-dose booster up to 14-days. The effect of the booster was observed as early as the fourth day after vaccination, which exceeded the detection limit (> 30,000 U/mL) by 2.3% on the fifth day, 12.2% on the sixth day, and 22.5% after the seventh day. Significant positive correlations were observed between the pre- and post-vaccination (the seventh and eighth days) antibody titers (correlation coefficient, 0.405; p < 0.001). FWT is useful for examining antibody titers as a point-of-care test. Rapid response of antibody titer started as early as the fourth day post-vaccination, while the presence of weak responders to BNT162b2 vaccine was indicated.

DOI： 10.1038/s41598-022-24464-3

Other Link： https://www.nature.com/articles/s41598-022-24464-3

Expert Consensus Recommendations on Biomarker Testing in Metastatic and Nonmetastatic NSCLC in Asia. Reviewed International journal

Tetsuya Mitsudomi, Daniel Tan, James Chih-Hsin Yang, Myung-Ju Ahn, Ullas Batra, Byoung-Chul Cho, Gerardo Cornelio, Tony Lim, Tony Mok, Kumar Prabhash, Thanyanan Reungwetwattana, Sheng-Xiang Ren, Navneet Singh, Shinichi Toyooka, Yi-Long Wu, Pan-Chyr Yang, Yasushi Yatabe

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 18 ( 4 ) 436 - 446 2022.11

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Most published guidelines for genomic biomarker testing in NSCLC reflect the disease epidemiology and treatments readily available in Europe and North America. Nevertheless, 60% of annual global NSCLC cases occur in Asia, where patient characteristics, tumor molecular profiles, and treatments vary greatly from the Western world. For example, mutations in the EGFR occur at a higher prevalence in Asia than in other world regions. Although medical associations such as the International Association for the Study of Lung Cancer, European Society for Medical Oncology, and American Society of Clinical Oncology have described principles for tumor genomic biomarker testing in NSCLC, there is a need for recommendations specific for Asia. METHODS: This report provides consensus recommendations for NSCLC biomarker testing from Asian lung cancer experts for clinicians working in Asia to improve patient care. Biomarker testing approaches for actionable genetic alterations in EGFR, ALK, ROS1, and others are discussed. RESULTS: These recommendations are divided into nonmetastatic and metastatic forms of adenocarcinoma and squamous cell carcinoma. Owing to the higher prevalence of EGFR mutations in Asia, the experts emphasized the need for EGFR testing to include not just common mutations (exon 19 deletions and L858R substitutions) but also other uncommon EGFR mutations. In addition to the assessment of biomarkers in the tumor tissue, the role of assessing tumor biomarkers by liquid biopsy is discussed. CONCLUSION: This consensus provides practical recommendations for biomarker testing in nonmetastatic and metastatic Asian NSCLC patients.

DOI： 10.1016/j.jtho.2022.10.021

Functional Blockage of S100A8/A9 Ameliorates Ischemia-Reperfusion Injury in the Lung. Reviewed International journal

Kentaro Nakata, Mikio Okazaki, Tomohisa Sakaue, Rie Kinoshita, Yuhei Komoda, Dai Shimizu, Haruchika Yamamoto, Shin Tanaka, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Hiromasa Yamamoto, Toshiaki Ohara, Seiichiro Sugimoto, Masaomi Yamane, Akihiro Matsukawa, Masakiyo Sakaguchi, Shinichi Toyooka

Bioengineering (Basel, Switzerland) 9 ( 11 ) 2022.11

Language：English Publishing type：Research paper (scientific journal)

(1) Background: Lung ischemia-reperfusion (IR) injury increases the mortality and morbidity of patients undergoing lung transplantation. The objective of this study was to identify the key initiator of lung IR injury and to evaluate pharmacological therapeutic approaches using a functional inhibitor against the identified molecule. (2) Methods: Using a mouse hilar clamp model, the combination of RNA sequencing and histological investigations revealed that neutrophil-derived S100A8/A9 plays a central role in inflammatory reactions during lung IR injury. Mice were assigned to sham and IR groups with or without the injection of anti-S100A8/A9 neutralizing monoclonal antibody (mAb). (3) Results: Anti-S100A8/A9 mAb treatment significantly attenuated plasma S100A8/A9 levels compared with control IgG. As evaluated by oxygenation capacity and neutrophil infiltration, the antibody treatment dramatically ameliorated the IR injury. The gene expression levels of cytokines and chemokines induced by IR injury were significantly reduced by the neutralizing antibody. Furthermore, the antibody treatment significantly reduced TUNEL-positive cells, indicating the presence of apoptotic cells. (4) Conclusions: We identified S100A8/A9 as a novel therapeutic target against lung IR injury.

DOI： 10.3390/bioengineering9110673

本邦における肺移植時の一酸化窒素(NO)ガス使用状況に関する実態調査

吉安展将, 佐藤雅昭, 中島大輔, 富岡泰章, 渡辺有為, 白石武史, 舟木壮一郎, 前田寿美子, 朝重耕一, 中島崇裕, 土谷智史, 杉本誠一郎, 吉野一郎, 永安武, 千田雅之, 南正人, 岡田克典, 豊岡伸一, 伊達洋至, 中島淳

日本呼吸器外科学会雑誌 36 ( 7 ) 722 - 734 2022.11

COVID-19禍における肺癌診療 NCDデータを用いたCOVID-19の日本の呼吸器外科手術に対する影響

佐藤幸夫, 山本博之, 池田徳彦, 小西宏, 遠藤俊輔, 岡田克典, 近藤晴彦, 新谷康, 豊岡伸一, 中村廣重, 星川康, 芳川豊史, 吉野一郎, 垣添忠生, 千田雅之

肺癌 62 ( 6 ) 496 - 496 2022.11

Hazard Function Analysis of Recurrence in Patients with Curatively Resected Lung Cancer: Results from the Japanese Lung Cancer Registry in 2010. International journal

Yoshikane Yamauchi, Masafumi Kawamura, Jiro Okami, Yasushi Shintani, Hiroyuki Ito, Takashi Ohtsuka, Shinichi Toyooka, Takeshi Mori, Shun-Ichi Watanabe, Hisao Asamura, Masayuki Chida, Shunsuke Endo, Mitsutaka Kadokura, Ryoichi Nakanishi, Etsuo Miyaoka, Hidemi Suzuki, Ichiro Yoshino, Hiroshi Date

Cancers 14 ( 20 ) 2022.10

Language：English Publishing type：Research paper (scientific journal)

To optimize postoperative surveillance of lung cancer patients, we investigated the hazard function of tumor recurrence in patients with completely resected lung cancer. We analyzed the records of 12,897 patients in the 2010 Japanese Joint Committee of Lung Cancer Registry who underwent lobectomy to completely resect pathological stage I-III lung cancer. The risk of postoperative recurrence was determined using a cause-specific hazard function. The hazard function for recurrence exhibited a peak at approximately 9 months after surgery, followed by a tapered plateau-like tail extending to 60 months. The peak risk for intrathoracic recurrence was approximately two-fold higher compared with that of extrathoracic recurrence. Subgroup analysis showed that patients with stage IIIA adenocarcinoma had a continuously higher risk of recurrence compared with patients with earlier-stage disease. However, the risk of recurrence in patients with squamous cell carcinoma was not significantly different compared with that more than 24 months after surgery, regardless of pathological stage. In conclusion, the characteristics of postoperative tumor recurrence hazard in a large cohort of lung cancer patients may be useful for determining the time after surgery at which patients are at the highest risk of tumor recurrence. This information may improve stage-related management of postoperative surveillance.

DOI： 10.3390/cancers14205119

The impact of COVID-19 on thoracic surgical procedures in Japan: Analysis of data from the National Clinical Database. International journal

Yukio Sato, Hiroyuki Yamamoto, Norihiko Ikeda, Hiroshi Konishi, Shunsuke Endo, Yoshinori Okada, Haruhiko Kondo, Yasushi Shintani, Shinichi Toyooka, Hiroshige Nakamura, Yasushi Hoshikawa, Toyofumi Fengshi Chen-Yoshikawa, Ichiro Yoshino, Tadao Kakizoe, Masayuki Chida

Lung cancer (Amsterdam, Netherlands) 172 127 - 135 2022.10

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: The COVID-19 pandemic has far-reaching collateral health impacts on the ongoing delivery of surgical care worldwide. The current study was designed to analyze the impact of the COVID-19 pandemic on the number of surgeries of general thoracic surgery in Japan. METHODS: Changes in the number of surgeries for total and three representative tumors were analyzed using the National Clinical Database data with reference to the pandemic infection rate and lung cancer screening. RESULTS: In 2020, the number of surgeries in total and for primary lung cancer and mediastinal lung tumor decreased by 4.9, 5.1, and 5.0 %, respectively. Considering the five-year trend towards a 5 % annual increase, there was a potential 10 % decrease in the number of primary lung cancer surgeries. The number of primary lung cancer surgeries bottomed in July 2020 but recovered towards the end of the year. In contrast, the number of metastatic lung tumor surgeries in 2020 increased by 3.2 %, following a similar trend observed over the previous five years. The number of lung cancer screening examinees decreased markedly with the lowest number in May. Our findings indicate that surgical triage had a limited impact on the decrease in primary lung cancer surgeries during the pandemic; rather, the decrease in lung cancer screening, which was a few months preceding, is most likely responsible. CONCLUSIONS: The decrease in primary lung cancer was mainly caused by the decrease in lung cancer screening, indicating that continuing screening is vital even during a pandemic.

DOI： 10.1016/j.lungcan.2022.08.011

臓器保存の最前線 Ex vivo lung perfusion技術を体内へ応用したIn vivo Lung Recoveryによる新規治療戦略

松原慧, 三好健太郎, 黒崎毅史, 川名伸一, 久保友次郎, 清水大, 橋本好平, 田中真, 岡崎幹生, 杉本誠一郎, 豊岡伸一

移植 57 ( 総会臨時 ) 182 - 182 2022.10

がん遺伝子パネルに基づく肉腫診療

中田英二, 藤原智洋, 平沢晃, 二川摩周, 遠西大輔, 山本英喜, 冨田秀太, 久保寿夫, 田端雅弘, 国定俊之, 豊岡伸一, 尾崎敏文

日本癌治療学会学術集会抄録集 60回 O49 - 4 2022.10

がん遺伝子パネルに基づく肉腫診療

中田英二, 藤原智洋, 平沢晃, 二川摩周, 遠西大輔, 山本英喜, 冨田秀太, 久保寿夫, 田端雅弘, 国定俊之, 豊岡伸一, 尾崎敏文

日本癌治療学会学術集会抄録集 60回 O49 - 4 2022.10

子宮平滑筋肉腫原発転移性肺腫瘍におけるTIL、TLS、NLRと予後の検討

松田直樹, 山本寛斉, 吉川真生, 大亀正義, 岩田一馬, 伊達慶一, 中田憲太郎, 枝國和彦, 諏澤憲, 豊岡伸一

日本癌治療学会学術集会抄録集 60回 O29 - 4 2022.10

Neuropeptide Y Antagonizes Development of Pulmonary Fibrosis Through IL-1β Inhibition. International journal

Junko Itano, Akihiko Taniguchi, Satoru Senoo, Noboru Asada, Yuka Gion, Yuria Egusa, Lili Guo, Naohiro Oda, Kota Araki, Yasuharu Sato, Shinichi Toyooka, Katsuyuki Kiura, Yoshinobu Maeda, Nobuaki Miyahara

American journal of respiratory cell and molecular biology 67 ( 6 ) 654 - 665 2022.9

Language：English Publishing type：Research paper (scientific journal)

Neuropeptide Y, a 36-amino acid residue polypeptide, distributed throughout the nervous system, acts on various immune cells in many organs, including the respiratory system. However, little is known about its role in the pathogenesis of pulmonary fibrosis. This study was performed to determine the effects of neuropeptide Y on pulmonary fibrosis. Neuropeptide Y-deficient and wild-type mice were intratracheally administered bleomycin. Inflammatory cells, cytokine levels, and morphological morphometry of the lungs were analyzed. Serum neuropeptide Y levels were also measured in idiopathic pulmonary fibrosis patients and healthy controls. Neuropeptide Y-deficient mice exhibited significantly enhanced pulmonary fibrosis and higher IL-1β levels in the lungs compared to wild-type mice. Exogenous neuropeptide Y treatment suppressed the development of bleomycin-induced lung fibrosis and decreased IL-1β levels in the lungs. Moreover, IL-1β neutralization in neuropeptide Y-deficient mice attenuated the fibrotic changes. Neuropeptide Y decreased IL-1β release, and Y1 receptor antagonists inhibited IL-1β release and induced epithelial mesenchymal transition in human alveolar epithelial cells. Patients with idiopathic pulmonary fibrosis had lower neuropeptide Y and greater IL-1β levels in the serums compared to healthy controls. Neuropeptide Y expression was mainly observed around bronchial epithelial cells in human idiopathic pulmonary fibrosis lungs. These data suggest that neuropeptide Y plays a protective role against pulmonary fibrosis by suppressing IL-1β release and manipulating the neuropeptide Y-Y1 receptor axis could be a potential therapeutic strategy for delaying disease progression.

DOI： 10.1165/rcmb.2021-0542OC

Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells

Nahoko Tomonobu, Rie Kinoshita, Hidenori Wake, Yusuke Inoue, I Made Winarsa Ruma, Ken Suzawa, Yuma Gohara, Ni Luh Gede Yoni Komalasari, Fan Jiang, Hitoshi Murata, Ken-ichi Yamamoto, I Wayan Sumardika, Youyi Chen, Junichiro Futami, Akira Yamauchi, Futoshi Kuribayashi, Eisaku Kondo, Shinichi Toyooka, Masahiro Nishibori, Masakiyo Sakaguchi

International Journal of Molecular Sciences 23 ( 18 ) 10300 - 10300 2022.9

Publishing type：Research paper (scientific journal) Publisher：MDPI AG

The dissection of the complex multistep process of metastasis exposes vulnerabilities that could be exploited to prevent metastasis. To search for possible factors that favor metastatic outgrowth, we have been focusing on secretory S100A8/A9. A heterodimer complex of the S100A8 and S100A9 proteins, S100A8/A9 functions as a strong chemoattractant, growth factor, and immune suppressor, both promoting the cancer milieu at the cancer-onset site and cultivating remote, premetastatic cancer sites. We previously reported that melanoma cells show lung-tropic metastasis owing to the abundant expression of S100A8/A9 in the lung. In the present study, we addressed the question of why melanoma cells are not metastasized into the brain at significant levels in mice despite the marked induction of S100A8/A9 in the brain. We discovered the presence of plasma histidine-rich glycoprotein (HRG), a brain-metastasis suppression factor against S100A8/A9. Using S100A8/A9 as an affinity ligand, we searched for and purified the binding plasma proteins of S100A8/A9 and identified HRG as the major protein on mass spectrometric analysis. HRG prevents the binding of S100A8/A9 to the B16-BL6 melanoma cell surface via the formation of the S100A8/A9 complex. HRG also inhibited the S100A8/A9-induced migration and invasion of A375 melanoma cells. When we knocked down HRG in mice bearing skin melanoma, metastasis to both the brain and lungs was significantly enhanced. The clinical examination of plasma S100A8/A9 and HRG levels showed that lung cancer patients with brain metastasis had higher S100A8/A9 and lower HRG levels than nonmetastatic patients. These results suggest that the plasma protein HRG strongly protects the brain and lungs from the threat of melanoma metastasis.

DOI： 10.3390/ijms231810300

CD8+ T-cell Responses Are Boosted by Dual PD-1/VEGFR2 Blockade after EGFR Inhibition in Egfr-Mutant Lung Cancer. International journal

Kazuya Nishii, Kadoaki Ohashi, Shuta Tomida, Takamasa Nakasuka, Atsuko Hirabae, Sachi Okawa, Jun Nishimura, Hisao Higo, Hiromi Watanabe, Hirohisa Kano, Chihiro Ando, Go Makimoto, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Heiichiro Udono, Yoshinobu Maeda, Katsuyuki Kiura

Cancer immunology research 10 ( 9 ) 1111 - 1126 2022.9

Language：English Publishing type：Research paper (scientific journal)

Epidermal growth factor receptor (EGFR) is the most frequently mutated driver oncogene in nonsmoking-related, non-small cell lung cancer (NSCLC). EGFR-mutant NSCLC has a noninflamed tumor microenvironment (TME), with low infiltration by CD8+ T cells and, thus, immune-checkpoint inhibitors, such as antiprogrammed cell death-1 (anti-PD-1), have weak antitumor effects. Here, we showed that CD8+ T-cell responses were induced by an EGFR-tyrosine kinase inhibitor (TKI) in syngeneic Egfr-mutant NSCLC tumors, which was further pronounced by the sequential dual blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2). However, the simultaneous triple blockade had no such effect. The PD-1/VEGFR2 dual blockade did not exert tumor-inhibitory effects without pretreatment with the EGFR-TKI, suggesting that the treatment schedule is crucial for the efficacy of the dual blockade therapy. Pretreatment with EGFR-TKI increased the CD8+ T-cell/regulatory T-cell (Treg) ratio, while also increasing the expression of immunosuppressive chemokines and chemokine receptors, as well as increasing the number of M2-like macrophages, in the TME. Discontinuing EGFR-TKI treatment reversed the transient increase of immunosuppressive factors in the TME. The subsequent PD-1/VEGFR2 inhibition maintained increased numbers of infiltrating CD8+ T cells and CD11c+ dendritic cells. Depletion of CD8+ T cells in vivo abolished tumor growth inhibition by EGFR-TKI alone and the sequential triple therapy, suggesting that EGFR inhibition is a prerequisite for the induction of CD8+ T-cell responses. Our findings could aid in developing an alternative immunotherapy strategy in patients with cancers that have driver mutations and a noninflamed TME.

DOI： 10.1158/2326-6066.CIR-21-0751

男女を問わず外科医が輝き続けるためにステレオタイプ・スレットという問題とニュースレターの果たす役割

竹原裕子, 溝尾妙子, 小林純子, 坂本美咲, 新田薫, 工藤由里絵, 安井和也, 菊池覚次, 黒田新士, 吉田龍一, 岡崎幹生, 枝園忠彦, 山根正修, 小谷恭弘, 豊岡伸一, 笠原真悟, 土井原博義, 藤原俊義

日本外科学会雑誌 123 ( 5 ) 501 - 502 2022.9

Safety of salvage lung resection after immunotherapy for unresectable non-small cell lung cancer.

Tsuyoshi Ueno, Motohiro Yamashita, Natsumi Yamashita, Masashi Uomoto, Osamu Kawamata, Yoshifumi Sano, Hidetoshi Inokawa, Shin Hirayama, Mikio Okazaki, Shinichi Toyooka

General thoracic and cardiovascular surgery 70 ( 9 ) 812 - 817 2022.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The safety of salvage lung resection after immune checkpoint inhibitor (ICI) therapy in patients with advanced non-small cell lung cancer (NSCLC) is not well understood. METHODS: In this retrospective multicenter study, we reviewed perioperative morbidity and mortality rates in 11 patients (8 men, 3 women; median age 70 years) who underwent salvage lung resection for unresectable NSCLC after ICI therapy in the 4 years since 2017. Operative factors were also compared according to operating time (> 6 h, n = 7; < 6 h, n = 4). RESULTS: The clinical stage at the time of diagnosis was IIIA in 2 patients, IIIB in 4, IVA in 2, and IVB in 3. Eight patients received pembrolizumab and 3 received durvalumab. Two patients received an ICI agent alone, 3 underwent chemoradiotherapy, and 6 received chemotherapy. Lobectomy was performed in 10 cases and bilobectomy in 1 case. All patients underwent complete resection. Median operating time was 429 (range 169-570) min with a median blood loss of 199 (range 10-5, 140) mL. The only intraoperative complication was damage to the pulmonary artery. The perioperative morbidity and mortality rates were 27% and 0%, respectively. The 90-day mortality rate was 9% (1 patient died of acute exacerbation of interstitial pneumonia). Patients in whom the operating time was > 6 h more frequently had lymph node metastasis at the time of initial diagnosis (100% vs 25%, p = 0.02). CONCLUSIONS: Salvage lung resection was tolerated after ICI therapy in these patients. Lymph node metastasis at the time of initial diagnosis might make salvage surgery difficult.

DOI： 10.1007/s11748-022-01798-3

男女を問わず外科医が輝き続けるためにステレオタイプ・スレットという問題とニュースレターの果たす役割

竹原裕子, 溝尾妙子, 小林純子, 坂本美咲, 新田薫, 工藤由里絵, 安井和也, 菊池覚次, 黒田新士, 吉田龍一, 岡崎幹生, 枝園忠彦, 山根正修, 小谷恭弘, 豊岡伸一, 笠原真悟, 土井原博義, 藤原俊義

日本外科学会雑誌 123 ( 5 ) 501 - 502 2022.9

がん関連線維芽細胞由来ペリオスチンを介するがん進展機構(Periostin secreted from CAF promotes cancer progression and drug resistance in non-small cell lung cancer)

諏澤憲, 冨田秀太, 枝園和彦, 山本寛斉, 豊岡伸一

日本癌学会総会記事 81回 P - 1252 2022.9

Inhibiting S100A8/A9 attenuates airway obstruction in a mouse model of heterotopic tracheal transplantation. International journal

Dai Shimizu, Mikio Okazaki, Seiichiro Sugimoto, Rie Kinoshita, Kentaro Nakata, Shin Tanaka, Kohei Hashimoto, Kentaroh Miyoshi, Masaomi Yamane, Akihiro Matsukawa, Masakiyo Sakaguchi, Shinichi Toyooka

Biochemical and biophysical research communications 629 86 - 94 2022.8

Language：English Publishing type：Research paper (scientific journal)

Although bronchiolitis obliterans syndrome (BOS) is a major cause of death after lung transplantation, an effective drug therapy for BOS has not yet developed. Here, we assessed the effectiveness of a neutralizing anti-S100 calcium binding protein (S100) A8/A9 antibody against BOS. A murine model of heterotopic tracheal transplantation was used. Mice were intraperitoneally administered control IgG or the S100A8/A9 antibody on day 0 and twice per week until they were sacrificed. Tissue sections were used to evaluate the obstruction ratio, epithelium-preservation ratio, α-smooth muscle actin (SMA)-positive myofibroblast infiltration, and luminal cell death. Quantitative reverse transcriptase-polymerase chain reaction analysis was performed to analyze the mRNA-expression levels of collagen, inflammatory cytokines, and chemokines on days 7, 14, and 21. The anti-S100A8/A9 antibody significantly improved the obstruction ratio and epithelium-preservation ratio, with less α-SMA-positive myofibroblast infiltration compared to the control group. Antibody treatment reduced the type-III collagen: type-I collagen gene-expression ratio. The antibody also significantly suppressed the number of dead cells in the graft lumen. The expression levels of tumor growth factor β1 and C-C motif chemokine 2 on day 21, but not those of interleukin-1β, interleukin-6, and tumor necrosis factor α, were significantly suppressed by S100A8/A9 antibody treatment. These findings suggest that S100A8/A9 may be a potential therapeutic target for BOS after lung transplantation.

DOI： 10.1016/j.bbrc.2022.08.087

Predictive value of immune genomic signatures from breast cancer cohorts containing data for both response to neoadjuvant chemotherapy and prognosis after surgery.

Yidan Zhu, Takayuki Iwamoto, Yukiko Kajiwara, Yuko Takahashi, Mariko Kochi, Tadahiko Shien, Naruto Taira, Shinichi Toyooka, Hiroyoshi Doihara

Breast cancer (Tokyo, Japan) 30 ( 1 ) 56 - 67 2022.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Previous studies of immune genomic signatures (IGSs) in breast cancer have attempted to predict the response to chemotherapy or prognosis and were performed using different patient cohorts. The purpose of this study was to evaluate the predictive functions of various IGSs using the same patient cohort that included data for response to chemotherapy as well as the prognosis after surgery. METHODS: We applied five previously described IGS models in a public dataset of 508 breast cancer patients treated with neoadjuvant chemotherapy. The prognostic and predictive values of each model were evaluated, and their correlations were compared. RESULTS: We observed a high proportion of expression concordance among the IGS models (r: 0.56-1). Higher scores of IGSs were detected in aggressive breast cancer subtypes (basal and HER2-enriched) (P < 0.001). Four of the five IGSs could predict chemotherapy responses and two could predict 5-year relapse-free survival in cases with hormone receptor-positive (HR +) tumors. However, the models showed no significant differences in their predictive abilities for hormone receptor-negative (HR-) tumors. CONCLUSIONS: IGSs are, to some extent, useful for predicting prognosis and chemotherapy response; moreover, they show substantial agreement for specific breast cancer subtypes. However, it is necessary to identify more compelling biomarkers for both prognosis and response to chemotherapy in HR- and HER2 + cases.

DOI： 10.1007/s12282-022-01397-3

Gene Expression Profiling between Patient Groups with High and Low Ki67 Levels after Short-term Preoperative Aromatase Inhibitor Treatment for Breast Cancer.

Yukiko Kajiwara, Takayuki Iwamoto, Yidan Zhu, Mariko Kochi, Tadahiko Shien, Naruto Taira, Hiroyoshi Doihara, Shinichi Toyooka

Acta medica Okayama 76 ( 4 ) 399 - 408 2022.8

Language：English Publishing type：Research paper (scientific journal)

According to a recent report, a low Ki67 level after short-term preoperative hormone therapy (post-Ki67) might suggest a more favorable prognosis compared with a high post-Ki67 level in patients with hormone receptorpositive/human epidermal growth factor 2-negative (HR+/HER2-) breast cancer with high levels of Ki67. This study aimed to evaluate the pre-treatment genetic differences between these two patient groups. Forty-five luminal B-like patients were stratified into two groups, namely, a group with high (H→H) and one with low (H→L) Ki67 levels after short-term preoperative aromatase inhibitor (AI) treatment. We compared pre-treatment gene expression profiles between the two groups. In gene level analysis, there was no significant difference between the two groups by the class comparison test. In pathway analysis, five metabolism-related gene sets were significantly upregulated in the H→L group (p≤0.05). In the search for novel targets, five genes (PARP, BRCA2, FLT4, CDK6, and PDCD1LG2) showed significantly higher expression in the H→H group (p≤0.05). Several metabolism-related pathways were associated with sensitivity to AI. In the future, it will be necessary to seek out new therapeutic strategies for the poor prognostic group with high post-Ki67.

DOI： 10.18926/AMO/63894

Lung recruitment after cardiac arrest during procurement of atelectatic donor lungs is a protective measure in lung transplantation. International journal

Eito Niman, Kentaroh Miyoshi, Toshio Shiotani, Tomohiro Toji, Takuro Igawa, Shinji Otani, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

Journal of thoracic disease 14 ( 8 ) 2802 - 2811 2022.8

Language：English Publishing type：Research paper (scientific journal)

Background: Brain-dead donors are susceptible to pulmonary atelectasis (AT). In procurement surgery, lung recruitment under circulatory conditions and cold-flushing for atelectatic donor lungs often provoke graft injury due to the acute blood inflow. We hypothesized that lung recruitment without blood circulation can mitigate graft injury. This study aimed to examine the benefits of lung recruitment subsequent to cardiac arrest using a porcine lung-transplant model. Methods: Thirteen donor pigs were categorized into the non-atelectatic (No-AT) group (n=3) representing a healthy control group; AT-BCR group (n=5), in which AT was reverted by conventional blood-circulated recruitment (BCR); and AT-no-BCR group (n=5), in which AT was reverted by no-BCR following circulatory arrest. In the atelectatic donor models, the left main bronchus was ligated for 24 hours prior to lung procurement. Left lung transplantation (LTx) was subsequently performed in the thirteen recipient pigs. After 6 hours evaluation, the recipients were euthanized and the lung grafts were excised. Results: The post-transplant PaO2/FiO2 ratio was significantly higher in the AT-no-BCR group than in the AT-BCR group (P=0.015). Wet/dry ratio, histological findings of graft injury and tissue interleukin-8 expression in the AT-no-BCR group were similar to those of the No-AT group. Conclusions: Lung recruitment without circulation after circulatory arrest could be more protective for atelectatic donor lung than the conventional procedure.

DOI： 10.21037/jtd-22-226

SRC Family Kinase Inhibition Targets YES1 and YAP1 as Primary Drivers of Lung Cancer and as Mediators of Acquired Resistance to ALK and Epidermal Growth Factor Receptor Inhibitors. International journal

Hiroki Sato, Daisuke Kubota, Huan Qiao, Achim Jungbluth, Natasha Rekhtman, Adam J Schoenfeld, Helena A Yu, Gregory J Riely, Shinichi Toyooka, Christine M Lovly, Paul Paik, Marc Ladanyi, Pang-Dian Fan

JCO precision oncology 6 e2200088 2022.8

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: The identification of novel oncogenic driver alterations and novel mechanisms of acquired resistance (AR) is the key for further development of personalized therapy. The current study investigates the potential role of YES1 amplification as a primary driver of tumorigenesis and of YES1/YAP1 amplifications as mediators of AR to ALK and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). METHODS: Models of ectopic expression were established and characterized for YES1 and YAP1 in human bronchial epithelial cells and ALK fusion-positive (ALK+) and EGFR-mutant lung adenocarcinoma cell lines. MSK-IMPACT data for all lung adenocarcinoma cases and for ALK and EGFR TKI AR cases were surveyed for YES1 and YAP1 amplification. RESULTS: We report response to SRC family kinase (SFK) inhibition in a patient whose lung cancer exhibited YES1 amplification, without any well-established primary driver alteration, suggesting that YES1 amplification can also function as a primary oncogenic driver. To investigate the possibility of YES1 as a primary driver in tumorigenesis, we established preclinical models of YES1 overexpression using human bronchial epithelial cells and normal human breast epithelial cells. We showed that YES1 overexpression conferred sensitivity to SFK TKIs and promoted EGF-independent growth in a YAP1-dependent manner. Analysis of clinical genomic sequencing data from cases of AR to EGFR and ALK inhibitors revealed acquired amplification of YAP1 in four cases. EGFR-mutant and ALK fusion-positive cells overexpressing YES1 or YAP1 were resistant to EGFR and ALK TKIs, respectively, but were sensitive to dual inhibition of the primary driver and YES1. CONCLUSION: Our results demonstrate the therapeutic potential of SFK inhibition in primary tumorigenesis and AR driven by YES1/YAP1 signaling.

DOI： 10.1200/PO.22.00088

Drug repositioning of tranilast to sensitize a cancer therapy by targeting cancer-associated fibroblast. International journal

Kosuke Ochi, Ken Suzawa, Yin Min Thu, Fumiaki Takatsu, Shimpei Tsudaka, Yidan Zhu, Kentaro Nakata, Tatsuaki Takeda, Kazuhiko Shien, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Tadahiko Shien, Yoshiharu Okamoto, Shuta Tomida, Shinichi Toyooka

Cancer science 113 ( 10 ) 3428 - 3436 2022.7

Language：English Publishing type：Research paper (scientific journal)

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment that mediate resistance of cancer cells to anticancer drugs. Tranilast is an antiallergic drug that suppresses the release of cytokines from various inflammatory cells. In this study, we investigated the inhibitory effect of tranilast on the interactions between non-small cell lung cancer (NSCLC) cells and the CAFs in the tumor microenvironment. Three EGFR-mutant NSCLC cell lines, two KRAS-mutant cell lines and three CAFs derived from NSCLC patients were used. To mimic the tumor microenvironment, the NSCLC cells were co-cultured with the CAFs in vitro, and the molecular profiles and sensitivity to molecular targeted therapy were assessed. Crosstalk between NSCLC cells and CAFs induced multiple biological effects on the NSCLC cells both in vivo and in vitro, including activation of the STAT3 signaling pathway, promotion of xenograft tumor growth, induction of epithelial-mesenchymal transition (EMT), and acquisition of resistance to molecular-targeted therapy, including of EGFR-mutant NSCLC cells to osimertinib and of KRAS-mutant NSCLC cells to selumetinib. Treatment with tranilast led to inhibition of IL-6 secretion from the CAFs, which, in turn, resulted in inhibition of CAF-induced phospho-STAT3 upregulation. Tranilast also inhibited CAF-induced EMT in the NSCLC cells. Finally, combined administration of tranilast with molecular-targeted therapy reversed the CAF-mediated resistance of the NSCLC cells to the molecular-targeted drugs, both in vitro and in vivo. Our results showed that combined administration of tranilast with molecular-targeted therapy is a possible new treatment strategy to overcome drug resistance caused by cancer- CAF interaction.

DOI： 10.1111/cas.15502

Robotic Mediastinal Tumor Resections: Position and Port Placement. International journal

Mikio Okazaki, Kazuhiko Shien, Ken Suzawa, Seiichiro Sugimoto, Shinichi Toyooka

Journal of personalized medicine 12 ( 8 ) 2022.7

Language：English Publishing type：Research paper (scientific journal)

This study aimed to determine the optimal position and port placement during robotic resection for various mediastinal tumors. For anterior mediastinal tumors, total or extended thymectomy is commonly performed in the supine position using the lateral or subxiphoid approach. Although it is unclear which approach is better during robotic thymectomy, technical advantages of subxiphoid approach are beneficial for patients with myasthenia who require extended thymectomy. Partial thymectomy is performed in the supine position using a lateral approach. Superior, middle, and posterior mediastinal tumors are resected in the decubitus position using the lateral approach, whereas dumbbell tumor resection, which requires a posterior approach, can be performed in the prone position. The position and port placement should be chosen depending on the size, location, and aggressiveness of the tumor. In this study, we describe how to choose which of these different robotic approaches can be used based on our experience and previous reports.

DOI： 10.3390/jpm12081195

境界領域の臨床解剖上縦隔

岡崎幹生, 豊岡伸一

耳鼻咽喉科 2 ( 1 ) 113 - 119 2022.7

学生発、がんゲノムゼミ。実臨床の経験を基にした自発的ゼミの立ち上げと報告

宮崎将司, 宇佐美佳耶, 加藤唯真, 川月章弘, 木山満就, 小堀貴之, 増田倫敦, 遠西大輔, 冨田秀太, 千々松良太, 山下範之, 豊岡伸一

医学教育 53 ( Suppl. ) 223 - 223 2022.7

Limited resection for stage IA radiologically invasive lung cancer: a real-world nationwide database study. International journal

Junichi Soh, Shinichi Toyooka, Yasushi Shintani, Jiro Okami, Hiroyuki Ito, Takashi Ohtsuka, Takeshi Mori, Shun-Ichi Watanabe, Hisao Asamura, Masayuki Chida, Shunsuke Endo, Ryoichi Nakanishi, Mitsutaka Kadokura, Hidemi Suzuki, Etsuo Miyaoka, Ichiro Yoshino, Hiroshi Date

European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 62 ( 1 ) 2022.6

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Radiologically invasive non-small-cell lung cancer, defined as consolidation size to maximum tumour diameter ratio of over 0.5, is associated with pathological invasiveness and worse prognosis. However, there are no real-world, nationwide database studies on limited resections that consider radiological invasiveness. This study aimed to investigate the prognostic validity of limited resection, such as segmentectomy and wedge resection, in cStage IA (TNM 8th edition) radiologically invasive lung cancer. METHODS: We conducted a retrospective analysis of patients who underwent complete resection according to the Japanese Joint Committee of Lung Cancer Registry Database. The relationship between surgical procedures and prognosis was examined using stratification by cT factor and radiological invasiveness. RESULTS: Among the 5,692 patients enrolled, lobectomy, segmentectomy and wedge resection were performed in 4,323 (80.0%), 657 (11.5%) and 712 (12.5%) patients, respectively. Multivariable analysis with or without propensity score matching indicated that older age, poor performance status and wedge resection were significantly associated with worse prognosis and that patients who underwent segmentectomy showed an equivalent prognosis to those who underwent lobectomy. Subset analyses revealed that segmentectomy showed an equivalent prognosis to lobectomy in patients with cT1b or less, but not in those with cT1c, especially for non-pure radiological invasive cT1c; 5-year overall survival rates were 91.4% vs 90.4% in cT1b with non-pure radiological invasiveness and 80.0% vs 83.8% in cT1b with pure radiological invasiveness, respectively. CONCLUSIONS: Segmentectomy can be an alternative to lobectomy in patients with radiologically invasive lung cancer with cT1b or less but not in those with cT1c.

DOI： 10.1093/ejcts/ezac342

外科治療における肺がんゲノム医療の現状と今後

枝園和彦, 豊岡伸一

肺癌 62 ( 3 ) 173 - 179 2022.6

Language：Japanese Publisher：(NPO)日本肺癌学会

新たなドライバー遺伝子の同定と分子標的薬の開発に伴い,非小細胞肺がんに対するゲノム検査および治療法は日々アップデートされてきた.これらドライバー遺伝子異常の検出を目的としたゲノム検査の対象は,主として薬物療法を考慮する進行・再発非小細胞肺がん患者であるため,呼吸器外科医が日常臨床でゲノム医療に接する機会はこれまで多くなかった.一方で,肺がんに対するゲノム検査が単一遺伝子検査からマルチプレックスコンパニオン診断および包括的がんゲノムプロファイリング検査へと進化する中で,呼吸器外科医が主にかかわる周術期治療の領域においても,治療の最適化,予後予測および発症予防という観点から,ゲノム検査を含むがんゲノム医療への理解の重要性が増している.本稿では,肺がんの診療を行う呼吸器外科医がかかわるゲノム医療の現状と今後の展望および課題について概説する.(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J01244&link_issn=&doc_id=20220714460001&doc_link_id=%2Fec7jaluc%2F2022%2F006203%2F001%2F0173-0179%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2022%2F006203%2F001%2F0173-0179%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

One-step nucleic acid amplification for intraoperative diagnosis of lymph node metastasis in lung cancer patients: a single-center prospective study. International journal

Kei Namba, Ken Suzawa, Kazuhiko Shien, Akihiro Miura, Yuta Takahashi, Shunsaku Miyauchi, Kota Araki, Kentaro Nakata, Shuta Tomida, Shin Tanaka, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Junichi Soh, Masaomi Yamane, Shinichi Toyooka

Scientific reports 12 ( 1 ) 7297 - 7297 2022.5

Language：English Publishing type：Research paper (scientific journal)

One-step nucleic acid amplification (OSNA) is a rapid intraoperative molecular detection technique for sentinel node assessment via the quantitative measurement of target cytokeratin 19 (CK19) mRNA to determine the presence of metastasis. It has been validated in breast cancer but its application in lung cancer has not been adequately investigated. 214 LNs from 105 patients with 100 primary lung cancers, 2 occult primary lung tumors, and 3 metastatic lung tumors, who underwent surgical lung resection with LN dissection between February 2018 and January 2020, were assessed. Resected LNs were divided into two parts: one was snap-frozen for OSNA and the other underwent rapidly frozen histological examination. Intraoperatively collected LNs were evaluated by OSNA using loop-mediated isothermal amplification and compared with intraoperative pathological diagnosis as a control. Among 214 LNs, 14 were detected as positive by OSNA, and 11 were positive by both OSNA and intraoperative pathological diagnosis. The sensitivity and specificity of OSNA was 84.6% and 98.5%, respectively. The results of 5 of 214 LNs were discordant, and the remainder all matched (11 positive and 198 negative) with a concordance rate of 97.7%. Although the analysis of public mRNA expression data from cBioPortal showed that CK19 expression varies greatly depending on the cancer type and histological subtype, the results of the five cases, except for primary lung cancer, were consistent. OSNA provides sufficient diagnostic accuracy and speed and can be applied to the intraoperative diagnosis of LN metastasis for non-small cell lung cancer.

DOI： 10.1038/s41598-022-11064-4

NCDデータを用いた我が国における喫煙が肺がん手術に及ぼす影響に関する調査研究

田中雄悟, 山本博之, 佐藤雅美, 豊岡伸一, 岡田守人, 遠藤俊輔, 佐藤幸夫, 鈴木健司, 眞庭謙昌, 福地絵梨子, 宮田裕章, 千田雅之

日本呼吸器外科学会雑誌 36 ( Suppl. ) np109 - np109 2022.5

Survival and prognostic factors in patients undergoing pulmonary metastasectomy for lung metastases from retroperitoneal sarcoma. International journal

Fumiaki Takatsu, Hiromasa Yamamoto, Yasuaki Tomioka, Shin Tanaka, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Shinji Otani, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Katsuhito Takahashi, Shinichi Toyooka

World journal of surgical oncology 20 ( 1 ) 114 - 114 2022.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Soft-tissue sarcomas are rare malignancies that consist of many different histologic subtypes and arise in various locations in the body. In patients with lung metastases from retroperitoneal sarcomas, the long-term outcomes and prognostic factors are unknown. This study is a retrospective review of patients undergoing pulmonary metastasectomy for retroperitoneal sarcoma metastases at one institution, with the purpose of determining prognostic factors and clinical outcomes. METHODS: This is a single-center, retrospective cohort study of patients undergoing pulmonary metastasectomy for lung metastases from various sarcomas at Okayama University Hospital from January 2006 to December 2018. The Kaplan-Meier method and log-rank test were used for the analyses, and cut-off values of continuous variables were determined by a receiver operating characteristic curve analysis. RESULTS: Twenty-four patients underwent the first pulmonary metastasectomy for lung metastases from retroperitoneal sarcoma in our hospital. Leiomyosarcoma was the most common histologic subtype of retroperitoneal sarcoma (79.2%, n = 19). Median overall survival was 49.9 months, and the 3-year and 5-year survival rates after the first pulmonary metastasectomy were 62.5% and 26.4% respectively. In univariate analysis, age ≥56 years, disease-free interval < 15 months, and size of metastasis (≥ 27 mm) were associated with poor survival. CONCLUSION: Pulmonary metastasectomy can be considered as an effective management strategy in retroperitoneal sarcoma patients with lung metastases in appropriately selected cases, just as it is for other sarcomas.

DOI： 10.1186/s12957-022-02552-y

[Chronic Lung Allograft Dysfunction after Living-donor Lobar Lung Transplantation].

Seiichiro Sugimoto, Shin Tanaka, Kentaroh Miyoshi, Shinichi Toyooka

Kyobu geka. The Japanese journal of thoracic surgery 75 ( 4 ) 297 - 301 2022.4

Language：Japanese Publishing type：Research paper (scientific journal)

Long-term survival after living-donor lobar lung transplantation (LDLLT) is hampered by the development of chronic lung allograft dysfunction( CLAD), similar to the clinical courses seen in some recipients of cadaveric lung transplantation( CLT). CLAD after bilateral LDLLT has been shown to be characterized by the development in the unilateral lung due to differences in the immunological features of the two donors. Based on this characteristic, we found that lung perfusion scintigraphy, which can show a perfusion shift to the contralateral unaffected lung with the development of CLAD, had the potential to predict unilateral CLAD after bilateral LDLLT. Moreover, we found that CLAD, especially restrictive allograft syndrome, developed significantly later after bilateral LDLLT than after bilateral CLT, although the CLAD-free survival and overall survival after bilateral LDLLT were similar to those after bilateral CLT. We describe our experience of CLAD after bilateral LDLLT since the first case of LDLLT in Japan.

【肺移植の現況と課題そして展望】生体肺移植後の慢性移植肺機能不全(CLAD)

杉本誠一郎, 田中真, 三好健太郎, 豊岡伸一

胸部外科 75 ( 4 ) 297 - 301 2022.4

ステレオタイプ・スレットという問題とニュースレターの果たす役割

竹原裕子, 溝尾妙子, 小林純子, 坂本美咲, 新田薫, 工藤由里絵, 安井和也, 菊池覚次, 黒田新士, 吉田龍一, 岡崎幹生, 杉本誠一郎, 枝園忠彦, 小谷恭弘, 豊岡伸一, 笠原真悟, 藤原俊義, 土井原博義

日本外科学会定期学術集会抄録集 122回 SP - 6 2022.4

ICI・TKI・SBRT時代の肺癌の集学的治療と外科手術局所進行肺がんに対する免疫チェックポイント阻害薬を用いた周術期治療の可能性 WJOG12119L試験

濱田顕, 宗淳一, 大泉弘幸, 坪井正博, 堀之内秀仁, 吉野一郎, 棚橋雅幸, 豊岡伸一, 岡田守人, 横見瀬裕保, 山下素弘, 光冨徹哉

日本外科学会定期学術集会抄録集 122回 SY - 1 2022.4

頭頸部癌の治療歴を有する肺癌手術症例に関する多施設共同後方視的検討

高津史明, 諏澤憲, 岡崎幹生, 渡邉元嗣, 葉山牧夫, 上野剛, 杉本龍士郎, 牧佑歩, 藤原俊哉, 沖田理貴, 井野川英利, 田尾裕之, 平見有二, 松田英祐, 片岡和彦, 山下素弘, 佐野由文, 松浦求樹, 水谷尚雄, 豊岡伸一

日本外科学会定期学術集会抄録集 122回 SF - 7 2022.4

ステレオタイプ・スレットという問題とニュースレターの果たす役割

竹原裕子, 溝尾妙子, 小林純子, 坂本美咲, 新田薫, 工藤由里絵, 安井和也, 菊池覚次, 黒田新士, 吉田龍一, 岡崎幹生, 杉本誠一郎, 枝園忠彦, 小谷恭弘, 豊岡伸一, 笠原真悟, 藤原俊義, 土井原博義

日本外科学会定期学術集会抄録集 122回 SP - 6 2022.4

ICI・TKI・SBRT時代の肺癌の集学的治療と外科手術局所進行肺がんに対する免疫チェックポイント阻害薬を用いた周術期治療の可能性 WJOG12119L試験

濱田顕, 宗淳一, 大泉弘幸, 坪井正博, 堀之内秀仁, 吉野一郎, 棚橋雅幸, 豊岡伸一, 岡田守人, 横見瀬裕保, 山下素弘, 光冨徹哉

日本外科学会定期学術集会抄録集 122回 SY - 1 2022.4

Paediatric lung transplantation: the impact of age on the survival.

Shinji Otani, Haruchika Yamamoto, Shin Tanaka, Yasuaki Tomioka, Kei Matsubara, Dai Shimizu, Toshio Shiotani, Ken Suzawa, Kentaroh Miyoshi, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

Surgery today 52 ( 11 ) 1540 - 1550 2022.3

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: We herein review the outcomes of paediatric lung transplantation (LTx) and analyse subgroups divided by age. METHODS: We retrospectively reviewed 43 consecutive paediatric LTx recipients (< 18 years old: cadaveric LTx [n = 9], living-donor lobar LTx [n = 34]). We also analysed subgroups of patients 1-6 years old (n = 10) and 7-17 years old (n = 33). RESULTS: The 1-, 5- and 10-year overall survival (OS) rates in paediatric recipients were 93%, 82% and 67%, respectively. The 1-, 5- and 10-year graft dysfunction (GD)-free survival rates in paediatric recipients were 85%, 59% and 31%, respectively. The 1- and 5-year OS in the 1- to 6-year-old vs. 7- to 17-year-old groups were 70% vs. 100% and 48% vs. 93%, respectively (p < 0.0001). The 1- and 5-year GD-free survival rates in the 1- to 6-year-old vs. 7- to 17-year-old groups were 60% vs. 93% and 24% vs. 69%, respectively (p = 0.024). The 1- to 6-year-old group showed higher rates of non-standard LTx (p = 0.0001), interstitial pneumonia (p = 0.004) and ventilator dependency (p = 0.007) than the 7- to 17-year-old group. CONCLUSION: Paediatric recipients under 7 years old seemed to have a higher risk of mortality and GD than those 7 years old and older.

DOI： 10.1007/s00595-022-02492-w

Identification of targetable kinases in idiopathic pulmonary fibrosis. International journal

Hisao Higo, Kadoaki Ohashi, Shuta Tomida, Sachi Okawa, Hiromasa Yamamoto, Seiichiro Sugimoto, Satoru Senoo, Go Makimoto, Kiichiro Ninomiya, Takamasa Nakasuka, Kazuya Nishii, Akihiko Taniguchi, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Nobuaki Miyahara, Yoshinobu Maeda, Shinichi Toyooka, Katsuyuki Kiura

Respiratory research 23 ( 1 ) 20 - 20 2022.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF). METHODS: Thirteen samples from five patients with IPF (Cases 1-5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC). RESULTS: Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions. CONCLUSIONS: We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF.

DOI： 10.1186/s12931-022-01940-y

Completely Video-assisted Thoracoscopic Lobectomy for Congenital Lobar Emphysema in a Young Adult.

Tsuyoshi Ryuko, Hiromasa Yamamoto, Seiichiro Sugimoto, Ken Suzawa, Kentaroh Miyoshi, Shinji Otani, Mikio Okazaki, Masaomi Yamane, Shinichi Toyooka

Acta medica Okayama 76 ( 1 ) 89 - 92 2022.2

Language：English

Congenital lobar emphysema (CLE) is defined as the hyperinflation of pulmonary lobes due to obstruction of the flow of air via a known or unknown etiology, which causes pressure symptoms in the adjacent organs. CLE is mainly diagnosed in the neonatal period, and very few adult cases have been reported. Here we report a 34-year-old male with muscular dystrophy who was diagnosed with CLE on examination. He underwent a right lower lobectomy via 3-portal completely video-assisted thoracoscopic surgery, and his symptoms improved. Thoracoscopic surgery helped preserve the respiratory muscles and led to the improvement of respiratory function in this patient.

DOI： 10.18926/AMO/63217

Acute Pulmonary Edema Due to Arteriovenous Shunt Placement after Lung Transplant. International journal

Dai Shimizu, Kentaroh Miyoshi, Seiichiro Sugimoto, Tomoko Toma, Yusuke Matsuda, Yasuaki Tomioka, Toshio Shiotani, Shinji Otani, Masaomi Yamane, Shinichi Toyooka

The Annals of thoracic surgery 2022.1

Language：English

Lung transplant recipients are often complicated by immunosuppressant-induced nephropathy, which may require renal replacement therapy. We report a case of unilateral lung edema and pulmonary hypertension due to arteriovenous fistula placement in a patient with unilateral chronic lung allograft dysfunction after bilateral living-donor lobar lung transplantation. Lung transplant recipients with limited residual vascular beds, such as lobar graft or severe deviation in lung perfusion, are vulnerable to the acute increase in blood flow due to arteriovenous fistula placement and can easily develop pulmonary edema regardless of the left ventricular function. Hence, careful volume control is required.

DOI： 10.1016/j.athoracsur.2021.12.017

Pulmonary Enteric Adenocarcinoma Harboring a BRAF G469V Mutation.

Dai Shimizu, Hiromasa Yamamoto, Kazuhiko Shien, Kohei Taniguchi, Kentaroh Miyoshi, Kei Namba, Kumi Mesaki, Seiichiro Sugimoto, Junichi Soh, Masaomi Yamane, Shinichi Toyooka

Acta medica Okayama 75 ( 6 ) 759 - 762 2021.12

Language：English

Pulmonary enteric adenocarcinoma (PEAC) is a rare subtype of lung cancer that should be differentiated from colorectal cancer metastasis. Little is known about its genetic background. An 84-year-old male with adenocarcinoma of the lung underwent left upper lobectomy. The histology of the surgical specimen was suggestive of PEAC. Gastrointestinal and colorectal fiberscopy revealed no evidence of colorectal cancer. Next-generation sequencing of the tumor identified a G469V substitution in serine/threonine-protein kinase B-raf (BRAF). Based on the higher prevalence of the G469 substitution in BRAF-mutant lung adenocarcinoma than in BRAFmutant colorectal cancer, the tumor likely originated from the lung. Identification of mutational genotype may be of some help in distinguishing PEAC from the lung metastasis of colorectal cancer.

DOI： 10.18926/AMO/62819

当院におけるロボット支援下肺区域切除術の手術成績 CVATS区域切除術と比較して

岡崎幹生, 三好健太郎, 山本寛斉, 山根正修, 豊岡伸一

日本内視鏡外科学会雑誌 26 ( 7 ) MO244 - 2 2021.12

YES1 as a Therapeutic Target for HER2-Positive Breast Cancer after Trastuzumab and Trastuzumab-Emtansine (T-DM1) Resistance Development. International journal

Miwa Fujihara, Tadahiko Shien, Kazuhiko Shien, Ken Suzawa, Tatsuaki Takeda, Yidan Zhu, Tomoka Mamori, Yusuke Otani, Ryo Yoshioka, Maya Uno, Yoko Suzuki, Yuko Abe, Minami Hatono, Takahiro Tsukioki, Yuko Takahashi, Mariko Kochi, Takayuki Iwamoto, Naruto Taira, Hiroyoshi Doihara, Shinichi Toyooka

International journal of molecular sciences 22 ( 23 ) 2021.11

Language：English Publishing type：Research paper (scientific journal)

Trastuzumab-emtansine (T-DM1) is a therapeutic agent molecularly targeting human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it is especially effective for MBC with resistance to trastuzumab. Although several reports have described T-DM1 resistance, few have examined the mechanism underlying T-DM1 resistance after the development of acquired resistance to trastuzumab. We previously reported that YES1, a member of the Src family, plays an important role in acquired resistance to trastuzumab in HER2-amplified breast cancer cells. We newly established a trastuzumab/T-DM1-dual-resistant cell line and analyzed the resistance mechanisms in this cell line. At first, the T-DM1 effectively inhibited the YES1-amplified trastuzumab-resistant cell line, but resistance to T-DM1 gradually developed. YES1 amplification was further enhanced after acquired resistance to T-DM1 became apparent, and the knockdown of the YES1 or the administration of the Src inhibitor dasatinib restored sensitivity to T-DM1. Our results indicate that YES1 is also strongly associated with T-DM1 resistance after the development of acquired resistance to trastuzumab, and the continuous inhibition of YES1 is important for overcoming resistance to T-DM1.

DOI： 10.3390/ijms222312809

Long-term outcomes of living-donor lobar lung transplantation. International journal

Seiichiro Sugimoto, Hiroshi Date, Kentaroh Miyoshi, Shinji Otani, Megumi Ishihara, Masaomi Yamane, Shinichi Toyooka

The Journal of thoracic and cardiovascular surgery 2021.11

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Although living-donor lobar lung transplantation (LDLLT) enables an intermediate survival similar to cadaveric lung transplantation, the long-term outcome remains unknown. We examined the long-term outcomes of 30 patients who received LDLLT more than 16 years previously. METHODS: We retrospectively reviewed the clinical data of 30 patients who underwent LDLLT (bilateral LDLLT, 29 patients; single LDLLT, 1 pediatric patient) between October 1998 and April 2004. RESULTS: LDLLT was performed for 25 female and 5 male patients ranging in age from 8 to 55 years. The diagnoses included pulmonary hypertension (n = 11), pulmonary fibrosis (n = 7), bronchiolitis obliterans (n = 5), and others (n = 7). At a median follow-up of 205 months, 22 patients were alive and 8 were dead. The causes of death were infection (n = 3), malignancy (n = 2), acute rejection (n = 2), and chronic lung allograft dysfunction (CLAD; n = 1). Unilateral CLAD occurred in 17 patients (56.7%), but only 1 of these patients subsequently developed bilateral CLAD. Two patients underwent bilateral cadaveric lung retransplantations. The 5-, 10-, and 15-year CLAD-free survival rates were 80.0%, 62.8%, and 44.3%, respectively. Malignancy occurred in 7 patients. Two of 5 patients with chronic kidney disease requiring hemodialysis underwent living-donor kidney transplantation. The 5-, 10-, and 15-year overall survival rates were 96.7%, 86.7%, and 73.3%, respectively. CONCLUSIONS: Although only 2 lobes are implanted, LDLLT provides encouraging long-term outcomes. In patients with unilateral CLAD, the functioning contralateral graft might contribute to a favorable long-term outcome.

DOI： 10.1016/j.jtcvs.2021.08.090

情熱・努力を継続できる外科教育外科マネージメントセンターによる情熱のある外科医教育・育成システム

菊地覚次, 吉田龍一, 黒田新士, 野間和広, 安井和也, 笠原真悟, 豊岡伸一, 土井原博義, 藤原俊義

日本外科学会雑誌 122 ( 6 ) 680 - 682 2021.11

Effect of preoperative long-term use of corticosteroids on the development of post-transplant lymphoproliferative disorders after lung transplantation: a single-center experience in Japan

Dai Shimizu, Shinji Otani, Seiichiro Sugimoto, Haruchika Yamamoto, Yasuaki Tomioka, Toshio Shiotani, Kentaroh Miyoshi, Mikio Okazaki, Masaomi Yamane, Shinichi Toyooka

Surgery Today 2021.10

Oncogenic potential of human pluripotent stem cell-derived lung organoids with HER2 overexpression. International journal

Akihiro Miura, Daisuke Yamada, Masahiro Nakamura, Shuta Tomida, Dai Shimizu, Yan Jiang, Tomoka Takao, Hiromasa Yamamoto, Ken Suzawa, Kazuhiko Shien, Masaomi Yamane, Masakiyo Sakaguchi, Shinichi Toyooka, Takeshi Takarada

International journal of cancer 149 ( 8 ) 1593 - 1604 2021.10

Language：English Publishing type：Research paper (scientific journal)

Lung adenocarcinoma (LUAD) is the most common types among lung cancers generally arising from terminal airway and understanding of multistep carcinogenesis is crucial to develop novel therapeutic strategy for LUAD. Here we used human induced pluripotent stem cells (hiPSCs) to establish iHER2-hiPSCs in which doxycycline induced the expression of the oncoprotein human epidermal growth factor receptor 2 (HER2)/ERBB2. Lung progenitors that differentiated from iHER2-hiPSCs, which expressed NKX2-1/TTF-1 known as a lung lineage maker, were cocultured with human fetal fibroblast and formed human lung organoids (HLOs) comprising alveolar type 2-like cells. HLOs that overexpressed HER2 transformed to tumor-like structures similar to atypical adenomatous hyperplasia, which is known for lung precancerous lesion and upregulated the activities of oncogenic signaling cascades such as RAS/RAF/MAPK and PI3K/AKT/mTOR. The degree of morphological irregularity and proliferation capacity were significantly higher in HLOs from iHER2-hiPSCs. Moreover, the transcriptome profile of the HLOs shifted from a normal lung tissue-like state to one characteristic of clinical LUAD with HER2 amplification. Our results suggest that hiPSC-derived HLOs may serve as a model to recapitulate the early tumorigenesis of LUAD and would provide new insights into the molecular basis of tumor initiation and progression.

DOI： 10.1002/ijc.33713

基礎からわかるゲノム医療がんゲノム医療と肺がん

豊岡伸一, 蓮岡佳代子, 久保寿夫, 遠西大輔, 冨田秀太

肺癌 61 ( 6 ) 522 - 522 2021.10

血漿Histidine-rich glycoprotein濃度と肺移植後一時移植機能不全との関係

塩谷俊雄, 杉本誠一郎, 富岡泰章, 田中真, 諏澤憲, 枝園和彦, 三好健太郎, 山本寛斉, 岡崎幹生, 山根正修, 豊岡伸一

日本胸部外科学会定期学術集会 74回 LOD17 - 1 2021.10

Protective effects of anti-HMGB1 monoclonal antibody on lung ischemia reperfusion injury in mice

Kentaro Nakata, Mikio Okazaki, Dai Shimizu, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Daiki Ousaka, Toshiaki Ohara, Akihiro Matsukawa, Masahiro Nishibori, Shinichi Toyooka

Biochemical and Biophysical Research Communications 573 164 - 170 2021.10

綿密な術前準備を行った低肺機能患者の両側続発性高度気胸の1手術例

土生智大, 諏澤憲, 坂田龍平, 久保友次郎, 岩田一馬, 松田直樹, 富岡泰章, 塩谷俊雄, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

日本胸部外科学会定期学術集会 74回 LCPA2 - 1 2021.10

片肺移植における二次性肺高血圧の影響当院の片側脳死肺移植症例の検討から

清水大, 三好健太郎, 杉本誠一郎, 久保友次郎, 川名伸一, 富岡泰章, 松原慧, 田中真, 岡崎幹生, 山根正修, 豊岡伸一

日本胸部外科学会定期学術集会 74回 LOP15 - 2 2021.10

複雑気管支形成の適応、手術手技と成績局所進行非小細胞肺癌に対する導入化学放射線療法後の複雑気管支形成術

山本寛斉, 田中真, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

日本胸部外科学会定期学術集会 74回 LPD2 - 7 2021.10

気管支断端被覆の適応と方法局所進行非小細胞肺癌に対する術前化学放射線療法後肺切除術における気管支断端および吻合部被覆の検討

土生智大, 山本寛斉, 田中真, 諏澤憲, 枝園和彦, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

日本胸部外科学会定期学術集会 74回 LDB2 - 5 2021.10

Current status of inhaled nitric oxide therapy for lung transplantation in Japan: a nationwide survey

Nobuyuki Yoshiyasu, Masaaki Sato, Daisuke Nakajima, Yasuaki Tomioka, Yui Watanabe, Takeshi Shiraishi, Soichiro Funaki, Sumiko Maeda, Koichi Tomoshige, Takahiro Nakajima, Tomoshi Tsuchiya, Seiichiro Sugimoto, Ichiro Yoshino, Takeshi Nagayasu, Masayuki Chida, Masato Minami, Yoshinori Okada, Shinichi Toyooka, Hiroshi Date, Jun Nakajima

GENERAL THORACIC AND CARDIOVASCULAR SURGERY 69 ( 10 ) 1421 - 1431 2021.10

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

Objectives Currently, inhaled nitric oxide (NO) therapy for lung transplantation is not covered by public health insurance in Japan. In this study, we evaluated the perioperative use and safety of inhaled NO therapy for lung transplantation. Methods Data regarding the duration of treatment and adverse events of inhaled NO therapy were collected for all lung transplantations performed from January 1, 2015, to December 31, 2019, at nine lung transplant facilities in Japan. Results During the study period, lung transplants were performed in 357 patients, among whom inhaled NO therapy was administered to 349 patients (98%). The median initial and median maximum inhaled NO doses were 10 and 20 ppm, respectively. Inhaled NO therapy was introduced during surgery and continued postoperatively in 313 patients (90%) for a median of 4 days. Significant improvements in oxygenation and decreases in pulmonary arterial pressure were observed in patients receiving inhaled NO therapy. Side effects of inhaled NO therapy, such as methemoglobinemia, were observed in 15 patients (4%), with a significant incidence in patients aged < 18 years. Conclusions Inhaled NO therapy was performed in almost all patients who underwent lung transplantation in Japan and showed reasonable efficacy. Therefore, public health insurance coverage for inhaled NO therapy during lung transplantation is recommended.

DOI： 10.1007/s11748-021-01648-8

Meticulous closure of collateral vessels in the perihilar mediastinal pleura to control intraoperative bleeding during lung transplantation for pulmonary hypertension. International journal

Haruchika Yamamoto, Seiichiro Sugimoto, Kentaro Imanishi, Kohei Hashimoto, Kentaroh Miyoshi, Shinji Otani, Masaomi Yamane, Shinichi Toyooka

Journal of thoracic disease 13 ( 10 ) 5658 - 5669 2021.10

Language：English Publishing type：Research paper (scientific journal)

Background: Massive blood transfusion compensating hemorrhage during lung transplantation (LT) results in primary graft dysfunction (PGD) and worse outcomes after LT. Collateral vessels in the perihilar mediastinal pleura could be the source of hemorrhage during LT in patients with pulmonary hypertension (PH). The purpose of this study was to examine the effect of closure with hemoclips of the vessels in the perihilar mediastinal pleura on the risk of intraoperative hemorrhage and outcomes after LT in patients with PH. Methods: We retrospectively reviewed 80 patients who underwent LT, including 13 patients with primary PH, 29 patients with secondary PH, and 38 patients with non-PH. Results: The median number of hemoclips was significantly higher in the primary PH group than in the non-PH group (P=0.0045) or secondary PH group (P=0.0060). The intraoperative blood loss, transfusion volume, maximum PGD grade, and the 30-day and 90-day mortality rates in the primary PH group were equivalent to those in the other two groups. Conclusions: Meticulous closure of collateral vessels in the perihilar mediastinal pleura during LT in patients with primary PH allowed intraoperative hemorrhage to be controlled and might be associated with acceptable mortality rate in these patients similar to that of LT in patients with other diseases.

DOI： 10.21037/jtd-21-1119

未来のための今大河の時代に入った心臓移植・肺移植心停止下肺移植本邦での挑戦

田中真, Mejia Lucas Hoyos, Gomez-De-Antonioa David, 松原慧, 枝園和彦, 諏澤憲, 三好健太郎, 山本寛斉, 岡崎幹生, 杉本誠一郎, 豊岡伸一

日本胸部外科学会定期学術集会 74回 SP7 - 6 2021.10

Current status of inhaled nitric oxide therapy for lung transplantation in Japan: a nationwide survey.

Nobuyuki Yoshiyasu, Masaaki Sato, Daisuke Nakajima, Yasuaki Tomioka, Yui Watanabe, Takeshi Shiraishi, Soichiro Funaki, Sumiko Maeda, Koichi Tomoshige, Takahiro Nakajima, Tomoshi Tsuchiya, Seiichiro Sugimoto, Ichiro Yoshino, Takeshi Nagayasu, Masayuki Chida, Masato Minami, Yoshinori Okada, Shinichi Toyooka, Hiroshi Date, Jun Nakajima

General thoracic and cardiovascular surgery 69 ( 10 ) 1421 - 1431 2021.10

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Currently, inhaled nitric oxide (NO) therapy for lung transplantation is not covered by public health insurance in Japan. In this study, we evaluated the perioperative use and safety of inhaled NO therapy for lung transplantation. METHODS: Data regarding the duration of treatment and adverse events of inhaled NO therapy were collected for all lung transplantations performed from January 1, 2015, to December 31, 2019, at nine lung transplant facilities in Japan. RESULTS: During the study period, lung transplants were performed in 357 patients, among whom inhaled NO therapy was administered to 349 patients (98%). The median initial and median maximum inhaled NO doses were 10 and 20 ppm, respectively. Inhaled NO therapy was introduced during surgery and continued postoperatively in 313 patients (90%) for a median of 4 days. Significant improvements in oxygenation and decreases in pulmonary arterial pressure were observed in patients receiving inhaled NO therapy. Side effects of inhaled NO therapy, such as methemoglobinemia, were observed in 15 patients (4%), with a significant incidence in patients aged < 18 years. CONCLUSIONS: Inhaled NO therapy was performed in almost all patients who underwent lung transplantation in Japan and showed reasonable efficacy. Therefore, public health insurance coverage for inhaled NO therapy during lung transplantation is recommended.

DOI： 10.1007/s11748-021-01648-8

包括的ゲノムプロファイリングを用いた神経内分泌癌の治療探索と生殖細胞系列の推定

山本英喜, 河内麻里子, 堀口繁, 榮浩行, 久保寿夫, 二宮貴一朗, 西森久和, 高本篤, 遠西大輔, 冨田秀太, 宮本理史, 田端雅弘, 柳井広之, 豊岡伸一, 平沢晃

日本癌治療学会学術集会抄録集 59回 O73 - 3 2021.10

肉腫多発肺転移に対する肺切除術

山本寛斉, 田中真, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 61 ( 6 ) 663 - 663 2021.10

当院での様々な開胸アプローチの経験

田中真, 富岡泰章, 枝園和彦, 諏澤憲, 三好健太郎, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 61 ( 6 ) 572 - 572 2021.10

小型肺癌の標準治療はどう変わる? 臨床病期IA期の画像的浸潤型肺癌に対する縮小切除の意義肺癌登録合同委員会データベース研究

宗淳一, 豊岡伸一, 新谷康, 岡見次郎, 伊藤宏之, 大塚崇, 森毅, 渡辺俊一, 淺村尚生, 千田雅之, 遠藤俊輔, 中西良一, 門倉光隆, 鈴木秀海, 宮岡悦良, 吉野一郎, 伊達洋至

肺癌 61 ( 6 ) 515 - 515 2021.10

複雑気管支形成の適応、手術手技と成績局所進行非小細胞肺癌に対する導入化学放射線療法後の複雑気管支形成術

山本寛斉, 田中真, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

日本胸部外科学会定期学術集会 74回 LPD2 - 7 2021.10

片肺移植における二次性肺高血圧の影響当院の片側脳死肺移植症例の検討から

清水大, 三好健太郎, 杉本誠一郎, 久保友次郎, 川名伸一, 富岡泰章, 松原慧, 田中真, 岡崎幹生, 山根正修, 豊岡伸一

日本胸部外科学会定期学術集会 74回 LOP15 - 2 2021.10

血漿Histidine-rich glycoprotein濃度と肺移植後一時移植機能不全との関係

塩谷俊雄, 杉本誠一郎, 富岡泰章, 田中真, 諏澤憲, 枝園和彦, 三好健太郎, 山本寛斉, 岡崎幹生, 山根正修, 豊岡伸一

日本胸部外科学会定期学術集会 74回 LOD17 - 1 2021.10

気管支断端被覆の適応と方法局所進行非小細胞肺癌に対する術前化学放射線療法後肺切除術における気管支断端および吻合部被覆の検討

土生智大, 山本寛斉, 田中真, 諏澤憲, 枝園和彦, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

日本胸部外科学会定期学術集会 74回 LDB2 - 5 2021.10

綿密な術前準備を行った低肺機能患者の両側続発性高度気胸の1手術例

土生智大, 諏澤憲, 坂田龍平, 久保友次郎, 岩田一馬, 松田直樹, 富岡泰章, 塩谷俊雄, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

日本胸部外科学会定期学術集会 74回 LCPA2 - 1 2021.10

未来のための今大河の時代に入った心臓移植・肺移植心停止下肺移植本邦での挑戦

田中真, Mejia Lucas Hoyos, Gomez-De-Antonioa David, 松原慧, 枝園和彦, 諏澤憲, 三好健太郎, 山本寛斉, 岡崎幹生, 杉本誠一郎, 豊岡伸一

日本胸部外科学会定期学術集会 74回 SP7 - 6 2021.10

OSNA法を用いた肺がん所属リンパ節転移診断の臨床有用性の検討

諏澤憲, 難波圭, 枝園和彦, 三浦章博, 荒木恒太, 宮内俊策, 中田憲太郎, 富岡泰章, 田中真, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 61 ( 6 ) 666 - 666 2021.10

小型肺癌の標準治療はどう変わる? 臨床病期IA期の画像的浸潤型肺癌に対する縮小切除の意義肺癌登録合同委員会データベース研究

宗淳一, 豊岡伸一, 新谷康, 岡見次郎, 伊藤宏之, 大塚崇, 森毅, 渡辺俊一, 淺村尚生, 千田雅之, 遠藤俊輔, 中西良一, 門倉光隆, 鈴木秀海, 宮岡悦良, 吉野一郎, 伊達洋至

肺癌 61 ( 6 ) 515 - 515 2021.10

岡山大学外科広域外科専門研修プログラム関連病院における専攻医の産前産後休暇・育児休業/休暇・介護休業/休暇、その他支援についての実態調査

竹原裕子, 溝尾妙子, 小林純子, 菊地覚次, 池田宏国, 岡崎幹生, 吉田龍一, 黒田新士, 枝園忠彦, 小谷恭弘, 山根正修, 豊岡伸一, 笠原真悟, 土井原博義, 藤原俊義

日本臨床外科学会雑誌 82 ( 増刊 ) S24 - S24 2021.10

OSNA法を用いた肺がん所属リンパ節転移診断の臨床有用性の検討

諏澤憲, 難波圭, 枝園和彦, 三浦章博, 荒木恒太, 宮内俊策, 中田憲太郎, 富岡泰章, 田中真, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 61 ( 6 ) 666 - 666 2021.10

肉腫多発肺転移に対する肺切除術

山本寛斉, 田中真, 枝園和彦, 諏澤憲, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 61 ( 6 ) 663 - 663 2021.10

岡山大学外科広域外科専門研修プログラム関連病院における専攻医の産前産後休暇・育児休業/休暇・介護休業/休暇、その他支援についての実態調査

竹原裕子, 溝尾妙子, 小林純子, 菊地覚次, 池田宏国, 岡崎幹生, 吉田龍一, 黒田新士, 枝園忠彦, 小谷恭弘, 山根正修, 豊岡伸一, 笠原真悟, 土井原博義, 藤原俊義

日本臨床外科学会雑誌 82 ( 増刊 ) S24 - S24 2021.10

当院での様々な開胸アプローチの経験

田中真, 富岡泰章, 枝園和彦, 諏澤憲, 三好健太郎, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 61 ( 6 ) 572 - 572 2021.10

Lung transplantation for idiopathic multicentric Castleman disease: potential efficacy and tolerability of a humanized anti-interleukin-6 receptor monoclonal antibody. International journal

Yasuaki Tomioka, Shinji Otani, Shin Tanaka, Kazuhiko Shien, Ken Suzawa, Kentaroh Miyoshi, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

Surgical case reports 7 ( 1 ) 209 - 209 2021.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a rare polyclonal lymphoproliferative disease caused by the overrepresentation of interleukin-6 (IL-6). Tocilizumab (TCZ) is a humanized monoclonal antibody that binds to the IL-6 receptor and is approved for the treatment of iMCD. The efficacy and tolerability of TCZ in patients with iMCD undergoing lung transplantation (LTx) remain unknown. CASE PRESENTATION: We present the case of a 48-year-old iMCD patient with end-stage lung disease (ESLD) who was successfully treated with cadaveric single-LTx. Intravenous TCZ was used to stabilize the iMCD patient every 2 weeks, except for withdrawal immediately after LTx. At 32 month post-transplant, the patient remained asymptomatic without evidence of rejection, development of de novo donor-specific antibody (DSA), and recurrent iMCD in the native lung. CONCLUSIONS: Single-LTx can be a feasible treatment option for ESLD caused by iMCD. TCZ can be used safely and may be beneficial in recipients with iMCD, and TCZ in combination with usual immunosuppression can be helpful in stabilizing iMCD patients pre- and post-LTx.

DOI： 10.1186/s40792-021-01297-2

ASO Author Reflections: Impact of the Postoperative Neutrophil-to-Lymphocyte Ratio in Locally Advanced Non-small Cell Lung Cancer Treated with Induction Chemoradiotherapy Followed by Surgery

Shimpei Tsudaka, Hiromasa Yamamoto, Hiroki Sato, Shinichi Toyooka

Annals of Surgical Oncology 28 ( 9 ) 4891 - 4892 2021.9

Pulmonary lymphatic involvement in metastatic uterine sarcomas: imaging and pathological appearance. International journal

Takahiro Kitayama, Takashi Tanaka, Takao Hiraki, Shinichi Toyooka, Hiroyuki Yanai, Susumu Kanazawa

Radiology case reports 16 ( 9 ) 2460 - 2462 2021.9

Language：English

Pulmonary lymphatic involvement of sarcomas is an extremely rare form of metastases. We report the computed tomography (CT) features of pathologically confirmed pulmonary lymphatic involvement from metastatic uterine sarcomas. The CT illustrated smooth or nodular thickenings of the interlobular septa and bronchovascular bundle. Moreover, ground-glass opacity along the interlobular septa was also detected. These findings suggest that lymphatic involvement has diagnostic value for detecting this rare form of metastatic sarcomas. We also discuss possible differential diagnoses in this case and review previous cases reporting pulmonary lymphatic involvement in metastatic sarcomas. To the best of our knowledge, this is the first report describing pulmonary lymphatic involvement in metastatic uterine sarcomas. Pulmonary lymphatic spread of sarcomas is a rare form of metastatic sarcomas, but it should be considered when these findings suggesting lymphatic involvement are detected on CT.

DOI： 10.1016/j.radcr.2021.05.076

肺移植に関連した感染症(待機中から術後慢性期まで) Clostridioides difficile感染症診療ガイドライン作成に伴う当院での肺移植周術期の検討

久保友次郎, 田中真, 石上恵美, 石原恵, 坂田龍平, 富岡泰章, 枝園和彦, 諏澤憲, 大谷真二, 山本寛斉, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

移植 56 ( 総会臨時 ) SSY4 - 4 2021.9

生体肺移植後CLADにおける2019年ISHLT新基準にもとづく予後評価

松原慧, 三好健太郎, 大谷真二, 川名伸一, 久保友次郎, 清水大, 富岡泰章, 田中真, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

移植 56 ( 総会臨時 ) O23 - 1 2021.9

肺移植後の慢性期合併症とその管理肺移植後の慢性腎臓病に対して血液透析を導入した症例の検討

富岡泰章, 杉本誠一郎, 川名伸一, 久保友次郎, 清水大, 松原慧, 田中真, 枝園和彦, 諏澤憲, 三好健太郎, 山本寛斉, 岡崎幹生, 山根正, 豊岡伸一

移植 56 ( 総会臨時 ) SWS8 - 4 2021.9

マウス異所性気管移植モデルを用いたS100A8/A9抗体の慢性移植肺機能不全に対する効果の検討

清水大, 岡崎幹生, 木下理恵, 中田憲太郎, 三好健太郎, 大谷真二, 杉本誠一郎, 山根正修, 阪口政清, 豊岡伸一

移植 56 ( 総会臨時 ) P2 - 11 2021.9

肺移植におけるドナー不足にどう取組むか心停止ドナー肺移植、スペインでの経験を踏まえて

田中真, 石上恵美, 石原恵, 富岡泰章, 枝園和彦, 諏澤憲, 三好健太郎, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

移植 56 ( 総会臨時 ) SSY9 - 4 2021.9

肺移植に関連した感染症(待機中から術後慢性期まで) びまん性汎細気管支炎に対する肺移植後の慢性期管理と長期成績

杉本誠一郎, 三好健太郎, 田中真, 富岡泰章, 石原恵, 石上恵美, 諏澤憲, 枝園和彦, 山本寛斉, 岡崎幹生, 山根正修, 豊岡伸一

移植 56 ( 総会臨時 ) SSY4 - 5 2021.9

肺移植における多職種連携新型コロナウイルス感染症(COVID-19)流行下での肺移植後患者フォローの工夫と課題

石原恵, 杉本誠一郎, 石上恵美, 鶴園真理, 山下里美, 難波由美子, 富岡泰章, 田中真, 三好健太郎, 大谷真二, 山根正修, 豊岡伸一

移植 56 ( 総会臨時 ) SWS3 - 2 2021.9

肺移植におけるドナー不足にどう取組むか心停止ドナー肺移植、スペインでの経験を踏まえて

田中真, 石上恵美, 石原恵, 富岡泰章, 枝園和彦, 諏澤憲, 三好健太郎, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

移植 56 ( 総会臨時 ) SSY9 - 4 2021.9

肺移植後の慢性期合併症とその管理肺移植後の慢性腎臓病に対して血液透析を導入した症例の検討

富岡泰章, 杉本誠一郎, 川名伸一, 久保友次郎, 清水大, 松原慧, 田中真, 枝園和彦, 諏澤憲, 三好健太郎, 山本寛斉, 岡崎幹生, 山根正, 豊岡伸一

移植 56 ( 総会臨時 ) SWS8 - 4 2021.9

肺移植に関連した感染症(待機中から術後慢性期まで) Clostridioides difficile感染症診療ガイドライン作成に伴う当院での肺移植周術期の検討

久保友次郎, 田中真, 石上恵美, 石原恵, 坂田龍平, 富岡泰章, 枝園和彦, 諏澤憲, 大谷真二, 山本寛斉, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

移植 56 ( 総会臨時 ) SSY4 - 4 2021.9

肺移植に関連した感染症(待機中から術後慢性期まで) びまん性汎細気管支炎に対する肺移植後の慢性期管理と長期成績

杉本誠一郎, 三好健太郎, 田中真, 富岡泰章, 石原恵, 石上恵美, 諏澤憲, 枝園和彦, 山本寛斉, 岡崎幹生, 山根正修, 豊岡伸一

移植 56 ( 総会臨時 ) SSY4 - 5 2021.9

生体肺移植後CLADにおける2019年ISHLT新基準にもとづく予後評価

松原慧, 三好健太郎, 大谷真二, 川名伸一, 久保友次郎, 清水大, 富岡泰章, 田中真, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

移植 56 ( 総会臨時 ) O23 - 1 2021.9

マウス異所性気管移植モデルを用いたS100A8/A9抗体の慢性移植肺機能不全に対する効果の検討

清水大, 岡崎幹生, 木下理恵, 中田憲太郎, 三好健太郎, 大谷真二, 杉本誠一郎, 山根正修, 阪口政清, 豊岡伸一

移植 56 ( 総会臨時 ) P2 - 11 2021.9

[Redo Operation for Mediastinal Tumor].

Masaomi Yamane, Shinichi Toyooka

Kyobu geka. The Japanese journal of thoracic surgery 74 ( 10 ) 839 - 844 2021.9

Language：Japanese Publishing type：Research paper (scientific journal)

The mediastinum contains large blood vessels, airways, and spinal cord, which are anatomically important parts of the human body because they survive by injury, obstruction, and compression, and are involved in activities of daily living( ADL). Therefore, even benign tumors have been indicated for aggressive surgical intervention. Dissection procedures from these anatomically important structures is extremely risky and difficult in reoperation for recurrence of mediastinal tumors, so careful consideration and attention must be paid to the surgical indications and methods. In this paper, we have described the points to be noted and points regarding the reoperation of mediastinal tumors with some review of the literature, including our own cases.

Sarcopenia is related to poor prognosis in patients after trimodality therapy for locally advanced non-small cell lung cancer.

Kuniaki Katsui, Takeshi Ogata, Kenta Watanabe, Kotaro Yoshio, Masahiro Kuroda, Masaomi Yamane, Takao Hiraki, Katsuyuki Kiura, Shinichi Toyooka, Susumu Kanazawa

International journal of clinical oncology 26 ( 8 ) 1450 - 1460 2021.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The association between sarcopenia and prognosis in patients with locally advanced non-small cell lung cancer (NSCLC) undergoing trimodality therapy, consisting of preoperative concurrent chemoradiotherapy and surgery, has not been reported. Therefore, we aimed to investigate the association of sarcopenia and fat mass with prognosis after trimodality therapy. METHODS: To assess sarcopenia, the psoas muscle mass was measured. Using computed tomography data, including third lumbar vertebra level images, psoas muscle mass and visceral and subcutaneous fat mass were measured. Additionally, body mass indices, and visceral/subcutaneous fat ratio, obtained by dividing the visceral fat index by the subcutaneous fat index, were calculated. We investigated the relationship between these parameters and overall survival. RESULTS: Ninety-nine eligible patients were included. In the univariate analysis, age, clinical stage, tumor location, psoas muscle index, and visceral/subcutaneous fat ratio were significant prognostic factors for overall survival (P = 0.008, P = 0.04, P = 0.04, P = 0.02, and P = 0.02, respectively). In the multivariate analysis, age and psoas muscle index were significant prognostic factors for overall survival (P = 0.01 and P = 0.03, respectively). The 5-year overall survival rates for the high and low psoas muscle index groups were 79.6% [95% confidence interval (CI), 67.1-94.5%] and 66.2% (95% CI, 54.1-81.1%), respectively; whereas, the 10-year overall survival rates were 61.9% (95% CI, 42.0-91.4%) and 25.3% (95% CI, 8.6-74.2%), respectively. CONCLUSION: Sarcopenia was related to poor overall survival in patients with locally advanced NSCLC undergoing trimodality therapy. Assessment of body composition prior to treatment may provide important information for formulating rational therapeutic strategies.

DOI： 10.1007/s10147-021-01927-7

Robot-assisted thoracoscopic lobectomy for severe incomplete interlober fissure. International journal

Mikio Okazaki, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

Journal of surgical case reports 2021 ( 8 ) rjab336 2021.8

Language：English Publishing type：Research paper (scientific journal)

An incomplete interlobar fissure makes thoracoscopic lobectomy difficult and is predictive of morbidity after thoracoscopic lobectomy. This report demonstrates the robot-assisted thoracoscopic (RATS) lobectomy technique for patients with severe incomplete interlobar fissures. A fissureless approach was chosen for pulmonary resection. Near-infrared fluorescence imaging with intravenous indocyanine green (ICG) was used to detect the interlobar line after transection of the bronchus, pulmonary artery and vein. Interlobar fissure was identified and divided by robotic staplers. This combined technique using ICG and fissureless lobectomy made RATS lobectomy safe for patients with severe incomplete interlobar fissures.

DOI： 10.1093/jscr/rjab336

Emphysematous changes and lower levels of plasma irisin are associated with bronchiolitis obliterans syndrome after bilateral living-donor lobar lung transplantation.

Toshio Shiotani, Seiichiro Sugimoto, Haruchika Yamamoto, Kentaroh Miyoshi, Shinji Otani, Ken Suzawa, Hiromasa Yamamoto, Mikio Okazaki, Masaomi Yamane, Shinichi Toyooka

Surgery today 52 ( 2 ) 294 - 305 2021.7

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Decreased irisin levels may be associated with the development of emphysema. Similarly, emphysematous changes may develop in patients with chronic lung allograft dysfunction (CLAD) after living-donor lobar lung transplantation (LDLLT). We investigated the severity of emphysematous changes and the relationship between irisin levels and CLAD after bilateral LDLLT and cadaveric lung transplantation (CLT). METHODS: The subjects of this retrospective study were 59 recipients of bilateral LDLLT (n = 31) or CLT (n = 28), divided into a non-CLAD group (n = 41), a LDLLT-CLAD group (n = 11), and a CLT-CLAD group (n = 7). We compared the severity of emphysematous changes, the skeletal muscle mass, and the plasma irisin levels among the groups. RESULTS: The emphysematous changes were significantly more severe in the LDLLT-CLAD and CLT-CLAD groups (p = 0.046 and 0.036), especially in patients with bronchiolitis obliterans syndrome (BOS), than in the non-CLAD group. Although the skeletal muscle mass was similar in all the groups, the plasma irisin levels were significantly lower in the LDLLT-CLAD group (p = 0.022), especially in the patients with BOS after LDLLT, than in the non-CLAD group. CONCLUSION: Emphysematous changes and lower levels of plasma irisin were associated with CLAD, especially in patients with BOS, after bilateral LDLLT.

DOI： 10.1007/s00595-021-02339-w

Publisher Correction: Sarcopenia is associated with poor prognosis after chemoradiotherapy in patients with stage III non-small-cell lung cancer: a retrospective analysis. International journal

Kuniaki Katsui, Takeshi Ogata, Soichi Sugiyama, Kotaro Yoshio, Masahiro Kuroda, Takao Hiraki, Katsuyuki Kiura, Yoshinobu Maeda, Shinichi Toyooka, Susumu Kanazawa

Scientific reports 11 ( 1 ) 14586 - 14586 2021.7

Appropriate use of cancer comprehensive genome profiling assay using circulating tumor DNA

Kuniko Sunami, Hideaki Bando, Yasushi Yatabe, Yoichi Naito, Hideaki Takahashi, Katsuya Tsuchihara, Shinichi Toyooka, Koshi Mimori, Shinji Kohsaka, Hiroyuki Uetake, Ichiro Kinoshita, Keigo Komine, Masayuki Takeda, Tetsu Hayashida, Kenji Tamura, Kazuto Nishio, Noboru Yamamoto

Cancer Science 2021.7

Lung transplantation for bronchiectasis due to hyper-immunoglobulin E syndrome. International journal

Dai Shimizu, Shinji Otani, Seiichiro Sugimoto, Haruchika Yamamoto, Yasuaki Tomioka, Toshio Shiotani, Kentaroh Miyoshi, Mikio Okazaki, Masaomi Yamane, Shinichi Toyooka

The Annals of thoracic surgery 113 ( 4 ) e251-e253 2021.7

Language：English

Hyper-immunoglobulin E syndrome (HIES) is one of the primary immunodeficiencies characterized by recurrent staphylococcal skin and lung infections that result in lung destruction and critically diminished pulmonary function. Despite the lack of definitive treatment, there have been no reports of successful lung transplantation (LTx) for HIES patients. We report the case of a 42-year-old female HIES patient with progressive bronchiectasis whose pulmonary infection was controlled prior to transplantation and subsequent LTx was uneventful. LTx may be feasible in HIES if the patient is immunologically stable preoperatively, and peri-operative infections, especially Aspergillus infections, are well-controlled.

DOI： 10.1016/j.athoracsur.2021.05.088

A New Scoring System for Predicting the Survival of Sarcoma Patients with Pulmonary Metastases: Sarcoma Lung Metastasis Score

Haruchika Yamamoto, Hiromasa Yamamoto, Shinichi Toyooka

Annals of Surgical Oncology 28 ( 7 ) 3891 - 3892 2021.7

Chronic Lung Injury After Trimodality Therapy for Locally Advanced Non-Small Cell Lung Cancer. International journal

Junichi Soh, Seiichiro Sugimoto, Kei Namba, Akihiro Miura, Toshio Shiotani, Haruchika Yamamoto, Ken Suzawa, Kazuhiko Shien, Hiromasa Yamamoto, Mikio Okazaki, Kuniaki Katsui, Masaomi Yamane, Katsuyuki Kiura, Susumu Kanazawa, Shinichi Toyooka

The Annals of thoracic surgery 112 ( 1 ) 279 - 288 2021.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Trimodality therapy is a treatment option for patients with locally advanced non-small cell lung cancer (LA-NSCLC). Thoracic radiation has both early (radiation pneumonitis) and late (chronic lung injury [CLI]) adverse effects on the lung. While CLI is expected to result in various problems in long-term survivors, these manifestations have not been precisely investigated. METHODS: We enrolled 112 LA-NSCLC patients who had received induction chemoradiotherapy followed by surgery, and then undergone follow-up computed tomography (CT) every 6 months for greater than 1 year. All chest CT images were reviewed to evaluate any injury of the pulmonary parenchyma. RESULTS: CLI at 1 year after surgery and its progression were observed in 94 (84%) and 38 (34%) patients, respectively. Progressive lung fibrosis as the first manifestation of CLI progression was most frequent after right middle and lower lobectomy. Cavity formation was the subsequent manifestation after progressive lung fibrosis , and chronic infection was the final stage of CLI. The cumulative rate of chronic infection was 76.4% at 10 years in patients with cavity formation. Ten patients with chronic infection included 7 cases of pulmonary aspergillosis and 2 cases of cavity infections with methicillin-resistant Staphylococcus aureus or Stenotrophomonas maltophilia. Among them, 4 patients required surgical interventions including completion pneumonectomy or fenestration. CONCLUSIONS: CLI is a common incidence after trimodality therapy for LA-NSCLC. CLI frequently results in cavity formation, which is a precursor of highly refractory chronic infections requiring surgical intervention. Appropriate management needs to be established for CLI developing after trimodality therapy.

DOI： 10.1016/j.athoracsur.2020.07.068

肺移植後成績の芳しくないレシピエント群-乳幼児肺移植

大谷真二, 石原恵, 石上恵美, 松原慧, 清水大, 富岡泰章, 山本治慎, 塩谷俊雄, 諏澤憲, 三好健太郎, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

移植 56 ( 1 ) 76 - 76 2021.7

脊柱側彎症患者に対する脳死両肺移植、術後合併症の経験

山本治慎, 大谷真二, 清水大, 松原慧, 富岡泰章, 塩谷俊雄, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

移植 56 ( 1 ) 102 - 102 2021.7

シャント造設を契機に片側肺の肺水腫及び肺高血圧を来した両側生体肺移植後CLADの一例

清水大, 三好健太郎, 東馬智子, 松田裕介, 松原慧, 富岡泰章, 塩谷俊雄, 山本治慎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

移植 56 ( 1 ) 104 - 104 2021.7

本邦における肺移植時の一酸化窒素ガス(NO)使用状況に関する実態調査

吉安展将, 佐藤雅昭, 中島大輔, 富岡泰章, 渡辺有為, 白石武史, 舟木壮一郎, 前田寿美子, 朝重耕一, 中島崇裕, 土谷智史, 杉本誠一郎, 吉野一郎, 永安武, 千田雅之, 南正人, 岡田克典, 豊岡伸一, 伊達洋至, 中島淳

移植 56 ( 1 ) 88 - 88 2021.7

BKウイルス感染症による出血性膀胱炎で周術期治療に難渋した小児生体肺移植の1例

富岡泰章, 大谷真二, 石上恵美, 石原恵, 松原慧, 清水大, 山本治慎, 塩谷俊雄, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

移植 56 ( 1 ) 100 - 100 2021.7

"Hybrid Lung Transplantation" Combining Living Donor and Cadaveric Lung Transplants: Report of 2 Cases. International journal

Takeshi Kurosaki, Takahiro Oto, Shinji Otani, Kentaroh Miyoshi, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

Transplantation proceedings 2021.6

Language：English Publishing type：Research paper (scientific journal)

We present 2 cases of "hybrid lung transplant," which included sequentially implanting a living lobar graft to 1 side and a cadaveric graft to the other side. This procedure was approved by the institutional review board at Okayama University Hospital. The 2 recipients were diagnosed with severe idiopathic pulmonary fibrosis, and living donor lobar lung transplant was considered; however, 2 appropriate donors were not available. Therefore, we accepted extended criteria donor lungs with a partial pressure of oxygen/fraction of inspired oxygen ratio of <251 mm Hg. However, 1 of the 2 patients developed grade 2 primary graft dysfunction. The living donor lobar lung had a low volume but was in good condition, which contributed to the patient's recovery after primary graft dysfunction during the perioperative period. The other patient's status of bronchiolitis obliterans syndrome had gradually progressed to grade 3, and only the living donor lung was functioning at that time. However, both patients are alive 5.5 and 4.2 years after lung transplant, respectively. Hybrid lung transplantation may increase patients' chances of receiving transplants because patients are not likely to survive while waiting for ideal donor lungs to become available.

DOI： 10.1016/j.transproceed.2021.04.019

Sarcopenia is associated with poor prognosis after chemoradiotherapy in patients with stage III non-small-cell lung cancer: a retrospective analysis. International journal

Kuniaki Katsui, Takeshi Ogata, Soichi Sugiyama, Kotaro Yoshio, Masahiro Kuroda, Takao Hiraki, Katsuyuki Kiura, Yoshinobu Maeda, Shinichi Toyooka, Susumu Kanazawa

Scientific reports 11 ( 1 ) 11882 - 11882 2021.6

Language：English Publishing type：Research paper (scientific journal)

We intended to investigate whether muscle and adipose masses were associated with prognosis among patients with stage III non-small-cell lung cancer (NSCLC) who were undergoing chemoradiotherapy (CCRT). We retrospectively explored data of patients with stage III NSCLC who underwent definitive CCRT (≥ 60 Gy) between January 2004 and March 2018 at our hospital. We examined the relationship of overall survival (OS) with body mass index (BMI), skeletal muscle index (SMI), psoas muscle index (PMI), visceral adipose tissue index (VAI), subcutaneous adipose tissue index (SAI), and visceral-to-subcutaneous adipose tissue area ratio (VSR) using log-rank tests for the univariate analysis and Cox proportional hazard models for the multivariate analysis. Overall, 16, 32, and 12 patients had stage IIIA, IIIB, and IIIC NSCLC, respectively. The total radiotherapy dose ranged from 60 Gy/30 fractions to 66 Gy/33 fractions. In the univariate analysis, the performance status (PS), BMI, and SMI were associated with OS, whereas the PMI, VAI, SAI, and VSR were not. In the multivariate analysis, the PS and SMI were associated with OS. The hazard ratios and 95% confidence intervals were 2.91 and 1.28-6.64 for PS, and 2.36 and 1.15-4.85 for SMI, respectively. The 1, 3, and 5-year OS rates were 92.1%, 59.6%, and 51.0% in patients with high SMI, and 63.6%, 53.8%, and 17.9% in patients with low SMI, respectively. The SMI correlated with prognosis in our study population, whereas adipose mass did not. Therefore, sarcopenia should be considered while predicting the OS in such patients.

DOI： 10.1038/s41598-021-91449-z

Clinical Outcome of Palliative Concurrent Chemoradiotherapy with Cisplatin/Docetaxel for Stage III Non-small Cell Lung Cancer.

Kuniaki Katsui, Takeshi Ogata, Kenta Watanabe, Kotaro Yoshio, Masahiro Kuroda, Takao Hiraki, Katsuyuki Kiura, Yoshinobu Maeda, Shinichi Toyooka, Susumu Kanazawa

Acta medica Okayama 75 ( 3 ) 269 - 277 2021.6

Language：English Publishing type：Research paper (scientific journal)

Palliative concurrent chemoradiotherapy (CCRT) is often administered to patients with stage III non-small cell lung cancer (NSCLC). We investigated the clinical outcomes of patients receiving palliative CCRT for NSCLC. Data of patients with NSCLC who underwent palliative CCRT (n=16), preoperative CCRT plus surgery (n=97), or definitive CCRT (n=48) were evaluated. In all groups, the concurrent chemotherapy regimens consisted of cisplatin and docetaxel. Rates of local control (LC), distant metastasis-free survival (DMFS), progression-free survival (PFS), overall survival (OS), and prognosis were compared. The 2-year rates of LC, DMFS, PFS, and OS in 16 patients who underwent palliative CCRT were 44.4%, 12.5%, 12.5%, and 18.8%, respectively. Univariate analysis showed that palliative CCRT was associated with poor LC (p<0.001), DMFS (p<0.001), PFS (p<0.001), and OS (p<0.001) outcomes in patients who completed CCRT as a preoperative treatment and poor LC (p=0.01), DMFS (p=0.003), PFS (p=0.04), and OS (p=0.004) outcomes in patients who were considered for definitive CCRT. Although there were some long-term survivors, the clinical outcomes of palliative CCRT were significantly inferior to those of the ideal treatments. Therefore, careful determination of the appropriate treatment indications and further studies are warranted.

DOI： 10.18926/AMO/62218

Robot-assisted intrathoracic procedure for dumbbell tumour in the prone position

Mikio Okazaki, Tomoyuki Takigawa, Ken Suzawa, Shinichi Toyooka

Interactive CardioVascular and Thoracic Surgery 2021.5

Publishing type：Research paper (scientific journal) Publisher：Oxford University Press (OUP)

<title>Abstract</title>
A 24-year-old man presented with a dumbbell-shaped right posterior mediastinal mass. The patient was placed in the prone position following general anaesthesia and intubation. After laminectomy and dissection of the dorsal part of the tumour using a posterior approach were performed, the tumour was completely resected using a robotic approach in the thoracic cavity without repositioning. This is the first report of robotic resection for posterior mediastinal tumour in the prone position as well as a novel combined posterior approach and robotic resection for dumbbell tumours.

DOI： 10.1093/icvts/ivab117

Circulating anti-human leukocyte antigen IgM antibodies as a potential early predictor of allograft rejection and a negative clinical outcome after lung transplantation.

Kazuaki Miyahara, Kentaroh Miyoshi, Takeshi Kurosaki, Shinji Otani, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

Surgery today 2021.5

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Anti-human leukocyte antigen (HLA) immunoglobulin (Ig) M production stimulated by an alloantigen is sensitive, making IgM a novel potential marker of allorejection after organ transplantation. This study examined the relationship between the serum levels of anti-HLA IgM early after clinical lung transplantation (LTx) and the post-transplant outcomes. METHODS: Thirty-one consecutive patients who underwent deceased LTx were included. Immunoreactivity against HLA was retrospectively analyzed by measuring the anti-HLA IgM levels in the serum sampled for the first 14 days after LTx. The flow panel reactive antibody technique was used. The ratio of the anti-class I IgM level at each day to baseline was obtained, and the peak IgM level was determined for each case. The correlation between the peak IgM level and subsequent development of acute rejection (AR), chronic lung allograft dysfunction (CLAD), and survival outcomes were examined. RESULTS: The peak IgM level was a significant risk factor for AR within 90 days in univariate and multivariate analyses. In the long term, the patients with positive IgM (peak level > 1.8) tended to have a poorer CLAD-free and overall survival than those with negative IgM. CONCLUSION: Elevation of anti-HLA IgM levels early after LTx may be correlated with a higher incidence of rejection and negative clinical outcomes.

DOI： 10.1007/s00595-021-02293-7

Randomized phase II study of daily and alternate-day administration of S-1 for adjuvant chemotherapy in completely-resected stage I non-small cell lung cancer: results of the Setouchi Lung Cancer Group Study 1301. International journal

Norihito Okumura, Junichi Soh, Hiroyuki Suzuki, Masao Nakata, Toshiya Fujiwara, Hiroshige Nakamura, Makoto Sonobe, Takuji Fujinaga, Kazuhiko Kataoka, Kenichi Gemba, Masafumi Kataoka, Katsuyuki Hotta, Hiroshige Yoshioka, Keitaro Matsuo, Junichi Sakamoto, Hiroshi Date, Shinichi Toyooka

BMC cancer 21 ( 1 ) 506 - 506 2021.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The aim of this multicenter, randomized phase II study was to analyze the feasibility and safety of alternate-day S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in patients with completely resected pathological stage I (tumor diameter > 2 cm) non-small cell lung cancer (NSCLC). METHODS: Patients were randomly assigned to receive adjuvant chemotherapy for 1 year comprising either alternate-day oral administration of S-1 (80 mg/m2/day) for 4 days a week (Group A) or a 2-week oral administration of S-1 (80 mg/m2/day) followed by 1 week of rest (Group B). The primary endpoint was feasibility, which was defined as the proportion of patients who completed the allocated intervention for 6 months with a relative dose intensity (RDI) of 70% or more. RESULTS: Ninety-three patients were enrolled of whom 90 patients received S-1 treatment. Median follow-up was 66.9 months. The treatment completion rate based on an RDI of 70% or more for 6 months was 84.4% (95%CI; 70.5-93.5%) in group A and 64.4% (95%CI; 48.8-78.1%) in group B. There were no grade 4 adverse events in either group. Moderate or severe adverse events (grade 2 or grade 3) were significantly more frequent in group B (67%) compared with group A (29%, P = 0.001). The 5-year relapse-free survival rate was 87.0 and 80.9% for group A and B, respectively (P = 0.451). The 5-year overall survival rate for all patients (n = 93) was 100 and 89.4% for group A and B, respectively (P = 0.136). CONCLUSION: Alternate-day oral administration of S-1 for 1 year as adjuvant chemotherapy was demonstrated to be feasible with low toxicity in completely resected stage I (tumor diameter > 2 cm) NSCLC. TRIAL REGISTRATION: Trial registration number: UMIN000011994 . Date of registration: 10/8/2013.

DOI： 10.1186/s12885-021-08232-6

Best practices for the extraction of genomic DNA from formalin-fixed paraffin-embedded tumor tissue for cancer genomic profiling tests. International journal

Hirofumi Inoue, Shuta Tomida, Shigeru Horiguchi, Hironari Kato, Hiromi Matsuoka, Etsuko Sanehira, Masashi Matsuoka, Hiroyuki Yanai, Akira Hirasawa, Shinichi Toyooka

Pathology international 71 ( 5 ) 360 - 364 2021.5

Language：English Publishing type：Research paper (scientific journal)

Recently, two cancer genomic profiling tests have been approved in Japan and implemented in routine clinical practice: the FDA-approved FoundationOne CDx test, and the OncoGuide NCC Oncopanel test. The quality and quantity of DNA significantly affects the sequencing results; therefore, preparing a sufficient amount of high-quality DNA for clinical cancer genomic profiling tests is important. We examined the best practices for the extraction of cancer genomic DNA from formalin-fixed paraffin-embedded (FFPE) tumor tissues of pancreatic, lung and colon cancer specimens. We found that the quality of cancer genomic DNA extracted from 10-μm-thick FFPE samples improved significantly, compared with that from 4-μm-thick FFPE samples, suggesting that 10-μm-thick FFPE samples are preferable for clinical cancer genomic profiling tests. For convenience, we created a quick reference table for calculating the required number of FFPE slides.

DOI： 10.1111/pin.13086

RATS? VATS? Uniportal VATS?〜あなたならどのアプローチを選ぶ?〜肥満症例や不全分葉症例から見たRATSの有用性

岡崎幹生, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 杉本誠一郎, 山根正修, 豊岡伸一

日本呼吸器外科学会雑誌 35 ( 3 ) PD3 - 3 2021.5

肺移植患者の周術期におけるClostridioides difficile感染症の検討

坂田龍平, 大谷真二, 石上恵美, 石原恵, 土生智大, 岩田一馬, 久保友次郎, 松田直樹, 清水大, 松原慧, 富岡泰章, 山本治慎, 塩谷俊雄, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

日本呼吸器外科学会雑誌 35 ( 3 ) O18 - 4 2021.5

肺移植における最適な術前予後予測スコアリング法 9つの術前予後予測スコアリング法の検証から

山本治慎, 杉本誠一郎, 富岡泰章, 塩谷俊雄, 清水大, 松原慧, 三好健太郎, 大谷真二, 岡崎幹生, 山根正修, 豊岡伸一

日本呼吸器外科学会雑誌 35 ( 3 ) O18 - 5 2021.5

N2肺癌に対する術前導入化学放射線療法後手術症例における好中球/リンパ球比の検討

山本寛斉, 津高慎平, 富岡泰章, 塩谷俊雄, 諏澤憲, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

日本呼吸器外科学会雑誌 35 ( 3 ) O8 - 1 2021.5

肺移植後移植片慢性機能不全におけるGoddard scoreの検討

塩谷俊雄, 杉本誠一郎, 山本治慎, 富岡泰章, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 山根正修, 豊岡伸一

日本呼吸器外科学会雑誌 35 ( 3 ) O18 - 3 2021.5

肺がん治療発展を目指した呼吸器外科医の役割家族性肺がんの経験

諏澤憲, 山本寛斉, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

日本呼吸器外科学会雑誌 35 ( 3 ) MO10 - 3 2021.5

ロボット支援手術第2世代術者のラーニングカーブ

大谷真二, 岡崎幹生, 坂田龍平, 松田直樹, 岩田一馬, 高津史明, 諏澤憲, 三好健太郎, 山本寛斉, 杉本誠一郎, 山根正修, 豊岡伸一

日本呼吸器外科学会雑誌 35 ( 3 ) MO58 - 1 2021.5

UNCX遺伝子多型と肺移植後の腎機能障害との関係

富岡泰章, 杉本誠一郎, 山本治慎, 清水大, 松原慧, 塩谷俊雄, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 山根正修, 豊岡伸一

日本呼吸器外科学会雑誌 35 ( 3 ) RO17 - 2 2021.5

Vessel sealerを常時用いたRATS手技

岡崎幹生, 諏澤憲, 大谷真二, 三好健太郎, 山本寛斉, 杉本誠一郎, 山根正修, 豊岡伸一

日本呼吸器外科学会雑誌 35 ( 3 ) RV5 - 1 2021.5

N2肺癌に対する免疫チェックポイント阻害剤を用いた周術期治療の可能性 WJOG12119L試験

濱田顕, 宗淳一, 大泉弘幸, 坪井正博, 堀之内秀仁, 吉野一郎, 棚橋雅幸, 豊岡伸一, 岡田守人, 横見瀬裕保, 山下素弘, 光冨徹哉

日本呼吸器外科学会雑誌 35 ( 3 ) S - 5 2021.5

肺移植における予後改善に向けての取組生体肺移植と脳死肺移植の違いに着目した慢性移植肺機能不全(CLAD)の早期診断を目指した取り組み

杉本誠一郎, 塩谷俊雄, 山本治慎, 富岡泰章, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 山根正修, 豊岡伸一

日本呼吸器外科学会雑誌 35 ( 3 ) PD2 - 4 2021.5

N2肺癌に対する免疫チェックポイント阻害剤を用いた周術期治療の可能性 WJOG12119L試験

濱田顕, 宗淳一, 大泉弘幸, 坪井正博, 堀之内秀仁, 吉野一郎, 棚橋雅幸, 豊岡伸一, 岡田守人, 横見瀬裕保, 山下素弘, 光冨徹哉

日本呼吸器外科学会雑誌 35 ( 3 ) S - 5 2021.5

病理病期I期NSCLC切除例に対するS-1隔日投与補助化学療法に関する多施設共同無作為化第II相試験(SLCG1301)

奥村典仁, 宗淳一, 鈴木弘行, 中田昌男, 藤原俊哉, 中村廣繁, 園部誠, 藤永卓司, 片岡和彦, 玄馬顕一, 片岡正文, 堀田勝幸, 吉岡弘鎮, 松尾恵太郎, 坂本純一, 伊達洋至, 豊岡伸一, 瀬戸内肺癌研究会

日本呼吸器外科学会雑誌 35 ( 3 ) RO12 - 5 2021.5

Phase II Study of Neoadjuvant Concurrent Chemo-immuno-radiation Therapy Followed by Surgery and Adjuvant Immunotherapy for Resectable Stage IIIA-B (Discrete N2) Non-small-cell Lung Cancer: SQUAT trial (WJOG 12119L). International journal

Akira Hamada, Junichi Soh, Akito Hata, Kiyoshi Nakamatsu, Mototsugu Shimokawa, Yasushi Yatabe, Hiroyuki Oizumi, Masahiro Tsuboi, Hidehito Horinouchi, Ichiro Yoshino, Masayuki Tanahashi, Shinichi Toyooka, Morihito Okada, Hiroyasu Yokomise, Motohiro Yamashita, Yasumasa Nishimura, Nobuyuki Yamamoto, Kazuhiko Nakagawa, Tetsuya Mitsudomi

Clinical lung cancer 22 ( 6 ) 596 - 600 2021.4

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: We describe our ongoing multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B (discrete N2) non-small-cell lung cancer (NSCLC) (registered at the Japan Pharmaceutical Information Center, Clinical Trials Information-195069). PATIENTS AND METHODS: Key inclusion criteria include (1) clinical T1-3/T4 (tumor size) N2 stage IIIA-B NSCLC, and (2) pathologically confirmed N2 without extranodal invasion (based on diagnostic imaging). Patients will receive concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m2] on days 1, 8, 15, 22, and 29, with involved-field radiation therapy [RT] [dose 50 Gy] on days 1-25) and neoadjuvant immunotherapy (durvalumab [1500 mg] on days 1 and 29). Surgical resection with mediastinal lymph node dissection is performed within 2 to 6 weeks after RT. Consolidation therapy with durvalumab is administered for up to 1 year after surgery. The primary endpoint is major pathologic response (MPR) (≤10% residual viable tumor) according to the central pathological assessment. Secondary endpoints are progression-free survival, overall survival, and safety. The sample size is planned to be 31 patients based on the exact binomial distribution with a 1-sided significance level of 5% and a power of 80%, and assuming a threshold MPR rate of 40% and an expected MPR rate of 65%. CONCLUSION: This trial will help establish a novel treatment strategy for resectable N2-positive NSCLC.

DOI： 10.1016/j.cllc.2021.04.006

Clinical features and prognostic impact of coexisting autoimmune disease other than myasthenia gravis in resected thymomas: analysis of a Japanese multi-institutional retrospective database. International journal

Tomoyuki Hishida, Hisao Asamura, Kazuo Yoshida, Masahiro Tsuboi, Kohei Yokoi, Shinichi Toyooka, Akihide Matsumura, Tetsuzo Tagawa, Meinoshin Okumura

European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 59 ( 3 ) 641 - 649 2021.4

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: The purpose of this study was to clarify the prevalence, clinical features and survival of patients with thymoma and non-myasthenia gravis autoimmune disease (NMAD) using a nationwide cohort. METHODS: The Japanese Association for Research on the Thymus nationwide database, which includes data from 32 institutions, was examined to clarify the prevalence and characteristics of NMAD associated with thymomas and elucidate the prognostic impact of NMAD for thymoma patients. RESULTS: Among the 2423 patients with thymomas who were surgically treated between 1991 and 2010, 114 (4.7%) were identified with NMAD. The most frequently observed NMAD was pure red cell aplasia (PRCA) in 44 (1.8%), followed by hypogammaglobulinaemia (0.5%) and rheumatic arthritis (0.5%). Twenty-eight percent of patients with NMAD had concomitant myasthenia gravis. The presence of NMAD was not an independent prognostic factor for overall survival (OS) irrespective of the type of NMAD [PRCA+: hazard ratio (HR) 1.99, 95% confidence interval 0.74-4.47; PRCA- NMAD: HR 1.28, 0.30-3.56]; however, there were more cases with advanced age and disease of the thymoma amongst PRCA+ patients and these showed a worse OS than patients with PRCA- NMAD (P < 0.001), who had an OS similar to those without NMAD (P = 0.489). The 10-year OS rates in PRCA+, PRCA- NMAD and NMAD- groups were 45.5%, 97.4% and 89.5%, respectively. The main causes of death in PRCA+ patients were the progression of thymoma and other diseases including pneumonia. CONCLUSIONS: Although the presence of NMAD itself did not significantly affect survival after surgery for thymoma, the type of NMAD was associated with different clinical features and prognosis. The NMAD+ thymomas should be separately categorized according to the presence or absence of PRCA.

DOI： 10.1093/ejcts/ezaa362

Long-term clinical follow-up after lung transplantation in patient with scoliosis: a case report.

Haruchika Yamamoto, Shinji Otani, Kentaroh Miyoshi, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

General thoracic and cardiovascular surgery 69 ( 4 ) 752 - 755 2021.4

Language：English Publishing type：Research paper (scientific journal)

Severe scoliosis causes anatomical distortion of structures in the chest, which raises concerns about donor-recipient size-mismatch in lung transplantation (LT), so that severe scoliosis is considered as an absolute contraindication for LT. Also, postoperative right-side bronchial stenosis is one of the common complications in LT recipients with severe scoliosis. To date, the long-term outcomes in severe scoliosis patients with bronchial stenosis after LT have not been reported. A 14-year-old female patient with scoliosis and interstitial pneumonia underwent bilateral cadaveric LT. Although she developed bronchial stenosis post-LT, necessitating bronchoscopic intervention on three occasions, her lung function and perfusion recovered to the levels recorded prior to development of the obstruction, with the good condition maintained for more than 5 years after the LT. Therefore, while patients with severe scoliosis are at an elevated risk of postoperative transient bronchial stenosis, scoliosis should not always be considered as a contraindication to LT.

DOI： 10.1007/s11748-020-01539-4

Effectiveness of scheduled intravenous acetaminophen in the postoperative pain management of video-assisted thoracic surgery.

Yoshinobu Shikatani, Junichi Soh, Kazuhiko Shien, Takeshi Kurosaki, Shinji Ohtani, Hiromasa Yamamoto, Arata Taniguchi, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Takahiro Oto, Hiroshi Morimatsu, Shinichi Toyooka

Surgery today 51 ( 4 ) 589 - 594 2021.4

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: The scheduled administration of intravenous acetaminophen (scheduled-IV-AcA) is one of the more effective multimodal analgesic approaches for postoperative pain in abdominal/orthopedic surgeries. However, there is little evidence concerning scheduled-IV-AcA after general thoracic surgery, especially when limited to video-assisted thoracoscopic surgery (VATS). We investigated the efficacy of scheduled-IV-AcA administration in patients after undergoing VATS. METHODS: Ninety-nine patients who underwent VATS lobectomy or segmentectomy via an 8-cm access window and 1 camera port were retrospectively reviewed by categorizing them into groups either with scheduled-IV-AcA (Group AcA: n = 29) or without it (Group non-AcA: n = 70). Group AcA received 1 g of IV-AcA every 6 h from the end of the operation until the end of POD2. Postoperative pain was measured using a numeric rating scale (NRS) three times per day until discharge. RESULTS: NRS scores were significantly lower in Group AcA with motion (on POD1 to the first point of POD2) than in Group non-AcA. Group non-AcA was also more likely to use additional analgesics than Group AcA (39% vs. 17%, p = 0.058). CONCLUSIONS: Scheduled-IV-AcA administration is a safe and effective multimodal analgesic approach in patients undergoing VATS pulmonary resection via an 8-cm access window.

DOI： 10.1007/s00595-020-02127-y

当院における小児肺移植の成績

大谷真二, 富岡泰章, 松原慧, 清水大, 山本治慎, 塩谷俊雄, 諏澤憲, 三好健太郎, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

日本外科学会定期学術集会抄録集 121回 PS - 8 2021.4

A PET/CT volumetric parameter predicts prognosis of non-small cell lung cancer treated using preoperative chemoradiotherapy and surgery: A retrospective case series study. International journal

Kuniaki Katsui, Takeshi Ogata, Akihiro Tada, Kenta Watanabe, Kotaro Yoshio, Masahiro Kuroda, Katsuyuki Kiura, Takao Hiraki, Shinichi Toyooka, Susumu Kanazawa

Molecular and clinical oncology 14 ( 4 ) 73 - 73 2021.4

Language：English Publishing type：Research paper (scientific journal)

The purpose of the present study was to clarify whether positron emission tomography/computed tomography (PET/CT) volumetric parameters were prognostic predictors of non-small cell lung cancer (NSCLC) treatment in patients who had undergone preoperative concurrent chemoradiotherapy (CCRT) and surgery. In the present study, retrospectively surveyed the data of patients with NSCLC who underwent preoperative CCRT and surgery at Okayama University Hospital (Okayama, Japan) between April 2006 and March 2018. The maximum standardized uptake value (SUVmax) and volumetric parameters, including metabolic tumor volume (MTV) and total lesion glycolysis (TLG), were calculated using PET/CT and the percentage decrease (Δ) in each parameter value post-CCRT. The SUVmax threshold for defining MTV was set at 2.5. Furthermore, the association between survival and PET parameter values was analyzed. A total of 52 patients were included in the present study. The median follow-up period was 50.65 months. In univariate analysis, ΔTLG was identified to be a significant predictor of progression-free survival (PFS; P=0.03). The 5-year PFS rates were 48.6 and 76.6% for patients with low ΔTLG and high ΔTLG, respectively. High ΔTLG was indicative of a higher overall survival rate (P=0.08). The present results suggest that ΔTLG calculated using PET/CT is a prognostic predictor of NSCLC treated using preoperative CCRT and surgery, and may help physicians determine treatment strategies.

DOI： 10.3892/mco.2021.2235

当院における小児肺移植の成績

大谷真二, 富岡泰章, 松原慧, 清水大, 山本治慎, 塩谷俊雄, 諏澤憲, 三好健太郎, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

日本外科学会定期学術集会抄録集 121回 PS - 8 2021.4

外科マネージメントセンターによる情熱のある外科医教育・育成システム

菊地覚次, 吉田龍一, 黒田新士, 野間和広, 安井和也, 笠原真悟, 豊岡伸一, 土井原博義, 藤原俊義

日本外科学会定期学術集会抄録集 121回 SP - 6 2021.4

岡山大学外科GRAPESの活動とこれから

竹原裕子, 吉田龍一, 溝尾妙子, 剱持礼子, 小林純子, 新田薫, 工藤由里絵, 元木崇之, 片岡正文, 池田宏国, 菊池覚次, 黒田新士, 枝園忠彦, 山根正修, 小谷恭弘, 大澤晋, 土井原博義, 豊岡伸一, 笠原慎悟, 藤原俊義

日本外科学会定期学術集会抄録集 121回 SF - 5 2021.4

外科マネージメントセンターによる情熱のある外科医教育・育成システム

菊地覚次, 吉田龍一, 黒田新士, 野間和広, 安井和也, 笠原真悟, 豊岡伸一, 土井原博義, 藤原俊義

日本外科学会定期学術集会抄録集 121回 SP - 6 2021.4

岡山大学外科GRAPESの活動とこれから

竹原裕子, 吉田龍一, 溝尾妙子, 剱持礼子, 小林純子, 新田薫, 工藤由里絵, 元木崇之, 片岡正文, 池田宏国, 菊池覚次, 黒田新士, 枝園忠彦, 山根正修, 小谷恭弘, 大澤晋, 土井原博義, 豊岡伸一, 笠原慎悟, 藤原俊義

日本外科学会定期学術集会抄録集 121回 SF - 5 2021.4

Role of surgery in a novel multimodal therapeutic approach to complete cure of advanced lung cancer: current and future perspectives.

Masaomi Yamane, Shinichi Toyooka

Surgery today 52 ( 1 ) 1 - 11 2021.3

Language：English Publishing type：Research paper (scientific journal)

Non-small cell lung cancer (NSCLC) is considered potentially curable by multimodal therapy in a subset of patients, including those with locally advanced (LA) disease or nodal spread, who would otherwise have a poor prognosis. Guidelines recommend perioperative chemotherapy with platinum-based regimens, with or without radiotherapy, as the standard treatment modality for high-risk resectable LA-NSCLC. Although the classical regimens of adjuvant chemotherapy have been platinum-based doublet or oral agents such as tegafur/uracil, some molecular targeted therapeutic agents and immune checkpoint inhibitors have been developed recently with an expected favorable effect. Recent trials of perioperative therapy using these agents have demonstrated favourable anticancer efficacy for LA-NSCLC with an acceptable adverse events profile. The ideal timing of perioperative therapy administration, before or after surgery, is still controversial. Because some speculation and concepts have arisen from basic research, several trials are ongoing to clarify the efficacy of newly developed agents in the adjuvant or neoadjuvant setting. This review discusses the role of surgery in the new era and analyzes when and which optimal perioperative multimodal therapy, including chemotherapy, radiotherapy, molecular-targeted therapy, and immunotherapy, should be administered for resectable or potentially resectable NSCLC to provide possible complete cure.

DOI： 10.1007/s00595-021-02228-2

Lung transplantation for Kartagener syndrome: technical aspects and morphological adaptation of the transplanted lungs.

Haruchika Yamamoto, Seiichiro Sugimoto, Kentaroh Miyoshi, Shinji Otani, Masaomi Yamane, Shinichi Toyooka

General thoracic and cardiovascular surgery 69 ( 3 ) 588 - 592 2021.3

Language：English Publishing type：Research paper (scientific journal)

While technical considerations in lung transplantation for Kartagener syndrome have been discussed, little information is available about the postoperative morphological changes of the grafted lungs. Herein, we discuss both the technical aspects and postoperative morphological adaptation of the grafted lungs in a case of Kartagener syndrome. A 46-year-old male patient with Kartagener syndrome underwent bilateral cadaveric lung transplantation. The right arterial anastomosis for transplantation of the size-matched grafts required technical elaboration. After the transplantation, we found a free space in the cardiac notch of the left lung and partial collapse of the lower lobe of the right lung due to dextrocardia. Follow-up computed tomography performed on day 42 after the transplantation demonstrated resolution of the atelectasis and morphological adaptation of the grafts into the recipient's chest cavity with dextrocardia. Considering such early morphological adaptation of size-matched grafts, lobar reduction could be avoided in lung transplantation for Kartagener syndrome.

DOI： 10.1007/s11748-020-01509-w

Relationships of physical and breast cancer phenotypes with three single-nucleotide polymorphisms (rs2046210, rs3757318, and rs3803662) associated with breast cancer risk in Japanese women.

Kengo Kawada, Naruto Taira, Taeko Mizoo, Yoko Suzuki, Yukiko Kajiwara, Minami Hatono, Takahiro Tsukioki, Mariko Kochi, Yuko Abe, Keiko Nishiyama, Takayuki Iwamoto, Hirokuni Ikeda, Tadahiko Shien, Hiroyoshi Doihara, Setsuko Ishihara, Hiroshi Kawai, Kensuke Kawasaki, Yoichi Ishibe, Yutaka Ogasawara, Shinichi Toyooka

Breast cancer (Tokyo, Japan) 28 ( 2 ) 478 - 487 2021.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Recent genome-wide association studies have shown that many single-nucleotide polymorphisms (SNPs) are associated with breast cancer risk. However, it is often unclear how these SNPs are related to breast cancer. Analysis of associations between SNPs and phenotypes may be important for determining mechanisms of action, including carcinogenesis. METHODS: In previous case-control studies, we found three SNPs (rs2046210, rs3757318, and rs3573318) associated with breast cancer risk in Japanese women. Among these SNPs, two (rs2046210 and rs3757318) are located at 6q25.1, in proximity to the estrogen receptor 1 gene (ESR1). Using data from these studies, we examined associations between factors related to breast cancer risk, such as height, weight, and breast density, and the three SNPs in cases and controls. We also investigated whether the SNPs correlated with breast cancer features, such as estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor type-2 (HER2) status, and clinical stage. RESULTS: There was a significant difference in mean height between risk and non-risk allele carriers for rs2046210 (156.0 ± 5.8 vs. 154.3 ± 5.5 cm, p = 0.002), and rs3757318 (155.8 ± 5.7 vs. 154.7 ± 5.6 cm, p = 0.035) in cases, but no significant associations between height and these SNPs in controls. There was also a significant difference in breast density between risk and non-risk allele carriers for rs2046210 (p = 0.040) and rs3757318 (p = 0.044) in cases. rs2046210 and rs3757318 risk allele carriers tended to have higher breast density in all subjects and in controls. In cases, rs3757318 risk allele carriers were also significantly more likely to be ER-negative compared to non-risk allele carriers (ER-positive rate: 77% vs. 84%, p = 0.036). CONCLUSIONS: SNPs rs2046210 and rs3757318, which are associated with breast cancer risk in Japanese women, were significantly associated with height and high breast density, and this association was particularly strong in those with breast cancer. These findings suggest that SNPs in the ESR1 gene region affect phenotypes such as height and breast density.

DOI： 10.1007/s12282-020-01185-x

脳死片肺移植を施行した多中心性キャッスルマン病の1例

富岡泰章, 大谷真二, 松原慧, 清水大, 山本治慎, 塩谷俊雄, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

移植 55 ( 4 ) 506 - 506 2021.3

高IgE症候群による気管支拡張症に対して両側脳死肺移植を施行した1例

清水大, 大谷真二, 富岡泰章, 松原慧, 塩谷俊雄, 山本治慎, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

移植 55 ( 4 ) 507 - 507 2021.3

反転肺移植術の可能性当院で経験した3症例

山本治慎, 大谷真二, 日笠友起子, 黒崎毅史, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一, 小林求, 大藤剛宏

移植 55 ( 4 ) 453 - 453 2021.3

小児に対するABO血液型不一致の両側脳死肺移植の経験

塩谷俊雄, 杉本誠一郎, 松原慧, 富岡泰章, 清水大, 山本治慎, 三好健太郎, 大谷真二, 岡崎幹生, 山根正修, 大藤剛宏, 豊岡伸一

移植 55 ( 4 ) 491 - 491 2021.3

肺移植手術手技を応用した自家肺移植

塩谷俊雄, 大谷真二, 青景圭樹, 黒崎毅史, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一, 坪井正博, 大藤剛宏

移植 55 ( 4 ) 451 - 451 2021.3

脳死肺移植後、タクロリムス濃度調整に難渋した、クローン病合併レシピエントの1例

松原慧, 大谷真二, 金聖暎, 今井祥子, 開原裕子, 長谷川祐子, 清水大, 富岡泰章, 山本治慎, 塩谷俊雄, 三好健太郎, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

移植 55 ( 4 ) 508 - 508 2021.3

肺腺癌におけるSpred2の発現と増殖、浸潤との関連の検討

太田陽子, 藤澤真義, 吉村禎造, スマルディカ・イワヤン, 枝園和彦, 阪口政清, 豊岡伸一, 松川昭博

日本病理学会会誌 110 ( 1 ) 291 - 291 2021.3

反転肺移植術の可能性当院で経験した3症例

山本治慎, 大谷真二, 日笠友起子, 黒崎毅史, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一, 小林求, 大藤剛宏

移植 55 ( 4 ) 453 - 453 2021.3

高IgE症候群による気管支拡張症に対して両側脳死肺移植を施行した1例

清水大, 大谷真二, 富岡泰章, 松原慧, 塩谷俊雄, 山本治慎, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

移植 55 ( 4 ) 507 - 507 2021.3

小児に対するABO血液型不一致の両側脳死肺移植の経験

塩谷俊雄, 杉本誠一郎, 松原慧, 富岡泰章, 清水大, 山本治慎, 三好健太郎, 大谷真二, 岡崎幹生, 山根正修, 大藤剛宏, 豊岡伸一

移植 55 ( 4 ) 491 - 491 2021.3

脳死片肺移植を施行した多中心性キャッスルマン病の1例

富岡泰章, 大谷真二, 松原慧, 清水大, 山本治慎, 塩谷俊雄, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

移植 55 ( 4 ) 506 - 506 2021.3

肺移植手術手技を応用した自家肺移植

塩谷俊雄, 大谷真二, 青景圭樹, 黒崎毅史, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一, 坪井正博, 大藤剛宏

移植 55 ( 4 ) 451 - 451 2021.3

Prognostic Significance of Neutrophil-to-Lymphocyte Ratio in Locally Advanced Non-small-cell Lung Cancer Treated with Trimodality Therapy. International journal

Shimpei Tsudaka, Hiromasa Yamamoto, Hiroki Sato, Kuniaki Katsui, Ken Suzawa, Kazuhiko Shien, Kentaroh Miyoshi, Shinji Otani, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Katsuyuki Kiura, Susumu Kanazawa, Shinichi Toyooka

Annals of surgical oncology 28 ( 9 ) 4880 - 4890 2021.2

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Current evidence suggests that the neutrophil-to-lymphocyte ratio (NLR) is a prognostic factor in several types of cancer. In this study, we aimed to evaluate the prognostic impact of clinicopathological factors, including postoperative NLR, in patients with locally advanced non-small-cell lung cancer (LA-NSCLC) who underwent surgery after chemoradiotherapy (CRT) with or without postoperative adjuvant chemotherapy. METHODS: The medical records of LA-NSCLC patients treated with trimodality therapy at our institution between June 1999 and May 2019 were reviewed. The association between several clinicopathological factors and overall survival (OS) was analyzed. RESULTS: A total of 168 patients were included in this study. Regarding the prognosis, the 5-year OS rate was 68.1%, and the 2-year recurrence-free survival rate was 66.1% in the entire population. In multivariate analysis, we identified that high postoperative NLR, not pretreatment or preoperative NLR, was one of the independent factors for unfavorable OS (NLR high vs NLR low; hazard ratio = 2.45, 95% confidence interval: 1.53-3.94, p < 0.001). In addition, among patients with high postoperative NLR, patients who received postoperative adjuvant chemotherapy showed significantly better 5-year OS compared with those who did not (p = 0.016). On the other hand, postoperative adjuvant chemotherapy had no impact on the prognosis in patients with low NLR (p = 0.19). CONCLUSIONS: Our results suggest that high postoperative NLR was not only an independent unfavorable prognostic factor in patients with LA-NSCLC who were treated with trimodality therapy, but also a promising indicator for postoperative treatment in this population.

DOI： 10.1245/s10434-021-09690-9

Lung stereotactic body radiation therapy for elderly patients aged ≥ 80 years with pathologically proven early-stage non-small cell lung cancer: a retrospective cohort study. International journal

Kenta Watanabe, Kuniaki Katsui, Soichiro Sugiyama, Kotaro Yoshio, Masahiro Kuroda, Takao Hiraki, Katsuyuki Kiura, Yoshinobu Maeda, Shinichi Toyooka, Susumu Kanazawa

Radiation oncology (London, England) 16 ( 1 ) 39 - 39 2021.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Stereotactic body radiation therapy (SBRT) is an established therapy for medically inoperable early-stage non-small cell lung cancer (NSCLC). Many elderly patients are medically inoperable owing to comorbidities. Therefore, SBRT may be a useful therapy for elderly patients. However, the application of SBRT for patients aged ≥ 80 years has not been completely elucidated. Therefore, this study aimed to assess the clinical utility of SBRT for elderly patients aged ≥ 80 years with pathologically proven early-stage NSCLC. METHODS: We retrospectively evaluated the data of patients aged ≥ 80 years with pathologically proven primary NSCLC who underwent SBRT at our institution between January 2009 and March 2020. Treatment outcomes and toxicities were analyzed. We used the Kaplan-Meier method to estimate survival curves and the log-rank test to compare the survival curves. We performed univariate and multivariate Cox regression analyses. p-values < 0.05 were regarded significant. RESULTS: Sixty-four patients (65 lesions) were included, and the median follow-up period was 38.7 (range 3.5-95.7) months. The median age was 82.9 (range 80.0-94.8) years. Sixteen patients were medically operable, and 48 patients were medically inoperable. The prescribed dose of SBRT was either 48 Gy in four fractions or 60 Gy in 10 fractions. The median survival time was 60.0 months (95% confidence interval, 43.5-71.1). The 1-, 3-, and 5-year local control, cancer-specific survival, progression-free survival, and overall survival rates were 98.4%, 98.4%, 81.0%, and 88.9%; 90.1%, 93.7%, 58.9%, and 68.3%; and 87.4%, 83.5%, 38.2%, and 47.5%, respectively. Multivariate analysis revealed that inoperability and solid nodules were the predictors of poor overall survival after SBRT in elderly patients. Two patients (3.1%) had grade 3 radiation pneumonitis, and one patient (1.6%) had grade 5 radiation pneumonitis. CONCLUSIONS: SBRT was feasible in patients aged ≥ 80 years with NSCLC. It achieved good local control with minimal toxicity. SBRT may be beneficial in elderly patients with early-stage NSCLC.

DOI： 10.1186/s13014-021-01769-7

Preoperative Cumulative Smoking Dose on Lung Cancer Surgery in a Japanese Nationwide Database. International journal

Yugo Tanaka, Hiroyuki Yamamoto, Masami Sato, Shinichi Toyooka, Morihito Okada, Shunsuke Endo, Yukio Sato, Kenji Suzuki, Yoshimasa Maniwa, Eriko Fukuchi, Hiroaki Miyata, Masayuki Chida

The Annals of thoracic surgery 2021.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Smoking is a known risk factor for postoperative mortality and morbidity. However, the significance of cumulative smoking dose in preoperative risk assessment has not been established. We examined the influence of preoperative cumulative smoking dose on surgical outcomes after lobectomy for primary lung cancer. METHODS: A total of 80,989 patients with primary lung cancer undergoing lobectomy from 2014 to 2016 were enrolled. Preoperative cumulative smoking dose was categorized by pack-years (PY): nonsmokers, PY = 0; light smokers, 0 < PY < 10; moderate smokers, 10 ≤ PY < 30; and heavy smokers, 30 ≤ PY. The risk of short-term outcomes was assessed according to PY by multivariable analysis adjusted for other covariates. RESULTS: Postoperative 30-day mortality, as well as pulmonary, cardiovascular, and infectious complications, increased with preoperative PY. Multivariable analysis revealed that the odds ratios (ORs) for postoperative mortality compared with nonsmokers were 1.76 for light smokers (P = .044), 1.60 for moderate smokers (P = .026), and 1.73 for heavy smokers (P = .003). The ORs for pulmonary complications compared with nonsmokers were 1.20 for light smokers (P = .022), 1.40 for moderate smokers (P < .001), and 1.72 for heavy smokers (P < .001). Heavy smokers had a significantly increased risk of postoperative cardiovascular (OR, 1.26; P = .002) and infectious (OR, 1.39; P = .007) complications compared with nonsmokers. CONCLUSIONS: The risk of mortality and morbidity after lung resection could be predicted according to preoperative cumulative smoking dose. These findings contribute to the development of strategies in perioperative management of lung resection patients.

DOI： 10.1016/j.athoracsur.2021.01.055

The prognostic nutritional index is correlated negatively with the lung allocation score and predicts survival after both cadaveric and living-donor lobar lung transplantation.

Haruchika Yamamoto, Seiichiro Sugimoto, Junichi Soh, Toshio Shiotani, Kentaroh Miyoshi, Shinji Otani, Mikio Okazaki, Masaomi Yamane, Shinichi Toyooka

Surgery today 51 ( 10 ) 1610 - 1618 2021.2

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: The prognostic nutritional index (PNI), calculated based on the serum albumin levels and the total lymphocyte count, has been identified as a predictor of clinical outcomes in various fields of surgery. In this study, we investigated the relationship between the PNI and the lung allocation score (LAS) as well as the impact of the PNI on the outcomes of both cadaveric lung transplantation (CLT) and living-donor lobar lung transplantation (LDLLT). METHODS: We reviewed retrospective data for 127 recipients of lung transplantation (LT), including 71 recipients of CLT and 56 recipients of LDLLT. RESULTS: The PNI was correlated significantly and negatively with the LAS (r = - 0.40, P = 0.0000037). Multivariate analysis revealed that age (P = 0.00093), BMI (P = 0.00087), and PNI (P = 0.0046) were independent prognostic factors of a worse outcome after LT. In a subgroup analysis, survival after both CLT (P = 0.015) and LDLLT (P = 0.041) was significantly worse in the low PNI group than in the high PNI group. CONCLUSION: Preoperative nutritional evaluations using the PNI can assist with the assessment of disease severity in LT recipients and may predict survival after both CLT and LDLLT.

DOI： 10.1007/s00595-021-02244-2

The prognostic impact of sarcopenia on elderly patients undergoing pulmonary resection for non-small cell lung cancer.

Akihiro Miura, Hiromasa Yamamoto, Hiroki Sato, Yasuaki Tomioka, Toshio Shiotani, Ken Suzawa, Kentaroh Miyoshi, Shinji Otani, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

Surgery today 51 ( 7 ) 1203 - 1211 2021.2

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: The number of elderly patients who undergo surgery is increasing, even though they are at a high risk due to a decreased physical strength. Furthermore, sarcopenia is generally associated with a poor prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: This study included NSCLC patients ≥ 65 years old who underwent pulmonary resection in our hospital between 2012 and 2015. Sarcopenia was assessed using the psoas muscle mass index based on computed tomography at the level of the third lumbar vertebra. We elucidated the impact of sarcopenia on short- and long-term outcomes after surgery. RESULTS: We enrolled 259 patients, including 179 with sarcopenia. Patients with sarcopenia before surgery tended to have postoperative complications (p = 0.0521), although they did not show a poor prognosis. In patients with sarcopenia, a multivariate analysis revealed that postoperative complications and the progression of sarcopenia 1 year after surgery were significant risk factors for a poor prognosis (p = 0.0169 and 0.00370, respectively). CONCLUSIONS: The progression of sarcopenia after surgery is associated with a poor prognosis in elderly NSCLC patients with sarcopenia. A strategy to prevent postoperative progressive sarcopenia may be necessary for improving the clinical outcome of this population.

DOI： 10.1007/s00595-020-02221-1

Successful Bronchoscopic Treatment for Postoperative Bronchopleural Fistula Using N-butyl-2-cyanoacrylate (NBCA): Report of a Post-completion Pneumonectomy Case with a History of Induction Chemoradiotherapy Followed by Bilobectomy for Advanced Lung Cancer.

Toshio Shiotani, Hiromasa Yamamoto, Riko Katsube, Yasuaki Tomioka, Ken Suzawa, Kentaroh Miyoshi, Shinji Otani, Mikio Okazaki, Seiichiro Sugimoto, Junichi Soh, Masaomi Yamane, Shinichi Toyooka

Acta medica Okayama 75 ( 1 ) 91 - 94 2021.2

Language：English Publishing type：Research paper (scientific journal)

Bronchopleural fistula (BPF) is a severe complication following lung resection. We present the case of a patient with a history of advanced lung cancer, who had undergone induction chemoradiotherapy followed by right middle and lower lobectomy, and who developed BPF after completion right pneumonectomy. Although we had covered the bronchial stump with an omental pedicled flap, BPF was found on postoperative day 19. We covered the fistula with n-butyl-2-cyanoacrylate (NBCA) using bronchoscopy. Although we had to repeat the NBCA treatment, we ultimately cured the patient's BPF and no recurrence was observed up to 15.2 months after surgery.

DOI： 10.18926/AMO/61440

Long-term Follow-up of Living-Donor Kidney Transplantation after Cadaveric Lung Transplantation.

Toshio Shiotani, Seiichiro Sugimoto, Kota Araki, Yasuaki Tomioka, Kentaroh Miyoshi, Shinji Otani, Masaomi Yamane, Shinichi Toyooka

Acta medica Okayama 75 ( 1 ) 87 - 89 2021.2

Language：English Publishing type：Research paper (scientific journal)

Although chronic kidney disease (CKD) commonly develops after lung transplantation (LT), living-donor kid-ney transplantation (LDKT) for CKD after LT is known to provide favorable outcomes. We describe the long-term follow-up findings of a patient who underwent LDKT after bilateral cadaveric LT. A 37-year-old male underwent LDKT for CKD 18 years after receiving bilateral cadaveric LT. He developed chronic lung allograft dysfunction (CLAD) 20 years after the LT; however, at 26 years after the initial LT, he is still alive with no pro-gression of CLAD or CKD. KT could be a viable option for CKD even after LT in Japan.

DOI： 10.18926/AMO/61439

Lung Laceration Caused by Short Hookwire Placement Before Video-Assisted Thoracoscopic Surgery. International journal

Kazuaki Munetomo, Yusuke Matsui, Toshihiro Iguchi, Takao Hiraki, Hiromasa Yamamoto, Shinichi Toyooka, Susumu Kanazawa

Cardiovascular and interventional radiology 44 ( 2 ) 339 - 341 2021.2

Volumetric PET Parameters Predict Prognosis after Definitive Chemoradiotherapy with Cisplatin/Docetaxel for Stage III Non-Small Cell Lung Cancer.

Kuniaki Katsui, Takeshi Ogata, Akihiro Tada, Soichi Sugiyama, Kotaro Yoshio, Masahiro Kuroda, Katsuyuki Kiura, Yoshinobu Maeda, Shinichi Toyooka, Takao Hiraki, Susumu Kanazawa

Acta medica Okayama 75 ( 1 ) 15 - 23 2021.2

Language：English Publishing type：Research paper (scientific journal)

The aim of this study was to investigate whether volumetric positron emission tomography (PET) parameters are prognostic predictors in stage III non-small cell lung cancer patients receiving definitive concurrent chemo-radiotherapy (CCRT) with cisplatin/docetaxel. Cases involving definitive CCRT were reviewed retrospectively, and the maximum standardized uptake value, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated. The relationships between these PET parameters and prognosis were analyzed. MTV and TLG were significant predictors of distant metastasis-free survival (DMFS) (p = 0.0003 and 0.0005, respectively) and progression-free survival (PFS) (p = 0.001 and 0.0007, respectively). The three-year DMFS rates in patients with low and high MTV were 13.3% and 64.6%, respectively, and the corresponding values in those with low and high TLG were 13.3% and 65.2%, respectively. The three-year PFS rates in patients with low and high MTV were 13.3% and 57.8%, respectively, and the corresponding values in patients with low and high TLG were 13.3% and 57.8%, respectively. However, MTV and TLG were not predictors of local control or overall sur-vival. We demonstrated that volumetric PET parameters were predictors of patients receiving definitive CCRT. Our findings contradict the findings of previous reports and warrant further research to validate them.

DOI： 10.18926/AMO/61429

Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment (edition 2.1)

Yoichi Naito, Hiroyuki Aburatani, Toraji Amano, Eishi Baba, Toru Furukawa, Tetsu Hayashida, Eiso Hiyama, Sadakatsu Ikeda, Masashi Kanai, Motohiro Kato, Ichiro Kinoshita, Naomi Kiyota, Takashi Kohno, Shinji Kohsaka, Keigo Komine, Itaru Matsumura, Yuji Miura, Yoshiaki Nakamura, Atsushi Natsume, Kazuto Nishio, Katsutoshi Oda, Naoyuki Oda, Natsuko Okita, Kumiko Oseto, Kuniko Sunami, Hideaki Takahashi, Masayuki Takeda, Shimon Tashiro, Shinichi Toyooka, Hideki Ueno, Shinichi Yachida, Takayuki Yoshino, Katsuya Tsuchihara

International Journal of Clinical Oncology 26 ( 2 ) 233 - 283 2021.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

<title>Abstract</title><sec>
<title>Background</title>
To promote precision oncology in clinical practice, the Japanese Society of Medical Oncology, the Japanese Society of Clinical Oncology, and the Japanese Cancer Association, jointly published “Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment” in 2017. Since new information on cancer genomic medicine has emerged since the 1st edition of the guidance was released, including reimbursement for NGS-based multiplex gene panel tests in 2019, the guidance revision was made.

</sec><sec>
<title>Methods</title>
A working group was organized with 33 researchers from cancer genomic medicine designated core hospitals and other academic institutions. For an impartial evaluation of the draft version, eight committee members from each society conducted an external evaluation. Public comments were also made on the draft. The finalized Japanese version was published on the websites of the three societies in March 2020.

</sec><sec>
<title>Results</title>
The revised edition consists of two parts: an explanation of the cancer genomic profiling test (General Discussion) and clinical questions (CQs) that are of concern in clinical practice. Particularly, patient selection should be based on the expectation that the patient's post-test general condition and organ function will be able to tolerate drug therapy, and the optimal timing of test should be considered in consideration of subsequent treatment plans, not limited to treatment lines.

</sec><sec>
<title>Conclusion</title>
We expect that the revised version will be used by healthcare professionals and will also need to be continually reviewed in line with future developments in cancer genome medicine.

</sec>

DOI： 10.1007/s10147-020-01831-6

Other Link： http://link.springer.com/article/10.1007/s10147-020-01831-6/fulltext.html

Staged surgery for empyema and lung gangrene caused by pseudoaneurysm after radiofrequency ablation. International journal

Kentaro Nakata, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

Interactive cardiovascular and thoracic surgery 32 ( 5 ) 831 - 833 2021.1

Language：English Publishing type：Research paper (scientific journal)

Lung gangrene is a potentially fatal disease, and primary or staged surgery, depending on the patient's condition, is reported to be useful. We describe successful management, by staged surgery, of a rare case of empyema and lung gangrene complicating lung radiofrequency ablation. The patient, who was a diabetic with colorectal pulmonary metastases, underwent embolization of a pulmonary artery pseudoaneurysm in the right basal segment that developed after lung radiofrequency ablation. He subsequently developed lung gangrene caused by lung ischaemia, and empyema, necessitating pleural decortication followed by open-window thoracostomy. Subsequently, right basal segmentectomy was performed, with thoracostoma closure. Staged surgery might be beneficial for high-risk patients with empyema and lung gangrene caused by lung ischaemia.

DOI： 10.1093/icvts/ivaa331

Allele-Specific Role of ERBB2 in the Oncogenic Function of EGFR L861Q in EGFR-Mutant Lung Cancers

Hiroki Sato, Michael Offin, Daisuke Kubota, Helena A. Yu, Clare Wilhelm, Shinichi Toyooka, Romel Somwar, Mark G. Kris, Marc Ladanyi

Journal of Thoracic Oncology 16 ( 1 ) 113 - 126 2021.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Inc.

Introduction: Unlike common EGFR mutations, many less common EGFR mutations remain poorly characterized in terms of oncogenic function and drug sensitivity. Here, we characterize the subset of lung adenocarcinoma harboring EGFR L861Q through both preclinical and clinical investigations. Methods: We reviewed clinical and genomic data from patients with EGFR-mutant lung cancer. We established cells expressing EGFR mutations and performed functional analysis of L861Q in comparison with common EGFR mutations. Results: Among the patients with lung cancer, 3.4% (47 of 1367) possess an EGFR L861Q mutation. Of the patients with L861Q, 23.4% (11 of 47) had a concurrent exon 18 mutation (typically involving G719). In vitro studies revealed that the oncogenic activity of L861Q is dependent on asymmetric dimerization. Cells expressing L861Q were less sensitive to EGFR-specific inhibitors compared with cells expressing L858R but were similarly sensitive to pan-ERBB inhibitors. In cells expressing L861Q, ERBB2 phosphorylation was markedly higher compared with cells expressing L858R, and an enhanced interaction between EGFR and ERBB2 was observed in coimmunoprecipitation studies. In addition, treatment with osimertinib enhanced expression of the antiapoptotic protein MCL1, and knockdown of ERBB2 suppressed the expression of MCL1 in L861Q, raising the possibility of differential allele-specific cross-phosphorylation of ERBB2. Moreover, compared with EGFR-specific inhibitors, pan-ERBB inhibitors exerted superior growth inhibitory effects on cells expressing compound L861Q/G719X mutations. Conclusions: Our results suggest that ERBB2 plays a previously unrecognized role in EGFR L861Q-driven tumorigenesis, and pan-ERBB inhibitors are likely to be more effective than selective EGFR tyrosine kinase inhibitors in this setting.

DOI： 10.1016/j.jtho.2020.09.019

Effect of isoflavones on breast cancer cell development and their impact on breast cancer treatments. International journal

Minami Hatono, Hirokuni Ikeda, Yoko Suzuki, Yukiko Kajiwara, Kengo Kawada, Takahiro Tsukioki, Mariko Kochi, Ken Suzawa, Takayuki Iwamoto, Hiromasa Yamamoto, Tadahiko Shien, Masaomi Yamane, Naruto Taira, Hiroyoshi Doihara, Shinichi Toyooka

Breast cancer research and treatment 185 ( 2 ) 307 - 316 2021.1

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Epidemiological studies have suggested that intake of soy isoflavones is associated with a reduced risk of development of breast cancer and an improved prognosis in patients with breast cancer. In addition, basic research has demonstrated the antitumor effects of these compounds on breast cancer cell lines. However, the detailed effects of the intake of equol, which is one of the metabolites of the soy isoflavones, are yet to be clarified on the risk of development and recurrence of breast cancer and its interactions with drugs used for treating breast cancer. This study aimed to determine the antitumor effects of equol and investigate the impact of adding equol to therapeutic agents for breast cancer using breast cancer cell lines. METHODS: We examined the antitumor effect of equol on breast cancer cell lines using MTS assay. We also studied the combined effect of equol and the existing hormonal or chemotherapeutic agents using combination index. We evaluated the expressions of the related proteins by Western blot analysis and correlated the findings with the antitumor effect. RESULTS: Equol showed bi-phasic protumor and antitumor effects; at a low concentration, it promoted the tumor growth in hormone receptor-positive cell lines, whereas antitumor effects were generally observed when an excessive amount of dose unexpected in the blood and the tissue was administered. When used with tamoxifen, equol might have some antagonistic effect, although it depends on equol concentration and the type of cancer cells. CONCLUSIONS: We confirmed that equol has dual action, specifically a tumor growth-promoting effect and an antitumor effect. Although the results suggested that equol might exert an antagonistic effect against tamoxifen depending on the concentration, equol did not exert an antagonistic effect on other therapeutic agents.

DOI： 10.1007/s10549-020-05957-z

The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis. International journal

Kota Araki, Rie Kinoshita, Nahoko Tomonobu, Yuma Gohara, Shuta Tomida, Yuta Takahashi, Satoru Senoo, Akihiko Taniguchi, Junko Itano, Ken-Ichi Yamamoto, Hitoshi Murata, Ken Suzawa, Kazuhiko Shien, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Kouichi Ichimura, Masahiro Nishibori, Nobuaki Miyahara, Shinichi Toyooka, Masakiyo Sakaguchi

Journal of molecular medicine (Berlin, Germany) 99 ( 1 ) 131 - 145 2021.1

Language：English Publishing type：Research paper (scientific journal)

In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts' differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia. HIGHLIGHTS: S100A8/A9 level is highly upregulated in the IPF patients' lungs as well as the blood. S100A8/A9 promotes not only the growth of fibroblasts but also differentiation to myofibroblasts. The cell surface RAGE acts as a crucial receptor to the extracellular S100A8/A9 in fibroblasts. The anti-S100A8/A9 antibody effectively suppresses the progression of IPF in a mouse model. In idiopathic pulmonary fibrosis (IPF), S100A8/A9, a heterodimer composed of S100A8 and S100A9 proteins, plays a crucial role in the onset of inflammation and the subsequent formation of a feed-forward inflammatory loop that promotes fibrosis. (1) The local, pronounced increase in S100A8/A9 in the injured inflammatory lung region-which is provided mainly by the activated neutrophils and macrophages-exerts strong inflammatory signals accompanied by dozens of inflammatory soluble factors including cytokines, chemokines, and growth factors that further act to produce and secrete S100A8/A9, eventually making a sustainable inflammatory circuit that supplies an indefinite presence of S100A8/A9 in the extracellular space with a mal-increased level. (2) The elevated S100A8/A9 compels fibroblasts to activate through receptor for advanced glycation end products (RAGE), one of the major S100A8/A9 receptors, resulting in the activation of NFκB, leading to fibroblast mal-events (e.g., elevated cell proliferation and transdifferentiation to myofibroblasts) that actively produce not only inflammatory cytokines but also collagen matrices. (3) Finally, the S100A8/A9-derived activation of lung fibroblasts under a chronic inflammation state leads to fibrosis events and constantly worsens fibrosis in the lung. Taken together, these findings suggest that the extracellular S100A8/A9 heterodimer protein is a novel mainstay soluble factor for IPF that exerts many functions as described above (1-3). Against this background, we herein applied the developed S100A8/A9 neutralizing antibody to prevent IPF. The IPF imitating lung fibrosis in an IPF mouse model was effectively blocked by treatment with the antibody, leading to enhanced survival. The developed S100A8/A9 antibody, as an innovative novel biologic, may help shed light on the difficulties encountered with IPF therapy in clinical settings.

DOI： 10.1007/s00109-020-02001-x

外科系新専門医制度のあるべきグランドデザイン地域枠医師に対する外科専門研修のあり方充実した地域医療の実現を目指して

黒田新士, 吉田龍一, 池田宏国, 岡崎幹生, 大澤晋, 小谷恭弘, 山根正修, 杉本誠一郎, 菊地覚次, 安井和也, 野田卓男, 笠原真悟, 豊岡伸一, 土井原博義, 藤原俊義

日本外科学会雑誌 122 ( 1 ) 83 - 85 2021.1

希望と安心をもたらす医療安全管理無過失補償制度の可能性も含めて外科領域の医療安全は手術室でのノンテクニカルスキル

山根正修, 豊岡伸一

日本外科学会雑誌 122 ( 1 ) 111 - 113 2021.1

外科系新専門医制度のあるべきグランドデザイン地域枠医師に対する外科専門研修のあり方充実した地域医療の実現を目指して

黒田新士, 吉田龍一, 池田宏国, 岡崎幹生, 大澤晋, 小谷恭弘, 山根正修, 杉本誠一郎, 菊地覚次, 安井和也, 野田卓男, 笠原真悟, 豊岡伸一, 土井原博義, 藤原俊義

日本外科学会雑誌 122 ( 1 ) 83 - 85 2021.1

Visceral Adipose Mass and Radiation Pneumonitis After Concurrent Chemoradiotherapy in Patients With Non-small-cell Lung Cancer. International journal

Kuniaki Katsui, Takeshi Ogata, Soichi Sugiyama, Kotaro Yoshio, Masahiro Kuroda, Masaomi Yamane, Takao Hiraki, Katsuyuki Kiura, Shinichi Toyooka, Susumu Kanazawa

Cancer diagnosis & prognosis 1 ( 2 ) 61 - 67 2021

Language：English Publishing type：Research paper (scientific journal)

AIM: To investigate whether muscle and adipose mass are associated with radiation pneumonitis (RP) in patients with non-small cell lung cancer undergoing preoperative concurrent chemoradiotherapy. PATIENTS AND METHODS: We calculated body mass index and determined skeletal muscle, psoas muscle, visceral adipose tissue (VAI), and subcutaneous adipose tissue indices, and visceral-to-subcutaneous adipose tissue area ratio for patients using computed tomography. We examined their relationship with grade 2 or more RP. RESULTS: Among 94 patients, 28 experienced grade 2 or more RP. On multivariate analysis, only VAI was associated with grade 2 or more RP (all p=0.026). The 6-month incidence rates of grade 2 or more RP were 21.4% and 36.8% in patients with VAI <39 and ≥39 cm 2 /m 2 , respectively. CONCLUSION: High visceral adipose mass is associated with grade 2 or more RP in patients undergoing preoperative concurrent chemoradiotherapy. Measuring visceral adipose mass may help to predict RP occurrence. Further studies are needed to validate our findings.

DOI： 10.21873/cdp.10009

Preoperative renal dysfunction and long-term survival after surgery for non–small cell lung cancer

Tomohito Saito, Tomohiro Murakawa, Yasushi Shintani, Jiro Okami, Etsuo Miyaoka, Ichiro Yoshino, Hiroshi Date, Hiroyuki Ito, Takashi Ohtsuka, Shinichi Toyooka, Takeshi Mori, Shun-ichi Watanabe, Hisao Asamura, Masayuki Chida, Shunsuke Endo, Mitsutaka Kadokura, Ryoichi Nakanishi, Japanese Joint Committee of Lung Cancer Registry

Journal of Thoracic and Cardiovascular Surgery 2021

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Inc.

Objective: To investigate the association of preoperative renal dysfunction and long-term outcomes following lung cancer surgery. Methods: Using the Japanese Lung Cancer Registry data, we retrospectively examined 16,377 patients who underwent surgery for non–small cell lung cancer during 2010. Patients' renal function status was categorized as follows: serum creatinine &lt
1.5 mg/dL (control, n = 16,169), serum creatinine ≥1.5 mg/dL with no dialysis (nondialysis-dependent chronic kidney disease, n = 113), and dialysis-dependent end-stage renal disease (n = 95). The association of patients' characteristics with overall survival was evaluated using multivariate Cox proportional hazard model. Results: The 5-year overall survival rates in patients with dialysis-dependent end-stage renal disease and with nondialysis-dependent chronic kidney disease were significantly worse than that in the control group (52.9% and 57.5% vs 78.0%
P &lt
.001 for both comparisons), but were comparable to the reported 5-year overall survival rates in the natural history of end-stage renal disease (∼60%) and moderate to severe chronic kidney disease (∼50%). Cancer causes not related to lung cancer accounted for 62.2% of deaths in dialysis-dependent end-stage renal disease, which was more frequent than that in the control group (P =.002). Dialysis-dependent end-stage renal disease and nondialysis-dependent chronic kidney disease were independent risk factors for overall survival after lung cancer surgery (hazard ratio, 2.05 [P &lt
.001] and hazard ratio, 2.04 [P =.001], respectively). Conclusions: Preoperative renal dysfunction may be adversely associated with overall survival after lung cancer surgery. Our findings could aid patients to set proper expectation of the risks and benefits about surgery for lung cancer.

DOI： 10.1016/j.jtcvs.2021.09.008

METex14 skipping testing guidance for lung cancer patients: The guidance from the biomarker committee, the Japan lung cancer society

Yasushi Yatabe, Koichi Goto, Shingo Matsumoto, Yutaka Hatanaka, Naoko Arakane, Sadakatsu Ikeda, Akira Inoue, Ichiro Kinoshita, Hideharu Kimura, Tomohiro Sakamoto, Miyako Satouchi, Junichi Shimizu, Kuniko Sunami, Koji Tsuta, Shinichi Toyooka, Kazuto Nishio, Kazumi Nishino, Masashi Mikubo, Tomoyuki Yokose, Hirotoshi Dosaka-Akita

Japanese Journal of Lung Cancer 61 ( 5 ) 361 - 370 2021

Language：English Publishing type：Research paper (scientific journal) Publisher：Japan Lung Cancer Society

MET, a proto-oncogene located in 7q21-q31, encodes a receptor tyrosine kinase, of which mutations, amplification, fusions and overexpression are reported to be associated with oncogenesis. MET exon 14 (METex14) skipping is one of such MET alterations, and this abnormality is caused by genetic deletions or mutations in the intron/exon boundary sites as splice-site abnormalities, resulting in the generation of a deleted transcript in exon 14. This exon encodes juxtamembrane domain, which contains the binding site of c-Cbl E 3 ubiquitin ligase. Therefore, lack of METex14 suppresses ubiquitination and degradation, which lead to functional MET activation. In 2020, tepotinib and capmatinib were approved for the treatment of advanced recurrent lung cancer with this alteration. To implement the molecular testing to detect METex14 skipping in clinical practice, a practical guidance was released from the Biomarker Committee of the Japan Lung Cancer Society, and the content is introduced in this article.

DOI： 10.2482/haigan.61.361

Prognostic nutrition index affects the prognosis of patients undergoing trimodality therapy for locally advanced non-small cell lung cancer.

Junichi Soh, Ken Suzawa, Kazuhiko Shien, Shinji Otani, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Kuniaki Katsui, Masaomi Yamane, Katsuyuki Kiura, Susumu Kanazawa, Shinichi Toyooka

Surgery today 50 ( 12 ) 1610 - 1618 2020.12

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Trimodality therapy, comprised of induction chemoradiotherapy (iCRT) followed by surgery, is a highly invasive treatment option for locally advanced non-small cell lung cancers (LA-NSCLCs; defined as a heterogenous disease). We conducted this study to investigate the prognostic nutritional index (PNI) of LA-NSCLC patients undergoing trimodality therapy, which has not been studied in detail before. METHODS: The subjects of this retrospective study were 127 patients who underwent trimodality therapy between 1999 and 2016. We measured the PNI at three points: before iCRT (pre-iCRT), before the operation, and after the operation. RESULTS: PNIs decreased significantly as treatment progressed. Patients with clinical T3/4 (cT3/4) disease had a significantly lower PNI than those with cT1/2 disease, but the extent of lymph-node metastasis did not affect the PNI at any point. Using the cut-off values of receiver-operating curve analyses, multivariable analyses revealed that a high PNI pre-iCRT correlated significantly with a better survival of LA-NSCLC patients, especially those with cT3/4 disease (hazard ratio 3.84; 95% confidential interval 1.34-12.5, P = 0.012). CONCLUSIONS: Measuring the PNI before trimodality therapy is important for predicting the clinical outcome of patients with LA-NSCLC, with differing predictive ability according to the disease extent. Perioperative intensive nutritional intervention must be considered for patients who undergo trimodality therapy for LA-NSCLC.

DOI： 10.1007/s00595-020-02067-7

Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction. International journal

Kazuya Nishii, Kadoaki Ohashi, Tomoki Tamura, Kiichiro Ninomiya, Takehiro Matsubara, Satoru Senoo, Hirohisa Kano, Hiromi Watanabe, Naohiro Oda, Go Makimoto, Hisao Higo, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Hiromasa Yamamoto, Shuta Tomida, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura

Oncology letters 20 ( 6 ) 393 - 393 2020.12

Language：English Publishing type：Research paper (scientific journal)

The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non-small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC-ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54-81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post-operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC-ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC-ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC-ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult.

DOI： 10.3892/ol.2020.12256

Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction

Kazuya Nishii, Kadoaki Ohashi, Tomoki Tamura, Kiichiro Ninomiya, Takehiro Matsubara, Satoru Senoo, Hirohisa Kano, Hiromi Watanabe, Naohiro Oda, Go Makimoto, Hisao Higo, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Hiromasa Yamamoto, Shuta Tomida, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura

ONCOLOGY LETTERS 20 ( 6 ) 2020.12

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non-small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube (TM) method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC-ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54-81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post-operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC-ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC-ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC-ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult.

DOI： 10.3892/ol.2020.12256

Multiplex gene-panel testing for lung cancer patients. International journal

Yasushi Yatabe, Kuniko Sunami, Koichi Goto, Kazuto Nishio, Naoko Aragane, Sadakatsu Ikeda, Akira Inoue, Ichiro Kinoshita, Hideharu Kimura, Tomohiro Sakamoto, Miyako Satouchi, Junichi Shimizu, Koji Tsuta, Shinichi Toyooka, Kazumi Nishino, Yutaka Hatanaka, Shingo Matsumoto, Masashi Mikubo, Tomoyuki Yokose, Hirotoshi Dosaka-Akita

Pathology international 70 ( 12 ) 921 - 931 2020.12

Language：English Publishing type：Research paper (scientific journal)

The year 2019 was considered to be the first year of cancer genome medicine in Japan, with three gene-panel tests using next-generation sequencing (NGS) techniques being introduced into clinical practice. Among the three tests, the Oncomine CDx Target test was approved under the category of regular molecular testing for lung cancer, which meant that this test could be used to select patients for molecularly targeted drugs. Conversely, the other two tests, NCC OncoPanel and FoundationOne CDx, were assigned to be used under the National Cancer Genome Medicine Network, and implementation was restricted to patients for whom standard treatment was completed or expected to be completed. These NGS tests can detect a series of genetic alterations in individual tumors, which further promotes the development of therapeutic agents and elucidates molecular pathways. The NGS tests require appropriate tissue size and tumor cell content, which can be accessed only by pathologists. In this report, we review the current reimbursement schema in our national healthcare policy and the requirements of the specimens for NGS testing based on the recently published 'Guidance of Gene-panel Testing Using Next-Generation Sequencers for Lung Cancer', by the Japanese Society of Lung Cancer.

DOI： 10.1111/pin.13023

Clinical features and outcomes of patients with stage I multiple primary lung cancers. International journal

Yasushi Shintani, Jiro Okami, Hiroyuki Ito, Takashi Ohtsuka, Shinichi Toyooka, Takeshi Mori, Shun-Ichi Watanabe, Hisao Asamura, Masayuki Chida, Hiroshi Date, Shunsuke Endo, Takeshi Nagayasu, Ryoichi Nakanishi, Etsuo Miyaoka, Meinoshin Okumura, Ichiro Yoshino

Cancer science 112 ( 5 ) 1924 - 1935 2020.11

Language：English Publishing type：Research paper (scientific journal)

The number of patients with multiple primary lung cancers (MPLC) is rising. We studied the clinical features and factors related to outcomes of MPLC patients, using the database of surgically resected lung cancer (LC) cases compiled by the Japanese Joint Committee of Lung Cancer Registry. From the 18,978 registered cases, 9,689 patients with clinical stage I non-small cell lung cancer who achieved complete resection were extracted. Tumors were defined as synchronous MPLC when multiple LC was simultaneously resected or treatment was performed within 2 years after the initial surgery, while metachronous MPLC was defined as second LC treated more than 2 years after the initial surgery. Of these cases, 579 (6.0%) were synchronous MPLC and 477 (5.0%) metachronous MPLC, with 51 overlapping cases. Whereas female, non-smoker, low consolidation tumor ratio (CTR), and adenocarcinoma were significantly more frequent in the synchronous MPLC group, patients with metachronous MPLC had higher frequencies of males, smokers, chronic obstructive pulmonary disease (COPD), and non-adenocarcinoma. There was no significant difference for survival rate between patients with and without synchronous or metachronous MPLC. Age, gender, CTR for second LC, and histological combination of primary and second LC were prognostic indicators for both types of MPLC, while logistic regression analysis showed that female, history of malignant disease other than LC, and COPD were risk factors for MPLC incidence. The present findings may have major implications regarding MPLC diagnosis and identification of independent prognosticators, and provide valuable information for postoperative management of patients with MPLC.

DOI： 10.1111/cas.14748

A Simple Prognostic Benefit Scoring System for Sarcoma Patients with Pulmonary Metastases: Sarcoma Lung Metastasis Score

Haruchika Yamamoto, Hiromasa Yamamoto, Junichi Soh, Etsuji Suzuki, Kei Namba, Ken Suzawa, Kentaroh Miyoshi, Shinji Otani, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Takashi Yorifuji, Katsuhito Takahashi, Shinichi Toyooka

Annals of Surgical Oncology 2020.11

Impact of the preoperative body mass index on the postoperative outcomes in patients with completely resected non-small cell lung cancer: A retrospective analysis of 16,503 cases in a Japanese Lung Cancer Registry Study. International journal

Koichi Fukumoto, Shoichi Mori, Yasushi Shintani, Jiro Okami, Hiroyuki Ito, Takashi Ohtsuka, Shinichi Toyooka, Takeshi Mori, Shun-Ichi Watanabe, Hisao Asamura, Masayuki Chida, Hiroshi Date, Shunsuke Endo, Takeshi Nagayasu, Ryoichi Nakanishi, Etsuo Miyaoka, Meinoshin Okumura, Ichiro Yoshino

Lung cancer (Amsterdam, Netherlands) 149 120 - 129 2020.11

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: The aim of this study was to evaluate the impact of the preoperative body mass index (BMI) on the postoperative outcomes in patients with completely resected non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The data of patients with NSCLC in whom R0 resection was achieved were extracted from the database of NSCLC samples accumulated by the Japanese Joint Committee of Lung Cancer Registry in the year 2010, and the surgical outcomes including postoperative morbidity, mortality and the prognosis, were evaluated. RESULTS: Among 18,978 registered lung cancer cases, 16,509 patients (9996 men and 6513 women) were extracted. The median of age was 69 years old, and the histologic types included adenocarcinoma (n = 12,029), squamous cell carcinoma (n = 3286), large-cell carcinoma (n = 488) and others. The patients were divided into three groups according to their BMI: normal (BMI 18.5 to <25), underweight (BMI < 18.5) and overweight (BMI ≥ 25). Multivariate logistic regression analyses of factors associated with postoperative morbidity and mortality showed no significant differences among the three groups. In comparison to the normal group, the overall survival (OS) of the underweight group was significantly worse (p < 0.001) while that of the overweight group was marginally better (p = 0.075). A multivariate analysis of factors associated with OS showed that in addition to the age, sex and clinical stage, the preoperative BMI (underweight group vs. normal group: hazard ratio [HR] 1.417 [95% confidence interval {CI}: 1.278-1.572, p < 0.001], overweight group vs. normal group: HR 0.883 [95% CI: 0.806-0.967, p = 0.007]) was an independent prognostic factor. A multivariate analysis for the disease-free survival (DFS) also showed the preoperative BMI to be an independent significant prognostic factor. CONCLUSIONS: The preoperative BMI is an independent prognostic factor in patients with completely resected NSCLC. A low preoperative BMI was associated with significantly poor survival in Japan.

DOI： 10.1016/j.lungcan.2020.09.011

夢を実現するためのキャリアパス・教育システム進化する外科マネージメントセンターそれぞれの夢を実現するためのキャリアパス支援システム

菊地覚次, 黒田新士, 吉田龍一, 香川俊輔, 山根正修, 小谷恭弘, 笠原真悟, 豊岡伸一, 藤原俊義

日本外科学会雑誌 121 ( 6 ) 669 - 671 2020.11

Continuing surgical education of non-technical skills. International journal

Masaomi Yamane, Seiichiro Sugimoto, Etsuji Suzuki, Keiju Aokage, Mikio Okazaki, Junichi Soh, Makio Hayama, Yuji Hirami, Takashi Yorifuji, Shinichi Toyooka

Annals of medicine and surgery (2012) 58 177 - 186 2020.10

Language：English Publishing type：Research paper (scientific journal)

Background: The non-technical skills for surgeons (NOTSS) system was developed as a tool to assess surgical skills for patient safety during surgery. This study aimed to develop a NOTSS-based training system for surgical trainees to acquire non-technical skills using a chest surgery scenario in a wet lab. Materials and methods: Trainees were categorized into three subgroups according to the years of experience as follows: Level A: 6 years or more; Level B: 3-5 years; and Level C: 1-2 years. Three stages of surgical procedure were designed: 1. chest wall resection and right upper lobe lobectomy, 2. right middle lobe sleeve lobectomy, and 3. right lower lobe lobectomy. One instructor was assigned to each operation table, who evaluated each participant's NOTSS scores consisting of 16 elements. Results: When comparing average NOTSS score of all the three procedures, significant differences were observed between Level A, B, and C trainees. As an example of varying elements by procedure, Level A trainees demonstrated differences in Situation Awareness, and a significant difference was observed in Level C trainees regarding the elements of Decision Making. On the contrary, no significant difference was observed among Level B trainees. In the comparison between first-time and experienced participants, a significant improvement was observed in some elements in Level B and C trainees. Conclusion: This study highlights the usefulness and feasibility of the NOTSS scoring system for surgeons with different experiences and the effectiveness of providing feedback to trainees during intraoperative handoffs in a wet lab.

DOI： 10.1016/j.amsu.2020.07.062

Chemoradiation therapy for non-small cell lung cancer exacerbates thoracic aortic calcification determined by computed tomography.

Takashi Miki, Shunsaku Miyauchi, Toru Miyoshi, Masashi Yoshida, Keishi Ichikawa, Junichi Soh, Kazufumi Nakamura, Katsuyuki Kiura, Susumu Kanazawa, Shinichi Toyooka, Hiroshi Ito

Heart and vessels 35 ( 10 ) 1401 - 1408 2020.10

Language：English Publishing type：Research paper (scientific journal)

Preoperative chemoradiation therapy (CRT) has been considered as an effective treatment for non-small cell lung cancer. However, there is concern that CRT progresses atherosclerosis in cancer survivors. This study sought to determine if preoperative CRT exacerbated thoracic aortic calcification (TAC) detected by computed tomography (CT) in patients with lung cancer. Among 473 patients who underwent surgery for lung cancer at Okayama University Hospital between 2011 and 2015, 34 patients undergoing preoperative CRT and surgery (CRT group) and 33 matched patients undergoing initial surgery (non-CRT group) were analyzed and compared. The volume of TAC between the 2nd and 12th thoracic vertebrae was quantitatively measured by CT at baseline and 1-year follow-up. Patients in the CRT group (62 ± 7 years old, 74% male) received cisplatin chemotherapy with docetaxel or vinorelbine and radiation therapy (mean 47.3 ± 4.0 Gy). The percent change in TAC volume was significantly greater in the CRT compared with the non-CRT group (58.7%, 95% confidence interval [CI] 41.7-75.7% vs. 27.2%, 95% CI 9.9-44.4%; p = 0.01). Multivariate logistic regression analysis identified CRT as an independent factor associated with greater TAC progression (> the median value) (odds ratio 3.63, 95% CI 1.19-11.08; p = 0.02). In conclusion, preoperative CRT for lung cancer exacerbates TAC. Follow-up of such patients should thus include careful longitudinal assessment for cardiovascular disease.

DOI： 10.1007/s00380-020-01611-2

A Giant Thymic Cyst Accompanied by Acute Mediastinitis.

Akihiro Miura, Kazuhiko Shien, Tomohiro Toji, Shinji Otani, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Junichi Soh, Masaomi Yamane, Shinichi Toyooka

Acta medica Okayama 74 ( 5 ) 431 - 433 2020.10

Language：English

We encountered a rare case of thymic cyst accompanied by mediastinitis. A 39-year-old Japanese male presented with fever and chest pain. The chest CT revealed a mass composed of a lobular cystic lesion with inflammation, suggesting the onset of mediastinitis. A definitive histological diagnosis was not obtained, and we performed a thymectomy. Pathologically, the thymic cyst was accompanied by multiple cavities, mimicking thymic cysts, caused by the inflammatory abscess. The surrounding adipose tissue showed inflammatory cell infiltrations with chronic fibrosis. These findings indicate that clinicians should be aware that thymic cysts may cause severe mediastinitis.

DOI： 10.18926/AMO/60804

肺移植待機患者の予後予測におけるPrognostic Nutrition Index(PNI)の有用性

松原慧, 大谷真二, 清水大, 富岡泰章, 山本治慎, 塩谷俊雄, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

移植 55 ( 総会臨時 ) 353 - 353 2020.10

左上顎洞腫瘤を契機に発見された左心室内への浸潤を伴う肺神経内分泌癌(小細胞癌)の集学的治療の一例

平生敦子, 加藤有加, 西達也, 岡崎幹生, 二宮貴一朗, 二宮崇, 久保寿夫, 頼冠名, 市原英基, 大橋圭明, 山根正修, 堀田勝幸, 田端雅弘, 豊岡伸一, 前田嘉信, 木浦勝行

肺癌 60 ( 6 ) 683 - 683 2020.10

集学的治療が行われた局所進行肺癌患者における末梢血好中球/リンパ球比(NLR)の予後的意義について

津高慎平, 山本寛斉, 諏澤憲, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 658 - 658 2020.10

最新低侵襲手術におけるリンパ節郭清手技:単孔式VATS vs ロボット支援手術 RATSにおけるリンパ節郭清手技

岡崎幹生, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 464 - 464 2020.10

高分化腺癌-いつ切るの? すりガラス成分を有する小型肺癌に対する治療の至適介入時期

諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 484 - 484 2020.10

希少がん診断と治療悪性軟部腫瘍の免疫ゲノムプロファイリング LOHはT・Bリンパ球浸潤と生存に相関する

高橋克仁, 宮地康僚, 樋口肇, 菰原義弘, 相田真一, 山本寛斉, 諏澤憲, 高橋侑子, 豊岡伸一, 楢原啓之, 四元淳子, 大山優, 矢嶋淳, 大野烈士, 寺岡慧

日本癌治療学会学術集会抄録集 58回 WS29 - 1 2020.10

非小細胞肺癌手術症例と末梢血リンパ球/単球比とその継時的変化の関連の検討

富岡泰章, 山本寛斉, 塩谷俊雄, 諏澤憲, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 587 - 587 2020.10

間質性肺炎合併肺癌:To treat, or not to treat? 間質性肺炎合併肺癌に対する外科的治療

山本寛斉, 松原慧, 富岡泰章, 塩谷俊雄, 諏澤憲, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 481 - 481 2020.10

ハイリスク症例をいかに手術に繋げるか? 導入放射線化学療法後の局所進行非小細胞肺癌に対する手術後に反回神経麻痺を発症した症例の検討

杉本誠一郎, 諏澤憲, 富岡泰章, 塩谷俊雄, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 492 - 492 2020.10

当院の肺移植後リンパ増殖性疾患7例の検討治療後のCLAD発症と日和見感染症による死亡をどう防ぐか

清水大, 大谷真二, 富岡泰章, 松原慧, 塩谷俊雄, 山本治慎, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

移植 55 ( 総会臨時 ) 246 - 246 2020.10

当院における高齢者レシピエント症例の検討

富岡泰章, 大谷真二, 清水大, 松原慧, 山本治慎, 塩谷俊雄, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

移植 55 ( 総会臨時 ) 253 - 253 2020.10

肺移植におけるLiquid biopsy ドナー由来血中遊離DNAとマイクロRNA

杉本誠一郎, 塩谷俊雄, 富岡泰章, 石上恵美, 石原恵, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 山根正修, 豊岡伸一

移植 55 ( 総会臨時 ) 242 - 242 2020.10

集学的治療が行われた局所進行肺癌患者における末梢血好中球/リンパ球比(NLR)の予後的意義について

津高慎平, 山本寛斉, 諏澤憲, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 658 - 658 2020.10

希少がん診断と治療悪性軟部腫瘍の免疫ゲノムプロファイリング LOHはT・Bリンパ球浸潤と生存に相関する

高橋克仁, 宮地康僚, 樋口肇, 菰原義弘, 相田真一, 山本寛斉, 諏澤憲, 高橋侑子, 豊岡伸一, 楢原啓之, 四元淳子, 大山優, 矢嶋淳, 大野烈士, 寺岡慧

日本癌治療学会学術集会抄録集 58回 WS29 - 1 2020.10

85歳以上高齢者肺癌手術の問題と課題について多施設共同研究の結果から

葉山牧夫, 藤原俊哉, 平見有二, 渡邉元嗣, 片岡正文, 西川仁士, 諏澤憲, 山本寛斉, 岡崎幹生, 豊岡伸一

肺癌 60 ( 6 ) 547 - 547 2020.10

非小細胞肺癌手術症例と末梢血リンパ球/単球比とその継時的変化の関連の検討

富岡泰章, 山本寛斉, 塩谷俊雄, 諏澤憲, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 587 - 587 2020.10

間質性肺炎合併肺癌:To treat, or not to treat? 間質性肺炎合併肺癌に対する外科的治療

山本寛斉, 松原慧, 富岡泰章, 塩谷俊雄, 諏澤憲, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 481 - 481 2020.10

高分化腺癌-いつ切るの? すりガラス成分を有する小型肺癌に対する治療の至適介入時期

諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 484 - 484 2020.10

ハイリスク症例をいかに手術に繋げるか? 導入放射線化学療法後の局所進行非小細胞肺癌に対する手術後に反回神経麻痺を発症した症例の検討

杉本誠一郎, 諏澤憲, 富岡泰章, 塩谷俊雄, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 492 - 492 2020.10

最新低侵襲手術におけるリンパ節郭清手技:単孔式VATS vs ロボット支援手術 RATSにおけるリンパ節郭清手技

岡崎幹生, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 464 - 464 2020.10

III期非小細胞肺癌に対する化学放射線療法後の放射線肺臓炎の検討

勝井邦彰, 尾形毅, 吉尾浩太郎, 黒田昌宏, 平木隆夫, 木浦勝行, 前田嘉信, 豊岡伸一, 金澤右

肺癌 60 ( 6 ) 577 - 577 2020.10

癌関連線維芽細胞を標的としたトラニラストの癌治療増感効果

大智宏祐, 諏澤憲, 枝園和彦, 武田達明, 山本寛斉, 岡本芳晴, 豊岡伸一

日本癌学会総会記事 79回 PJ14 - 8 2020.10

Overcoming epithelial-mesenchymal transition-mediated drug resistance with monensin-based combined therapy in non-small cell lung cancer. Reviewed International journal

Kosuke Ochi, Ken Suzawa, Shuta Tomida, Kazuhiko Shien, Jui Takano, Shunsaku Miyauchi, Tatsuaki Takeda, Akihiro Miura, Kota Araki, Kentaro Nakata, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Tadahiko Shien, Masaomi Yamane, Kazuo Azuma, Yoshiharu Okamoto, Shinichi Toyooka

Biochemical and biophysical research communications 529 ( 3 ) 760 - 765 2020.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis and is also associated with drug resistance. Thus, controlling EMT status is a research of interest to conquer the malignant tumors. MATERIALS AND METHODS: A drug repositioning analysis of transcriptomic data from a public cell line database identified monensin, a widely used in veterinary medicine, as a candidate EMT inhibitor that suppresses the conversion of the EMT phenotype. Using TGF-β-induced EMT cell line models, the effects of monensin on the EMT status and EMT-mediated drug resistance were assessed. RESULTS: TGF-β treatment induced EMT in non-small cell lung cancer (NSCLC) cell lines and the EGFR-mutant NSCLC cell lines with TGF-β-induced EMT acquired resistance to EGFR-tyrosine kinase inhibitor. The addition of monensin effectively suppressed the TGF-β-induced-EMT conversion, and restored the growth inhibition and the induction of apoptosis by the EGFR-tyrosine kinase inhibitor. CONCLUSION: Our data suggested that combined therapy with monensin might be a useful strategy for preventing EMT-mediated acquired drug resistance.

DOI： 10.1016/j.bbrc.2020.06.077

A phase 2 basket trial of combination therapy with trastuzumab and pertuzumab in patients with solid cancers harboring human epidermal growth factor receptor 2 amplification (JUPITER trial). International journal

Kenta Takahashi, Eri Ishibashi, Toshio Kubo, Yohei Harada, Hideyuki Hayashi, Masayuki Kano, Yasushi Shimizu, Hidekazu Shirota, Yukiko Mori, Manabu Muto, Chikashi Ishioka, Hirotoshi Dosaka-Akita, Hisahiro Matsubara, Hiroshi Nishihara, Naoko Sueoka-Aragane, Shinichi Toyooka, Akihiro Hirakawa, Ukihide Tateishi, Satoshi Miyake, Sadakatsu Ikeda

Medicine 99 ( 32 ) e21457 2020.8

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) gene amplification and mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. However, even if an actionable gene alteration is found, the incidence of HER2 amplification in these cancers is less than 5%. It is too difficult to conduct a conventional randomized, controlled trial in a rare fraction. Therefore, we have designed a organ-agnostic basket study, which covers a variety of solid cancers harboring HER2 amplification, in 1 study protocol. METHODS/DESIGN: This trial is a multicenter, single-arm, basket phase 2 study in Japan. Patients with solid cancers harboring HER2 amplification that have progressed with standard treatment, or rare cancers for which there is no standard treatment, will be eligible. Target cancers include bile duct, urothelial, uterine, ovarian, and other solid cancers where HER2 amplification is detected by comprehensive genomic profiling using next-generation sequencing technology. A total of 38 patients will be treated with combination therapy with trastuzumab and pertuzumab every 3 weeks until disease progression, unmanageable toxicity, death, or patient refusal. The primary endpoint is the objective response rate, and secondary endpoints are progression-free survival, overall survival, and duration of response. DISCUSSION: The aim of this trial is to evaluate the safety and efficacy of combination therapy with trastuzumab and pertuzumab in patients with locally advanced or metastatic, solid cancers harboring HER2 amplification. Instead of focusing on 1 organ type, our trial design uses a basket study focusing on HER2 amplification, regardless of the site or origin of the cancer. The results of our study will advance clinical and scientific knowledge concerning the treatment of locally advanced, rare solid cancers harboring HER2 amplification, using the combination of trastuzumab and pertuzumab. TRIAL REGISTRATION: This trial was registered in Japan Registry of Clinical Trials (jCRT) on February 25, 2019, as jRCT2031180150.

DOI： 10.1097/MD.0000000000021457

The neutrophil-to-lymphocyte ratio as a novel independent prognostic factor for multiple metastatic lung tumors from various sarcomas. Reviewed

Hiromasa Yamamoto, Kei Namba, Haruchika Yamamoto, Tomohiro Toji, Junichi Soh, Kazuhiko Shien, Ken Suzawa, Takeshi Kurosaki, Shinji Otani, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Katsuhito Takahashi, Toshiyuki Kunisada, Takahiro Oto, Shinichi Toyooka

Surgery today 2020.8

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Sarcomas are among the most refractory malignant tumors and often recur as pulmonary metastasis. Although the presence of a high neutrophil-to-lymphocyte ratio (NLR) has been associated with the prognosis of several malignancies, the relationship between the NLR and sarcoma with pulmonary metastasis is unclear. We investigated the impact of the NLR in patients who underwent surgical resection for metastatic lung tumors from various sarcomas. METHODS: The subjects of this retrospective study were 158 patients with metastatic lung tumors from various sarcomas, who underwent initial pulmonary metastasectomy between 2006 and 2015. We examined the clinicopathological variables, including the NLR and the characteristics of surgical procedures. Survival was estimated by the Kaplan-Meier method and prognostic factors were evaluated by multivariate analysis. RESULTS: Multivariate analysis revealed significantly better survival of the group with an NLR < 2.26 immediately before the most recent pulmonary metastasectomy, in addition to such factors as the largest resected lesion being < 22 mm, a disease-free interval of > 2 years, and 3 or more pulmonary metastasectomies. CONCLUSION: The NLR immediately before the most recent pulmonary metastasectomy is a novel independent prognostic factor, which may be helpful when considering repeated pulmonary metastasectomy.

DOI： 10.1007/s00595-020-02093-5

Fibrosis or Necrosis in Resected Lymph Node Indicate Metastasis Before Chemoradiotherapy in Lung Cancer Patients. Reviewed International journal

Yuta Takahashi, Junichi Soh, Kazuhiko Shien, Hiromasa Yamamoto, Masaomi Yamane, Katsuyuki Kiura, Susumu Kanazawa, Hiroyuki Yanai, Shinichi Toyooka

Anticancer research 40 ( 8 ) 4419 - 4423 2020.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND/AIM: The histological features of lymph nodes (LNs) treated by chemoradiotherapy (CRT) in non-small cell lung cancer (NSCLC) have not been well studied. The purpose of this study was to evaluate the histological findings of LNs affected by CRT. PATIENTS AND METHODS: Among 107 clinically N2 NSCLC patients who underwent induction CRT followed by surgery from 1999 to 2017, 24 patients who received pathological evaluation of mediastinal LN before CRT were enrolled in this study. Postoperatively, we histologically reviewed all resected LNs (n=117) of the station evaluated before CRT. RESULTS: Fibrosis and/or necrosis were observed in all investigated LN stations. Histological observation of fibrosis and/or necrosis in the resected LNs after CRT indicated the presence of LN metastasis before CRT. CONCLUSION: The metastatic LNs that responded to CRT showed specific histological features, which enabled us to know the accurate clinical stage of the patient even though cancer cells were not found in the post-treated LNs.

DOI： 10.21873/anticanres.14447

ウェットラボでのノンテクニカルスキル評価システムの有用性の検討

山根正修, 杉本誠一郎, 岡崎幹生, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) RO28 - 2 2020.8

肉腫多発肺転移に対する肺切除術

山本寛斉, 諏澤憲, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) O44 - 7 2020.8

外科系新専門医制度の発展・継続を加速する広域指導者養成プログラムの開発・運用

山根正修, 万代康弘, 伊野英男, 豊岡伸一

日本外科学会定期学術集会抄録集 120回 SSF - 2 2020.8

自然気胸後の器質化期膿胸に対する醸膿胸膜切除術明瞭な臓側胸膜外層の同定に基づいた剥離

清水大, 三好健太郎, 松原慧, 山本治慎, 諏澤憲, 大谷真二, 山本寛斎, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) MO59 - 10 2020.8

肉腫多発肺転移に対する肺切除術

山本寛斉, 諏澤憲, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) O44 - 7 2020.8

抗HMGB1抗体による肺虚血再灌流障害の抑制

中田憲太郎, 岡崎幹生, 清水大, 宮内俊作, 荒木恒太, 三浦章博, 塩谷俊雄, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 杉本誠一郎, 山根正修, 大藤剛弘, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) O47 - 4 2020.8

気胸を合併し、発見された肺原発血管肉腫の1切除例

毛利謙吾, 岡崎幹生, 塩谷俊雄, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) SP4 - 3 2020.8

肺移植から学ぶ呼吸器外科学肺移植から学ぶゲノム医療

杉本誠一郎, 塩谷俊雄, 山本治慎, 田中真, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) S - 7 2020.8

ロボット支援下肺葉切除術時の肺動脈損傷に対する対応

岡崎幹生, 諏澤憲, 塩谷俊雄, 三好健太郎, 大谷真二, 山本寛斉, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) V1 - 1 2020.8

臨床的N0・病理学的リンパ節転移陽性肺がんに対する肺切除の現状

諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) O3 - 1 2020.8

肺移植の問題点と改善策高度無気肺を合併したドナー肺による移植成績

塩谷俊雄, 杉本誠一郎, 山本治慎, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) PD1 - 3 2020.8

右下肺静脈・左心房経由で左心室まで浸潤した小細胞肺癌に対する緊急手術の1例

岡崎幹生, 諏澤憲, 塩谷俊雄, 三好健太郎, 大谷真二, 山本寛斉, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) RV3 - 1 2020.8

右下肺静脈・左心房経由で左心室まで浸潤した小細胞肺癌に対する緊急手術の1例

岡崎幹生, 諏澤憲, 塩谷俊雄, 三好健太郎, 大谷真二, 山本寛斉, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) RV3 - 1 2020.8

ロボット支援下肺葉切除術時の肺動脈損傷に対する対応

岡崎幹生, 諏澤憲, 塩谷俊雄, 三好健太郎, 大谷真二, 山本寛斉, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) V1 - 1 2020.8

ウェットラボでのノンテクニカルスキル評価システムの有用性の検討

山根正修, 杉本誠一郎, 岡崎幹生, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) RO28 - 2 2020.8

地域枠医師に対する外科専門研修のあり方充実した地域医療の実現を目指して

黒田新士, 吉田龍一, 池田宏国, 岡崎幹生, 大澤晋, 小谷恭弘, 山根正修, 杉本誠一郎, 菊地覚次, 安井和也, 野田卓男, 笠原真悟, 豊岡伸一, 土井原博義, 藤原俊義

日本外科学会定期学術集会抄録集 120回 SP - 4 2020.8

肺移植から学ぶ呼吸器外科学肺移植から学ぶゲノム医療

杉本誠一郎, 塩谷俊雄, 山本治慎, 田中真, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) S - 7 2020.8

肺移植の問題点と改善策高度無気肺を合併したドナー肺による移植成績

塩谷俊雄, 杉本誠一郎, 山本治慎, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) PD1 - 3 2020.8

気胸を合併し、発見された肺原発血管肉腫の1切除例

毛利謙吾, 岡崎幹生, 塩谷俊雄, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) SP4 - 3 2020.8

抗HMGB1抗体による肺虚血再灌流障害の抑制

中田憲太郎, 岡崎幹生, 清水大, 宮内俊作, 荒木恒太, 三浦章博, 塩谷俊雄, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 杉本誠一郎, 山根正修, 大藤剛弘, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) O47 - 4 2020.8

自然気胸後の器質化期膿胸に対する醸膿胸膜切除術明瞭な臓側胸膜外層の同定に基づいた剥離

清水大, 三好健太郎, 松原慧, 山本治慎, 諏澤憲, 大谷真二, 山本寛斎, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) MO59 - 10 2020.8

臨床的N0・病理学的リンパ節転移陽性肺がんに対する肺切除の現状

諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

日本呼吸器外科学会雑誌 34 ( 3 ) O3 - 1 2020.8

進化する外科マネージメントセンターそれぞれの夢を実現するためのキャリアパス支援システム

菊地覚次, 黒田新士, 吉田龍一, 香川俊輔, 山根正修, 小谷恭弘, 笠原真悟, 豊岡伸一, 藤原俊義

日本外科学会定期学術集会抄録集 120回 SP - 8 2020.8

外科の輝ける「未来」のために、我々が「今」できること

竹原裕子, 吉田龍一, 溝尾妙子, 剱持礼子, 光井恵麻, 佃和寧, 土井原博義, 豊岡伸一, 笠原真悟, 藤原俊義

日本外科学会定期学術集会抄録集 120回 SSF - 2 2020.8

Survival Outcomes of Treatment with Radiofrequency Ablation, Stereotactic Body Radiotherapy, or Sublobar Resection for Patients with Clinical Stage I Non-Small-Cell Lung Cancer: A Single-Center Evaluation. Reviewed International journal

Toshihiro Iguchi, Takao Hiraki, Yusuke Matsui, Toshiharu Mitsuhashi, Norihisa Katayama, Kuniaki Katsui, Junichi Soh, Jun Sakurai, Hideo Gobara, Shinichi Toyooka, Susumu Kanazawa

Journal of vascular and interventional radiology : JVIR 31 ( 7 ) 1044 - 1051 2020.7

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To retrospectively compare the outcomes of radiofrequency (RF) ablation, stereotactic body radiotherapy (SBRT), and sublobar resection (SLR) in patients with stage I non-small-cell lung cancer (NSCLC) at a single center. MATERIALS AND METHODS: Overall, 289 patients (38 RF ablation, 58 SBRT, and 193 SLR) were included. Kaplan-Meier curves were generated, multiple propensity score was estimated using a multinomial logistic regression model, and relationships between treatments and outcomes were assessed using a Cox proportional hazard model. Hazard ratios (HRs) for death from any cause and disease progression or death from any cause were examined by a crude model, an inverse probability of treatment weighting (IPTW) model, and an IPTW model adjusted for missing variables. RESULTS: The 5-year overall and progression-free survival rates were 58.9% and 39.9%, respectively, for RF ablation; 42.0% and 34.9%, respectively, for SBRT; and 85.5% and 75.9%, respectively, for SLR. Significantly longer survival time and lower HR were observed for SLR than other treatments. However, after statistical adjustment, these relationships were not significant except for reduced HR of disease progression or death from any cause of SLR compared to RF ablation in the IPTW model. The median hospital stays for RF ablation, SBRT, and SLR were 6.5, 6, and 16 days, respectively. Adverse events of grade 3 or higher occurred only in 11 SLR cases. CONCLUSIONS: SLR achieved the longest survival. However, after statistical adjustment, there were no significant outcome differences among RF ablation, SBRT, and SLR, except for 1 model. RF ablation or SBRT may be alternative treatments for selected patients with early-stage NSCLC.

DOI： 10.1016/j.jvir.2019.11.035

Influences of preoperative metformin on immunological factors in early breast cancer. International journal

Takahiro Tsukioki, Tadahiko Shien, Takehiro Tanaka, Yoko Suzuki, Yukiko Kajihara, Minami Hatono, Kengo Kawada, Mariko Kochi, Takayuki Iwamoto, Hirokuni Ikeda, Naruto Taira, Hiroyoshi Doihara, Shinichi Toyooka

Cancer chemotherapy and pharmacology 86 ( 1 ) 55 - 63 2020.7

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Metformin has been suggested to possibly reduce cancer risk. However, the mechanism underlying the positive effects of metformin on cancer treatment remains unclear. We conducted a prospective study to evaluate the effects of preoperative metformin in patients with early breast cancer. METHOD: We evaluated the effects on immunological factors (TILs, CD4 + , CD8 + , PD-L1, IFNγ and IL-2) by comparing core needle biopsies (CNB) obtained before metformin treatment with surgical specimens. Seventeen patients were enrolled in this prospective study from January to December 2016. We also analyzed 59 patients undergoing surgery during the same period to reveal the correlation of immune factors between CNB and surgical specimen. RESULT: There was a moderate correlation between CNB and surgical specimens on TILs and CD8 + lymphocyte. (TILs Rs = 0.63, CD4 + Rs = 0.224, CD8 + Rs = 0.42) In the metformin group, TILs increases were confirmed in five (29%) patients, while a decrease was confirmed in two (12%). The expressions of CD4 + and CD8 + by TILs were increased in 41% and 18% of surgical specimens, respectively. However, TILs number (p = 0.0554), CD4+ (p = 0.0613) and CD8 + (p = 0.0646) expressions did not significantly increased. Furthermore, IFNγ expression appeared to be increased in response to metformin (p = 0.08). CONCLUSION: Preoperative metformin tends to increase TILs, as well as the numbers of CD4 and CD8 positive lymphocytes, and IFNγ levels. Metformin might improve immune function and have a possibility of chemo-sensitivity and thereby increase the effectiveness of immunotherapy, based on the results of this preliminary study.

DOI： 10.1007/s00280-020-04092-2

Radiation pneumonitis after definitive concurrent chemoradiotherapy with cisplatin/docetaxel for non-small cell lung cancer: Analysis of dose-volume parameters. International journal

Kuniaki Katsui, Takeshi Ogata, Kenta Watanabe, Norihisa Katayama, Masahiro Kuroda, Katsuyuki Kiura, Takao Hiraki, Yoshinobu Maeda, Shinichi Toyooka, Susumu Kanazawa

Cancer medicine 9 ( 13 ) 4540 - 4549 2020.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Radiation pneumonitis (RP) is a major pulmonary adverse event of chest radiotherapy. The PACIFIC trial that identified durvalumab as an effective subsequent-line therapy after concurrent chemoradiotherapy (CCRT) found that patients with grade 2 or higher RP may have to be excluded from treatment under certain criteria. The purpose of this study was to investigate the relationship between grade ≥2 RP and the parameters of dose-volume histograms after CCRT with cisplatin/docetaxel for stage III non-small cell lung cancer and conduct a subset analysis of severe RP that can lead to the permanent discontinuation of treatment per the PACIFIC trial criteria to help determine treatment strategy. METHODS: We calculated the percentage of the lung volume received at least 5 Gy (V5) and 20 Gy (V20), the mean lung dose (MLD), and the lung volume spared from a 5 Gy dose (VS5) to the total lung volume. Factors affecting the incidence of grade ≥2 RP were identified; severe RP was defined as grade ≥3 as well as grade 2 RP that required ≥10 mg prednisolone for at least 12 weeks. RESULTS: This study included 45 patients. On univariate analysis, all parameters and total lung volume were found to be significant predictors of grade ≥2 RP (P = .001, .003, .03, .004, and .02, respectively). On multivariate analysis, V20 was a significant predictive factor of grade ≥2 RP (P = .007). Severe RP developed in 6 of 37 patients (16.2%) whose V20 values were 35% or lower. On univariate analysis, only V20 was a significant predictor of severe RP in these patients (P = .01). CONCLUSIONS: The best approach to reduce the rate of grade ≥2 RP is to maintain the V5, V20, MLD, and VS5 as low as possible during radiotherapy planning in patients receiving definitive CCRT with cisplatin/docetaxel.

DOI： 10.1002/cam4.3093

Lung perfusion scintigraphy to detect chronic lung allograft dysfunction after living-donor lobar lung transplantation. Reviewed International journal

Haruchika Yamamoto, Seiichiro Sugimoto, Takeshi Kurosaki, Kentaroh Miyoshi, Shinji Otani, Mikio Okazaki, Masaomi Yamane, Takahiro Oto, Shinichi Toyooka

Scientific reports 10 ( 1 ) 10595 - 10595 2020.6

Language：English Publishing type：Research paper (scientific journal)

Because chronic lung allograft dysfunction (CLAD) develops predominantly on one side after bilateral living-donor lobar lung transplantation (LDLLT), lung perfusion scintigraphy (Q-scinti) was expected to show a perfusion shift to the contralateral unaffected lung with the development of CLAD. Our study examined the potential usefulness of Q-scinti in the diagnosis of CLAD after bilateral LDLLT. We conducted a single-center retrospective cohort study of 58 recipients of bilateral LDLLT. The unilateral shift values on Q-scinti were calculated and compared between the CLAD group (N = 27) and the non-CLAD group (N = 31) from 5 years before to 5 years after the diagnosis of CLAD. The unilateral shift values in Q-scinti were significantly higher in the CLAD group than in the non-CLAD group from 5 years before the diagnosis of CLAD to 5 years after the diagnosis (P < 0.05). The unilateral shift values in Q-scinti were significantly correlated with the percent baseline values of the forced expiratory volume in 1 s (P = 0.0037), the total lung capacity (P = 0.0028), and the forced vital capacity (P = 0.00024) at the diagnosis of CLAD. In patients developing unilateral CLAD after bilateral LDLLT, Q-scinti showed a unilateral perfusion shift to the contralateral unaffected lung. Thus, Q-scinti appears to have the potential to predict unilateral CLAD after bilateral LDLLT.

DOI： 10.1038/s41598-020-67433-4

Clinical impacts of EGFR mutation status: analysis of 5,780 surgically resected lung cancer cases. Reviewed International journal

Kenichi Suda, Tetsuya Mitsudomi, Yasushi Shintani, Jiro Okami, Hiroyuki Ito, Takashi Ohtsuka, Shinichi Toyooka, Takeshi Mori, Shun-Ichi Watanabe, Hisao Asamura, Masayuki Chida, Hiroshi Date, Shunsuke Endo, Takeshi Nagayasu, Ryoichi Nakanishi, Etsuo Miyaoka, Meinoshin Okumura, Ichiro Yoshino

The Annals of thoracic surgery 2020.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: To elucidate the clinical, pathologic, and prognostic impacts of EGFR mutation and mutation subtypes in early-stage lung cancer, we conducted a retrospective analysis of the Japanese Joint Committee of Lung Cancer Registry database (a nationwide database for surgically-resected lung cancer patients; n = 18,973). METHODS: Of 13,951 patients classified as non-squamous non-small cell lung cancer in the database, 5,780 patients (41.0%) had been tested for EGFR mutation and were included in this study. RESULTS: EGFR mutation was detected in 2,410 patients (41.7%), and presence of EGFR mutation was significantly correlated with clinicopathological factors such as the presence of ground-glass opacity (P < 0.001) and better prognosis. Analysis of initial recurrence sites identified significantly higher frequencies of brain and adrenal gland metastases in patients with and without EGFR mutation, respectively. Of 2,410 patients with EGFR mutations, 983 (40.8%) had exon 19 deletion (Exon 19 Del), 1,170 (48.5%) had L858R mutation, and 257 (10.7%) had other EGFR mutations. Higher smoking rate was found in patients with other EGFR mutations (p = 0.02). In the comparison of Exon 19 Del and L858R, we found that Exon 19 Del correlated with younger age (P < 0.001), higher rate of pure solid tumors (P < 0.001), advanced pathological stage (trend P = 0.0004), and poorer recurrence-free survival (P = 0.001). CONCLUSIONS: In addition to clinicopathological and prognostic impacts of EGFR mutation status, tumors with Exon 19 Del have a more aggressive phenotype and poorer prognosis than those with L858R in early-stage lung cancers.

DOI： 10.1016/j.athoracsur.2020.05.041

MAPK Pathway Alterations Correlate with Poor Survival and Drive Resistance to Therapy in Patients with Lung Cancers Driven by ROS1 Fusions. International journal

Hiroki Sato, Adam J Schoenfeld, Evan Siau, Yue Christine Lu, Huichun Tai, Ken Suzawa, Daisuke Kubota, Allan J W Lui, Besnik Qeriqi, Marissa Mattar, Michael Offin, Masakiyo Sakaguchi, Shinichi Toyooka, Alexander Drilon, Neal X Rosen, Mark G Kris, David Solit, Elisa De Stanchina, Monika A Davare, Gregory J Riely, Marc Ladanyi, Romel Somwar

Clinical cancer research : an official journal of the American Association for Cancer Research 26 ( 12 ) 2932 - 2945 2020.6

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: ROS1 tyrosine kinase inhibitors (TKI) provide significant benefit in lung adenocarcinoma patients with ROS1 fusions. However, as observed with all targeted therapies, resistance arises. Detecting mechanisms of acquired resistance (AR) is crucial to finding novel therapies and improve patient outcomes. EXPERIMENTAL DESIGN: ROS1 fusions were expressed in HBEC and NIH-3T3 cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9-mediated genomic engineering (EZR/ROS1). We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) patients treated with ROS1 TKIs, and genetic alterations hypothesized to confer AR were modeled in these cell lines. RESULTS: Eight of the 75 patients with a ROS1 fusion had a concurrent MAPK pathway alteration and this correlated with shorter overall survival. In addition, the induction of ROS1 fusions stimulated activation of MEK/ERK signaling with minimal effects on AKT signaling, suggesting the importance of the MAPK pathway in driving ROS1 fusion-positive cancers. Of 8 patients, 2 patients harbored novel in-frame deletions in MEK1 (MEK1delE41_L54) and MEKK1 (MEKK1delH907_C916) that were acquired after ROS1 TKIs, and 2 patients harbored NF1 loss-of-function mutations. Expression of MEK1del or MEKK1del, and knockdown of NF1 in ROS1 fusion-positive cells activated MEK/ERK signaling and conferred resistance to ROS1 TKIs. Combined targeting of ROS1 and MEK inhibited growth of cells expressing both ROS1 fusion and MEK1del. CONCLUSIONS: We demonstrate that downstream activation of the MAPK pathway can mediate of innate acquired resistance to ROS1 TKIs and that patients harboring ROS1 fusion and concurrent downstream MAPK pathway alterations have worse survival. Our findings suggest a treatment strategy to target both aberrations.

DOI： 10.1158/1078-0432.CCR-19-3321

Prognostic value of OCT4A and SPP1C transcript variant co-expression in early-stage lung adenocarcinoma. International journal

Seijiro Koshimune, Mitsuko Kosaka, Nobuhiko Mizuno, Hiromasa Yamamoto, Tomoyuki Miyamoto, Kohta Ebisui, Shinichi Toyooka, Aiji Ohtsuka

BMC cancer 20 ( 1 ) 521 - 521 2020.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Octamer-binding transcription factor 4A (OCT4A) is essential for cell pluripotency and reprogramming both in humans and mice. To date, however, the function of human OCT4 in somatic and/or tumour tissues is largely unknown. METHODS: RT-PCR was used to identify full-length splice forms of OCT4 transcripts in normal and cancer cells. A FLAG-tagged OCT4 genomic transgene was used to identify OCT4-positive cancer cells. A potential role for OCT4 in somatic cancer cells was examined by cell ablation of OCT4-positive cells using promoter-driven diphtheria toxin A. OCT4 and secreted phosphoprotein 1 (SPP1) transcripts in early-stage lung adenocarcinoma tumours were analysed and compared with pathohistological features. RESULTS: The results show that, unlike in murine cells, OCT4A and OCT4B variants are transcribed in both human cancer cells and in adult tissues such as lung, kidney, uterus, breast, and eye. We found that OCT4A and SPP1C are co-expressed in highly aggressive human breast, endometrial, and lung adenocarcinoma cell lines, but not in mesothelial tumour cell lines. Ablation of OCT4-positive cells in lung adenocarcinoma cells significantly decreased cell migration and SPP1C mRNA levels. The OCT4A/SPP1C axis was found in primary, early-stage, lung adenocarcinoma tumours. CONCLUSIONS: Co-expression of OCT4 and SPP1 may correlate with cancer aggressiveness, and the OCT4A/SPP1C axis may help identify early-stage high-risk patients with lung adenocarcinoma. Contrary to the case in mice, our data strongly suggest a critical role for OCT4A and SPP1C in the development and progression of human epithelial cancers.

DOI： 10.1186/s12885-020-06969-0

気管支断端瘻閉鎖後の治癒経過から考える治療方針

山本治慎, 三好健太郎, 松原慧, 塩谷俊雄, 諏澤憲, 大谷真二, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

日本臨床外科学会雑誌 81 ( 6 ) 1206 - 1206 2020.6

Randomized Phase III Study of Pemetrexed Plus Cisplatin Versus Vinorelbine Plus Cisplatin for Completely Resected Stage II to IIIA Nonsquamous Non-Small-Cell Lung Cancer. Reviewed International journal

Hirotsugu Kenmotsu, Nobuyuki Yamamoto, Takeharu Yamanaka, Katsuo Yoshiya, Toshiaki Takahashi, Tsuyoshi Ueno, Koichi Goto, Haruko Daga, Norihiko Ikeda, Kenji Sugio, Takashi Seto, Shinichi Toyooka, Hiroshi Date, Tetsuya Mitsudomi, Isamu Okamoto, Kohei Yokoi, Hideo Saka, Hiroaki Okamoto, Yuichi Takiguchi, Masahiro Tsuboi

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 38 ( 19 ) JCO1902674 - 2196 2020.5

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To evaluate the efficacy of pemetrexed plus cisplatin versus vinorelbine plus cisplatin as postoperative adjuvant chemotherapy in patients with pathologic stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We performed a randomized, open-label, phase III study at 50 institutions within 7 clinical study groups in Japan. Patients with completely resected pathologic stage II-IIIA (TNM 7th edition) nonsquamous NSCLC were randomly assigned to receive either pemetrexed (500 mg/m2, day 1) plus cisplatin (75 mg/m2, day 1) or vinorelbine (25 mg/m2, days 1 and 8) plus cisplatin (80 mg/m2, day 1) with stratification by sex, age, pathologic stage, EGFR mutation, and institution. These treatments were planned to be given every 3 weeks for 4 cycles. The primary end point was recurrence-free survival in the modified intent-to-treat population, excluding ineligible patients. RESULT: Between March 2012 and August 2016, 804 patients were enrolled (402 assigned to vinorelbine plus cisplatin and 402 assigned to pemetrexed plus cisplatin). Of 784 eligible patients, 410 (52%) had stage IIIA disease and 192 (24%) had EGFR-sensitive mutations. At a median follow-up of 45.2 months, median recurrence-free survival was 37.3 months for vinorelbine plus cisplatin and 38.9 months for pemetrexed plus cisplatin, with a hazard ratio of 0.98 (95% CI, 0.81 to 1.20; 1-sided P = .474). Grade 3-4 toxicities reported more frequently for vinorelbine plus cisplatin than for pemetrexed plus cisplatin were febrile neutropenia (11.6% v 0.3%, respectively), neutropenia (81.1% v 22.7%, respectively), and anemia (9.3% v 2.8%, respectively). One treatment-related death occurred in each arm. CONCLUSION: Although this study failed to show the superiority of pemetrexed plus cisplatin for patients with resected nonsquamous NSCLC, this regimen showed a better tolerability as adjuvant chemotherapy.

DOI： 10.1200/JCO.19.02674

Antitumor Effects of Pan-RAF Inhibitor LY3009120 Against Lung Cancer Cells Harboring Oncogenic BRAF Mutation. Reviewed International journal

Shunsaku Miyauchi, Kazuhiko Shien, Tatsuaki Takeda, Kota Araki, Kentaro Nakata, Akihiro Miura, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Ken Suzawa, Hiromasa Yamamoto, Mikio Okazaki, Junichi Soh, Shuta Tomida, Masaomi Yamane, Masakiyo Sakaguchi, Shinichi Toyooka

Anticancer research 40 ( 5 ) 2667 - 2673 2020.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND/AIM: The therapeutic strategy for patients with non-small-cell lung cancer (NSCLC) harboring the BRAF non-V600E mutation has not been established. LY3009120, a newly discovered pan-RAF inhibitor, has shown strong antitumor effects in cancers with various BRAF genotypes. This study investigated the antitumor effects of LY3009120 in NSCLC cells harboring the BRAF non-V600E mutation. MATERIALS AND METHODS: We examined the antitumor effects of LY3009120 by MTS assay and flow cytometry. We analyzed the expression status of proteins by western blot. The mouse xenograft models were used for the in vivo experiments. RESULTS: LY3009120 suppressed BRAF-related downstream pathway molecules and induced cleavage of poly ADP-ribose polymerase in all examined NSCLC cell lines. LY3009120 also inhibited in vivo tumor growth in NSCLC cells harboring the BRAF non-V600E mutation. CONCLUSION: LY3009120 is a potent therapeutic agent for patients with BRAF non-V600E mutant NSCLC.

DOI： 10.21873/anticanres.14237

チームアプローチで実現するゲノム医療と薬剤師の役割ゲノム医療におけるデータサイエンティストの役割と育成

冨田秀太, 森田瑞樹, 山下範之, 平沢晃, 豊岡伸一

薬学雑誌 140 ( 5 ) 657 - 661 2020.5

Language：Japanese Publisher：(公社)日本薬学会

次世代シークエンサーを用いた遺伝子パネル検査とそのデータ解析はゲノム医療の根幹であるにもかかわらず、その担い手であるデータサイエンティストが極端に不足している。基本的なデータ解析の流れを理解し、解析結果の解釈ができる人材育成が喫緊の課題である。遺伝子パネル検査の流れを概説するとともに、遺伝子変異量(TMB)の概念と遺伝子パネル検査におけるTMBの算出方法について解説した。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01459&link_issn=&doc_id=20200528480008&doc_link_id=%2Fcs7yakug%2F2020%2F014005%2F010%2F0657-0661%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcs7yakug%2F2020%2F014005%2F010%2F0657-0661%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

チームアプローチで実現するゲノム医療と薬剤師の役割ゲノム医療におけるデータサイエンティストの役割と育成

冨田秀太, 森田瑞樹, 山下範之, 平沢晃, 豊岡伸一

薬学雑誌 140 ( 5 ) 657 - 661 2020.5

Language：Japanese Publisher：(公社)日本薬学会

次世代シークエンサーを用いた遺伝子パネル検査とそのデータ解析はゲノム医療の根幹であるにもかかわらず、その担い手であるデータサイエンティストが極端に不足している。基本的なデータ解析の流れを理解し、解析結果の解釈ができる人材育成が喫緊の課題である。遺伝子パネル検査の流れを概説するとともに、遺伝子変異量(TMB)の概念と遺伝子パネル検査におけるTMBの算出方法について解説した。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01459&link_issn=&doc_id=20200528480008&doc_link_id=%2Fcs7yakug%2F2020%2F014005%2F010%2F0657-0661%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcs7yakug%2F2020%2F014005%2F010%2F0657-0661%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Computed tomography fluoroscopy-guided cutting needle biopsy of pulmonary nodules ≤8 mm: A retrospective study including 117 nodules. International journal

Yanqing Zhao, Yusuke Matsui, Takao Hiraki, Toshihiro Iguchi, Koji Tomita, Mayu Uka, Hideo Gobara, Shinichi Toyooka, Susumu Kanazawa

European journal of radiology 125 108903 - 108903 2020.4

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To evaluate the diagnostic yield and safety of computed tomography (CT) fluoroscopy-guided cutting needle biopsy (CNB) for pulmonary nodules ≤ 8 mm. METHOD: Data of CT fluoroscopy-guided CNB for pulmonary nodules ≤ 8 mm performed in a single institution were retrospectively analyzed. One hundred and seventeen biopsy procedures for 117 pulmonary nodules (mean size, 7.4 mm) in 114 patients were included in the study. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall diagnostic accuracy were calculated. Univariate analyses were performed to elucidate the risk factors for diagnostic failure (i.e., non-diagnostic, false-positive, or false-negative results). Complications were graded per the Clavien-Dindo Classification. RESULTS: One (0.9 %) non-diagnostic biopsy result was found. The diagnostic accuracy was 95.7 % (112/117). The sensitivity and specificity were 95.8 % (91/95) and 95.5 % (21/22), respectively. PPV and NPV were 98.9 % (91/92) and 87.5 % (21/24), respectively. Univariate analyses showed that nodules in the lower lobes (p = 0.006) and prone biopsy position (p = 0.021) were the significant risk factors for diagnostic failure. The incidence of pneumothorax requiring chest tube placement (Grade IIIa) was 6.8 % (8/117). No Grade IIIb or higher complications were observed. CONCLUSION: CT fluoroscopy-guided CNB for pulmonary nodules ≤ 8 mm showed a high diagnostic yield without severe complications.

DOI： 10.1016/j.ejrad.2020.108903

Plasma micro-RNA Levels are Associated with the Development of Chronic Lung Allograft Dysfunction after Bilateral Living-Donor and Cadaveric Lung Transplantation

T. Shiotani, S. Sugimoto, H. Yamamoto, D. Shimizu, K. Miyoshi, S. Otani, M. Okazaki, M. Yamane, T. Oto, S. Toyooka

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 39 ( 4 ) S194 2020.4

Publishing type：Research paper (scientific journal)

Copyright © 2020. Published by Elsevier Inc. PURPOSE: Micro-RNAs (miRNAs) regulate genes by selectively silencing their target messenger RNAs. Recently, serum levels of miRNA related to pulmonary fibrosis (miR-21 and miR-155), have been shown to be associated with the development of chronic lung allograft dysfunction (CLAD) after cadaveric lung transplantation (CLT). We investigated the relationship between miRNAs levels and CLAD after bilateral living-donor lobar lung transplantation (LDLLT) and CLT. METHODS: Blood samples were collected from a total of 70 patients who underwent bilateral LDLLT (n=39) and bilateral CLT (n=31), including patients with CLAD (the CLAD group, n=25) and those without CLAD (the non-CLAD group, n=45). Plasma miRNA levels (miR-21 and miR-155) were quantified using real-time PCR and compared between the two groups. The relationship between miRNA levels and the results of pulmonary function tests at the onset of CLAD was assessed. Appropriate cut-off values of miRNA levels were set for the diagnosis of CLAD. RESULTS: The median follow-up period was 3074 (1071-7523) days. Plasma miRNA levels of the CLAD group were significantly higher than those of the non-CLAD group (miR-21, P<0.001; miR-155, P=0.013) (Fig. 1). In the CLAD group, miRNA levels after LDLLT were comparable to those after CLT. Moreover, miRNA levels were significantly negatively correlated with the baseline values of forced expiratory volume in 1 second (FEV1) (miR-21, P<0.001; miR-155, P=0.039) and those of total lung cavity (TLC) (miR-21, P<0.001; miR-155, P=0.0012) (Fig. 2). An ROC analysis of the performance of miR-21 level as a marker of CLAD yielded an AUC of 0.94 at a threshold level of 6.51. Patients with miR-21 level≥6.51 showed significantly better CLAD-free survival than those with miR-21 level<6.51 (P<0.001) (Fig. 3). CONCLUSION: Plasma miRNA levels are associated with the development of CLAD after bilateral LDLLT and CLT, and might be a potential biomarker for the diagnosis of CLAD.

DOI： 10.1016/j.healun.2020.01.792

Prognostic Nutritional Index Negatively Correlates with Lung Allocation Score and Predicts Survival after Both Cadaveric and Living-Donor Lobar Lung Transplantation

H. Yamamoto, S. Sugimoto, T. Shiotani, K. Miyoshi, S. Otani, M. Okazaki, M. Yamane, T. Oto, S. Toyooka

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 39 ( 4 ) S311 2020.4

Publishing type：Research paper (scientific journal)

Copyright © 2020. Published by Elsevier Inc. PURPOSE: The preoperative nutritional status affects the clinical outcome of surgery. To predict the clinical outcome, a prognostic nutritional index (PNI) calculated using serum albumin levels (ALB) and total lymphocyte count (TLC) has been shown to be valuable in various fields of surgery. In this study, we investigated the relationship between PNI and lung allocation score (LAS) as well as the impact of PNI on outcomes of lung transplantation (LT), including cadaveric lung transplantation (CLT) and living-donor lobar lung transplantation (LDLLT). METHODS: Between June 2003 and August 2016, a total of 127 patients underwent LT at Okayama University Hospital, including 71 recipients of CLT and 56 recipients of LDLLT. The PNI was calculated by the following equation: PNI = (10 × ALB(g/dl)+(0.005 × TLC(/mm3)). The overall survival was evaluated by univariate analysis (the log rank test) and multivariate analysis (the Cox proportional hazard regression model) using preoperative factors, including sex, age, BMI, diagnosis, oxygen concentration, mechanical ventilation, tracheostomy, ECMO support, use of glucocorticoids, serum creatinine level, diabetes mellitus, LAS, and PNI. RESULTS: PNI was significantly negatively correlated with LAS (r=-0.3, P=0.00062) (Fig. 1A). The univariate analysis revealed that the overall survival was significantly worse in the patients with age>28 (P=0.047), BMI<24.2 (P=0.0098), LAS>58.04 (P=0.000072), PNI<46.35 (P=0.018) (Fig. 1B). The multivariate analysis demonstrated that age (P=0.00093), BMI (P=0.0024), and PNI (P=0.0047) were independent prognostic factors of worse outcome. In the subgroup analysis, low PNI is a significant prognostic factor of worse survival after CLT (P=0.015) (Fig. 1C) and LDLLT (P=0.041) (Fig. 1D). CONCLUSION: Preoperative nutritional evaluation using PNI could contribute to the assessment of LT recipient's severity and predict survival after both CLT and LDLLT.

DOI： 10.1016/j.healun.2020.01.700

Association between Histological Types and Enhancement of Dynamic CT for Primary Lung Cancer.

Shogo Fukuma, Takayoshi Shinya, Junichi Soh, Ryuichiro Fukuhara, Nanako Ogawa, Fumiyo Higaki, Takehiro Tanaka, Eiki Ichihara, Takao Hiraki, Shinichi Toyooka, Susumu Kanazawa

Acta medica Okayama 74 ( 2 ) 129 - 135 2020.4

Language：English Publishing type：Research paper (scientific journal)

The aim of this study was to explore enhancement patterns of different types of primary lung cancers on 2-phase dynamic computed tomography (CT). This study included 217 primary lung cancer patients (141 adenocarcinomas [ADs], 48 squamous cell carcinomas [SCCs], 20 small cell lung carcinomas [SCLCs], and 8 others) who were examined using a 2-phase dynamic scan. Regions of interest were identified and mean enhancement values were calculated. After excluding the 20 SCLCs because these lesions had different clinical stages from the other cancer types, the mean attenuation values and subtractions between phases were compared between types of non-small cell lung carcinomas (NSCLCs) using the Kruskal-Wallis test. Late phase attenuation and attenuation of the late minus unenhanced phase (LMU) of SCCs were significantly higher than those of ADs (p<0.05). To differentiate SCC and AD in the late phase, a threshold of 80.21 Hounsfield units (HU) gave 52.9% accuracy. In LMU, a threshold of 52.16 HU gave 59.3% accuracy. Dynamic lung CT has the potential to aid in differentiating among NSCLC types.

DOI： 10.18926/AMO/58271

Evaluation of Therapeutic Target Gene Expression Based on Residual Cancer Burden Classification After Neoadjuvant Chemotherapy for HER2-Negative Breast Cancer. International journal

Yuko Takahashi, Takayuki Iwamoto, Yoko Suzuki, Yukiko Kajiwara, Minami Hatono, Takahiro Tsukioki, Kengo Kawada, Mariko Kochi, Hirokuni Ikeda, Tadahiko Shien, Naruto Taira, Junji Matsuoka, Hiroyoshi Doihara, Shinichi Toyooka

Clinical breast cancer 20 ( 2 ) 117 - 124 2020.4

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Patients with residual disease usually have a poor prognosis after neoadjuvant chemotherapy for breast cancer. The aim of this study was to explore therapeutic targets and potential additional adjuvant treatments for patients with residual disease after standard neoadjuvant chemotherapy. PATIENTS AND METHODS: We retrieved publicly available complementary DNA microarray data from 399 human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer samples from patients who underwent standard neoadjuvant chemotherapy. We analyzed the messenger RNA (mRNA) expression levels of key breast cancer markers and therapeutic target genes according to residual cancer burden (RCB) classification: RCB-0/I, RCB-II, and RCB-III. RESULTS: Among hormone receptor-positive samples, there were more luminal A tumors by PAM50 (Prediction Analysis of Microarray 50 [Prosigna], aka Prosigna Breast Cancer Prognostic Gene Signature Assay) in RCB-III than in RCB-0/I and RCB-II (P < .01). The mRNA expressions of ESR1 and PGR were significantly higher, and that of MKI67 was lower in RCB-II and RCB-III than in RCB-0/I. The mRNA expression of cyclin D1 was up-regulated in RCB-III and that of CDKN2A was down-regulated in RCB-III (P = .027 and < .01). Among triple-negative (TN) samples, RCB-III had higher clinical stage and more lymph node-positive samples than RCB-0/1 and RCB-II (P < .01). In both subtypes, VEGF-C expression was significantly higher in RCB-III than in RCB-0/I and RCB-II. CONCLUSION: In hormone receptor-positive breast cancer, biological features such as luminal A were associated with RCB; this trend was not observed in TN breast cancer. Further, some targeted therapies should be tested as new strategies after standard neoadjuvant chemotherapy in future clinical trials.

DOI： 10.1016/j.clbc.2019.07.001

CTガイド下生検では診断困難であった肺門部結節影

松原慧, 大谷真二, 高津史明, 富岡泰章, 津高慎平, 山本治慎, 塩谷俊雄, 難波圭, 諏澤憲, 三好健太郎, 山本寛斉, 岡崎幹雄, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

岡山医学会雑誌 132 ( 1 ) 46 - 46 2020.4

Pulmonary resection in a prone position for lung cancer invading the spine. Reviewed

Shunsaku Miyauchi, Junichi Soh, Kazuhiko Shien, Masato Tanaka, Hiromasa Yamamoto, Toshifumi Ozaki, Shinichi Toyooka

General thoracic and cardiovascular surgery 68 ( 3 ) 298 - 301 2020.3

Language：English Publishing type：Research paper (scientific journal)

The prone position is usually not selected for pulmonary resection. The intraoperative body position is an important issue in surgery for non-small cell lung cancer invading the spine because the standard intraoperative body position for a vertebrectomy is a prone position, while that for a pulmonary resection is a lateral decubitus position. Intraoperative changes in body position can cause several complications. Using an O-arm with a navigation system, a partial vertebrectomy was completed with the patient in a prone position thanks to the recognition of accurate surgical margins in the vertebral body; then, without changing the patient's body position, a lobectomy with systemic lymph node dissection was performed via a posterior approach. Especially for procedures requiring a wide resection of the chest wall, a prone position can be selected for a lobectomy with systemic lymph node dissection via a posterior approach without any significant difficulties.

DOI： 10.1007/s11748-019-01113-7

Influence of breast density on breast cancer risk: a case control study in Japanese women.

Keiko Nishiyama, Naruto Taira, Taeko Mizoo, Mariko Kochi, Hirokuni Ikeda, Takayuki Iwamoto, Tadahiko Shien, Hiroyoshi Doihara, Setuko Ishihara, Hiroshi Kawai, Kensuke Kawasaki, Yoichi Ishibe, Yutaka Ogasawara, Shinichi Toyooka

Breast cancer (Tokyo, Japan) 27 ( 2 ) 277 - 283 2020.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Mammography is the standard examination for breast cancer screening of woman aged ≥ 40 years. High breast density on mammography indicates that mammary gland parenchyma occupy a high percentage of the breast. The objective of this study was to investigate factors associated with breast density and the risk of high breast density for breast cancer. METHODS: A multicenter case-control study was performed in 530 patients and 1043 controls. Breast density was classified as C1-C4 using the Breast Imaging Reporting and Data System (BI-RADS). Clinical factors were obtained from questionnaires or medical records, and the influence of each factor (breast density, menopausal status, body mass index (BMI), parity, presence or absence of breastfeeding history, age at menarche, age at first birth, and familial history of breast cancer) on breast cancer risk in all patients was calculated as an age-adjusted odds ratio (OR). Multivariate logistic regression analyses were then performed in all patients and in pre- and postmenopausal and BMI-stratified groups using factors with a significant age-adjusted OR as adjustment factors. RESULTS: Age-adjusted ORs for breast cancer were significant for breast density, BMI, parity, and breast feeding, but not for age at menarche, age at first birth, or family history of breast cancer. In multivariate analysis, there was a significant correlation between breast density and breast cancer in postmenopausal women (OR for C1 vs. C2 1.90 [95% CI 1.34-2.70]; C1 vs. C4 2.85 [95% CI 1.10-7.16]). This correlation was also significant in patients in the third BMI quartile (22.3-24.5 kg/m2) (OR for C1 vs. C4 8.76 [95% CI 2.38-42.47]); and fourth BMI quartile (>24.5 kg/m2) (OR for C1 vs. C2 1.92 [95% CI 1.17-3.15]; C1 vs. C4 11.89 [95% CI 1.56-245.17]). CONCLUSION: Breast density on mammography is a risk factor for breast cancer after adjustment for other risk factors. This risk is particularly high in postmenopausal women and those with a high BMI.

DOI： 10.1007/s12282-019-01018-6

Embolization using hydrogel-coated coils for pulmonary arteriovenous malformations. Reviewed International journal

T Iguchi, T Hiraki, Y Matsui, H Fujiwara, J Sakurai, K Baba, S Toyooka, H Gobara, S Kanazawa

Diagnostic and interventional imaging 101 ( 3 ) 129 - 135 2020.3

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To prospectively evaluate the efficacy and safety of embolization using hydrogel-coated coils for the treatment of pulmonary arteriovenous malformations (PAVMs). MATERIALS AND METHODS: The outcomes of 21 PAVMs in 19 patients (3 men and 16 women; mean age, 58.8±15.2 [SD] years; age range 14-78 years) treated by venous sac embolization (VSE) with additional feeding artery embolization were prospectively evaluated. For VSE, using one or more 0.018-inch hydrogel-coated coils was mandatory. Recanalization and/or reperfusion were evaluated by pulmonary arteriography 1 year after embolization. RESULTS: The mean feeding artery and venous sac sizes were 4.0mm and 8.5mm, respectively. Embolization was successfully completed in 20/21 PAVMs, yielding a technical success rate of 95%. The feeding artery was also embolized in 17/20 successful PAVMs (85%). A technical failure occurred in one PAVM, where embolization was abandoned because of migration of one bare coil to the left ventricle. The mean numbers of hydrogel-coated coils and bare platinum detachable coils used for VSE were 3.3±2.1 (SD) (range, 1-8) and 4.4±3.9 (SD) (range, 1-17), respectively. The mean percentages of hydrogel-coated coils in number, length, and estimated volume were 42.9%, 33.3%, and 72.7% respectively. One patient with one PAVM was lost to follow-up after 3 months. Neither recanalization nor reperfusion was noted in the remaining 19 PAVMs (success rate, 19/19 [100%]). One grade 4 (coil migration) adverse event occurred, and it was treated without any sequelae. CONCLUSION: VSE using hydrogel-coated coils with additional feeding artery embolization is a safe and effective treatment for PAVM.

DOI： 10.1016/j.diii.2019.10.008

Right single lung transplantation using an inverted left donor lung: interposition of pericardial conduit for pulmonary venous anastomosis - a case report. Reviewed International journal

Haruchika Yamamoto, Kentaroh Miyoshi, Shinji Otani, Takeshi Kurosaki, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka, Motomu Kobayashi, Takahiro Oto

BMC pulmonary medicine 20 ( 1 ) 46 - 46 2020.2

Language：English

BACKGROUND: Lung transplantation (LTx) is still limited by the shortage of suitable donor lungs. Developing flexible surgical procedures can help to increase the chances of LTx by unfolding recipient-to-donor matching options based on the pre-existing organ allocation concept. We report a case in which a successful left-to-right inverted LTx was completed using the interposition of a pericardial conduit for pulmonary venous anastomosis. CASE PRESENTATION: A left lung graft was offered to a 59-year-old male who had idiopathic pulmonary fibrosis with predominant damage in the right lung. He had been prescribed bed rest with constant oxygen inhalation through an oxymizer pendant and had been on the waiting list for 20 months. Considering the condition of the patient (LAS 34.3) and the scarcity of domestic organ offers, the patient was highly likely to be incapable of tolerating any additional waiting time for another donor organ if he was unable to accept the presently reported offer of a left lung. Eventually, we decided to transplant the left donor lung into the right thorax of the recipient. Because of the anterior-posterior position gap of the hilar structures, the cuff lengths of the pulmonary veins had to be adjusted. The patient did not develop any anastomotic complications after the transplantation. CONCLUSIONS: A left-to-right inverted LTx is technically feasible using an autologous pericardial conduit for pulmonary venous anastomosis in selected cases. This technique provides the potential benefit of resolving challenging situations in which surgeons must deal with a patient's urgency and the logistical limitations of organ allocation.

DOI： 10.1186/s12890-020-1075-4

A Surgical Instructor Training Course for the Next Generation. Reviewed

Masaomi Yamane, Yasuhiro Mandai, Hideo Ino, Akihiro Matsukawa, Shinichi Toyooka

Acta medica Okayama 74 ( 1 ) 73 - 76 2020.2

Language：English

In 2016, Gunma University Hospital's Medical Accident Investigation Committee released a report reiterating the necessity of medical education and the need for surgeons to master non-technical skills. We designed a 17-h training course for surgical instructors, designed to teach participants how to sufficiently educate surgeon trainees and encourage their professional identity formation. A post-training survey showed that participants improved their awareness, and their behavioral changes led to favorable team performances. We then began offering a 3-h workshop focusing on the participants' experiences. We propose that the training course using participant narratives is required and effective to establish surgeons' self-reflection and professional identity as surgeons.

DOI： 10.18926/AMO/57956

肺内Solitary fibrous tumorの1例

三道幹大, 正岡佳久, 岡本聡一郎, 小河七子, 福原隆一郎, 田中高志, 稲井良太, 松井裕輔, 新家崇義, 金澤右, 田中健大, 大谷真二, 豊岡伸一

Japanese Journal of Radiology 38 ( Suppl. ) 72 - 72 2020.2

DV200 index for assessing RNA integrity in next-generation sequencing Reviewed International journal

Takehiro Matsubara, Junichi Soh, Mizuki Morita, Takahiro Uwabo, Shuta Tomida, Toshiyoshi Fujiwara, Susumu Kanazawa, Shinichi Toyooka, Akira Hirasawa

BioMed Research International 2020 9349132 - 9349132 2020.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Hindawi

Poor quality of biological samples will result in an inaccurate analysis of next-generation sequencing (NGS). Therefore, methods to accurately evaluate sample integrity are needed. Among methods for evaluating RNA quality, the RNA integrity number equivalent (RINe) is widely used, whereas the DV200, which evaluates the percentage of fragments of >200 nucleotides, is also used as a quality assessment standard. In this study, we compared the RINe and DV200 RNA quality indexes to determine the most suitable RNA index for the NGS analysis. Seventy-one RNA samples were extracted from formalin-fixed paraffin-embedded tissue samples (n = 30), fresh-frozen samples (n = 25), or cell lines (n = 16). After assessing RNA quality using the RINe and DV200, we prepared two kinds of stranded mRNA sequencing libraries. Finally, we calculated the correlation between each RNA quality index and the amount of library product (1st PCR product per input RNA). The DV200 measure showed stronger correlation with the amount of library product than the RINe (R 2 = 0.8208 for the DV200 versus 0.6927 for the RINe). Receiver operating characteristic curve analyses revealed that the DV200 was the better marker for predicting efficient library production than the RINe using a threshold of >10 ng/ng for the amount of the 1st PCR product per input RNA (cutoff value for the RINe and DV200, 2.3 and 66.1%; area under the curve, 0.99 and 0.91; sensitivity, 82% and 92%; and specificity, 93% and 100%, respectively). Our results indicate that NGS libraries prepared using RNA samples with the DV200 value > 66.1% exhibit greater sensitivity and specificity than those prepared with the RINe values > 2.3. These findings suggest that the DV200 is superior to the RINe, especially for low-quality RNA, because it is a more consistent assessment of the amount of the 1st NGS library product per input.

DOI： 10.1155/2020/9349132

多発小腸GISTに対し手術を施行した神経線維腫症1型の1例

母里淑子, 重安邦俊, 吉岡貴裕, 永坂岳司, 原賀順子, 香川俊輔, 寺石文則, 豊岡伸一, 平沢晃, 藤原俊義

家族性腫瘍 19 ( 2 ) 77 - 82 2020.2

Language：Japanese Publisher：(一社)日本遺伝性腫瘍学会

症例は54歳男性.大量出血を伴う小腸多発GIST(Gastrointestinal stromal tumor)を認めて緊急入院となった.姉が神経線維腫症1型(neurofibromatosis type 1:NF1)と診断されており,患者にもおよそ20個の神経線維腫を疑う腫瘤とcafe au lait斑を6個以上認めたためNF1と診断した.出血コントロール目的に開腹手術を行ったが,GISTはおよそ20個多発しており,大量小腸切除を避けるために10mm以上の腫瘍のみ外科的切除を行い,多発微小腫瘍は経過観察とした不完全切除を選択した.切除標本の病理検査では紡錘形核と好酸性胞体を有する紡錘形細胞が密に錯綜する腫瘍を認め,免疫染色でKIT陽性.核分裂数は5以下/50HPFsであり低悪性度GISTと診断した.NF1に伴うGISTは比較的予後が良いとの報告もあるが,このような多発微小病変については明らかな治療指針がない.今後さらなる症例の集積と検討を要する.(著者抄録)

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J03931&link_issn=&doc_id=20200310200005&doc_link_id=%2Fcg3kazok%2F2019%2F001902%2F005%2F0077-0082%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcg3kazok%2F2019%2F001902%2F005%2F0077-0082%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Pulmonary aspergillosis as a late complication after surgery for locally advanced non-small cell lung cancer treated with induction chemoradiotherapy. Reviewed

Seiichiro Sugimoto, Junichi Soh, Ken Suzawa, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Mikio Okazaki, Masaomi Yamane, Takahiro Oto, Susumu Kanazawa, Katsuyuki Kiura, Shinichi Toyooka

Surgery today 2020.1

Language：English

PURPOSE: Some long-term survivors after surgery for locally advanced non-small cell lung cancer (NSCLC) treated with induction chemoradiotherapy (trimodality treatment) develop chronic pulmonary aspergillosis (CPA). The aim of our study was to assess the characteristics and outcomes of CPA that develops after trimodality treatment. METHODS: We retrospectively reviewed the data of 187 NSCLC patients who underwent trimodality treatment between 1999 and 2018. RESULTS: Six male ever-smoker patients developed CPA. All 6 patients had undergone extended resection for NSCLC and had a history of either adjuvant chemotherapy (n = 3) or radiation pneumonitis (n = 4). Among the 4 patients with CPA localized in a single lung, 3 patients were treated surgically (completion pneumonectomy or cavernostomy) and 1 patient was treated with antifungal therapy alone. Both treatments led to the improved control of CPA. In contrast, patients with CPA in both lungs were not candidates for surgery, and died of CPA. The survival rates after trimodality treatment in the CPA group and the group without CPA were comparable (10-year survival rate, 50.0% vs. 57.6%, P = 0.59). CONCLUSION: The early diagnosis of CPA localized in a single lung after NSCLC surgery is critical to improving control and survival in patients with CPA.

DOI： 10.1007/s00595-020-01960-5

[Training Medical Staff with Basic Skills for Data Science in Genomic Medicine].

Shuta Tomida, Mizuki Morita, Noriyuki Yamashita, Akira Hirasawa, Shinichi Toyooka

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 140 ( 5 ) 657 - 661 2020

Language：Japanese Publishing type：Research paper (scientific journal)

The development of specialized training programs for medical personnel, particularly nurses, clinical laboratory technicians, and pharmacists, is considered critical for the promotion of genomic medicine throughout Japan. Specifically, medical personnel skilled at analyzing and understanding high-throughput genomic data are in high demand. In this symposium, we will introduce the basic knowledge and skills necessary for processing genomic data.

DOI： 10.1248/yakushi.19-00217-2

肺移植におけるLiquid biopsy：ドナー由来血中遊離DNAとマイクロRNA

杉本誠一郎, 塩谷俊雄, 富岡泰章, 石上恵美, 石原恵, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 山根正修, 豊岡伸一

移植 55 ( Supplement ) 242_2 - 242_2 2020

Language：Japanese Publisher：一般社団法人日本移植学会

【背景】低侵襲に血液や体液を採取し解析を行うLiquid biopsyは、癌領域では既に臨床応用され治療方針の決定に一役買っているが、移植領域ではまだ発展途上である。当科では肺移植におけるLiquid biopsyとして、ドナー由来血中遊離DNA（dd-cf-DNA）とマイクロRNA（miRNA）を標的にした研究を行ってきたため、その成果を報告する。【方法】ドナーとレシピエントの一塩基多型を比較してdd-cf-DNAを測定し、生体肺移植後の急性拒絶反応（AR）における診断的意義を検討した。次にレシピエントのみの検体で評価できるmiRNAを測定し、脳死・生体肺移植後の移植片慢性機能不全（CLAD）における診断的意義を検討した。【結果】dd-cf-DNAは、感染群（p=0.028）や安定群（p=0.001）よりAR群で有意に増加しており、生体肺移植後ARの診断に有用であった（Sci Rep 2018）。また線維化に関与するmiRNAが、非CLAD群よりCLAD群で有意に増加しており（p=0.008）、一秒量の変化率とも相関し（p=0.014）、CLAD診断に有用であった。【結論】肺移植のLiquid biopsy として、dd-cf-DNAは生体肺移植後ARの診断に、またmiRNAはCLADの診断に有用である。今後の臨床応用を目指して症例数の集積と簡便で精度の高い方法の開発が望まれる。

DOI： 10.11386/jst.55.supplement_242_2

当院における高齢者レシピエント症例の検討

富岡泰章, 大谷真二, 清水大, 松原慧, 山本治慎, 塩谷俊雄, 三好健太郎, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

移植 55 ( Supplement ) 253_1 - 253_1 2020

Language：Japanese Publisher：一般社団法人日本移植学会

【背景】日本における高齢者レシピエントの長期成績に関しての報告は少ない．今回当院における高齢者レシピエントの長期成績について後方視的に検討した.【対象と方法】1998年1月～2020年1月に施行した18歳以上の肺移植症例161例を対象とした.60歳以上の高齢群(H群：n=10)と18-59歳の非高齢群(L群:n=151)の2群に分けて,全生存期間(OS)およびCLAD発症までの期間(CFS)について解析を行った.【結果】H群ではL群と比較して片肺移植(p=0.03),間質性肺炎(p=0.02),男性(p=0.04)の割合が有意に多かった.BMI,ドナー年齢,総虚血時間,LASスコアには有意差は認めなかった.H群とL群の5年OSはそれぞれ51.9%と75.5%であり,有意差を認めた(p=0.02).H群とL群の5年CFSはそれぞれ53.3%と72.5%であった.サブグループ解析では，H群の片肺移植症例(5年:OS 25%)は両肺移植症例(5年OS:75%)と比較してOSが悪い傾向にあった(p=0.08)が，H群の両肺移植症例はL群の両肺移植症例(5年OS:74.2%)と比較しても同等の成績であった（p=0.5）.【結語】60歳以上のレシピエントの成績は60歳未満と比較し不良だが，両肺移植がより望ましい可能性が示唆された.

DOI： 10.11386/jst.55.supplement_253_1

Surgical treatment for N2 non-small cell lung cancer

Seiichiro Sugimoto, Shinichi Toyooka

Japanese Journal of Lung Cancer 59 ( 7 ) 1129 - 1133 2019.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Lung Cancer Society

Because the control of the local tumor and possible distant micrometastases is essential for curing N2 non-small cell lung cancer, multimodality approaches have been considered the preferred treatment for patients with N2 non-small cell lung cancer, including radiotherapy, surgery and chemotherapy. Although induction treatment followed by surgery has been shown to offer a possible survival benefit in select patients with N2 non-small cell lung cancer, randomized phase III trials have failed to demonstrate an advantage of induction treatment followed by surgery over definitive chemoradiotherapy. However, in patients with resectable N2 non-small cell lung cancer, induction chemoradiotherapy followed by surgery has been shown to contribute to improved outcomes in the subgroup of patients who underwent lobectomy. Therefore, induction chemoradiotherapy followed by surgery may be a viable option in a select subset of patients. Recently, the use of immune checkpoint inhibitors after concurrent chemoradiotherapy has been shown to demonstrate a survival advantage in patients with unresectable N2 non-small cell lung cancer, suggesting that the advent of immune checkpoint inhibitors has led to an increase in therapeutic options. In this review, we outline some clinical trials of induction treatment followed by surgery for N2 non-small cell lung cancer and describe our experience in the perioperative management and surgical treatment with induction chemoradiotherapy followed by surgery as well as discuss future perspectives.

DOI： 10.2482/haigan.59.1129

Final overall survival results of WJTOG3405, a randomized phase III trial comparing gefitinib versus cisplatin with docetaxel as the first-line treatment for patients with stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. International journal

H Yoshioka, M Shimokawa, T Seto, S Morita, Y Yatabe, I Okamoto, J Tsurutani, M Satouchi, T Hirashima, S Atagi, K Shibata, H Saito, S Toyooka, N Yamamoto, K Nakagawa, T Mitsudomi

Annals of oncology : official journal of the European Society for Medical Oncology 30 ( 12 ) 1978 - 1984 2019.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Primary analysis of the phase III study WJTOG 3405 demonstrated superiority of progression-free survival (PFS) for gefitinib (G) in patients treated with the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) gefitinib compared with cisplatin plus docetaxel (CD) as the first-line treatment of stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. This report presents final overall survival (OS) data. PATIENTS AND METHODS: Patients were randomized between G (250 mg/day orally) and cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 i.v.), administered every 21 days for three to six cycles. After the exclusion of 5 patients, 172 patients (86 in each group, modified intention-to-treat population) were included in the survival analysis. OS was re-evaluated using updated data (data cutoff, 30 September 2013; median follow-up time 59.1 months). The Kaplan-Meier method and the log-rank test were used for analysis, and hazard ratios (HRs) for death were calculated using the Cox proportional hazards model. RESULTS: OS events in the G group and CD group were 68 (79.1%) out of 86 and 59 (68.6%) out of 86, respectively. Median survival time for G and CD were 34.9 and 37.3 months, respectively, with an HR of 1.252 [95% confidence interval (CI): 0.883-1.775, P = 0.2070]. Multivariate analysis identified postoperative recurrence and stage IIIB/IV disease as independent prognostic factors, with an HR of 0.459 (95% CI: 0.312-0.673, P < 0.001). Median survival time (postoperative recurrence versus stage IIIB/IV disease) were 44.5 and 27.5 months in the G group and 45.5 and 32.8 months in the CD group, respectively. CONCLUSION: G did not show OS benefits over CD as the first-line treatment. OS of patients with postoperative recurrence was better than that of stage IIIB/IV disease, even though both groups had metastatic disease.This study was registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.

DOI： 10.1093/annonc/mdz399

YES1 activation induces acquired resistance to neratinib in HER2-amplified breast and lung cancers. Reviewed

Takeda T, Yamamoto H, Suzawa K, Tomida S, Miyauchi S, Araki K, Nakata K, Miura A, Namba K, Shien K, Soh J, Shien T, Kitamura Y, Sendo T, Toyooka S

Cancer science 111 ( 3 ) 849 - 856 2019.12

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib-resistant cell lines from HER2-amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib-resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1-amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.

DOI： 10.1111/cas.14289

Negative impact of recipient SPRED2 deficiency on transplanted lung in a mouse model. Reviewed

Hashimoto K, Yamane M, Sugimoto S, Hirano Y, Kurosaki T, Otani S, Miyoshi K, Ohara T, Okazaki M, Yoshimura T, Oto T, Matsukawa A, Toyooka S

Transplant immunology 57 101242 2019.12

Airway bacteria of the recipient but not the donor are relevant to post-lung transplant pneumonia. Reviewed

Konishi Y, Miyoshi K, Kurosaki T, Otani S, Sugimoto S, Yamane M, Oto T, Toyooka S

General thoracic and cardiovascular surgery 2019.12

N2非小細胞肺癌に対する外科治療

杉本誠一郎, 豊岡伸一

肺癌 59 ( 7 ) 1129 - 1133 2019.12

Language：Japanese Publisher：(NPO)日本肺癌学会

N2陽性の非小細胞肺癌では、局所の制御を目的とした放射線治療や手術と、遠隔転移の制御を目的とした化学療法を組み合わせた集学的治療が行われてきた。N2非小細胞肺癌に対する導入療法後手術の有用性が示唆されていたが、第III相試験では、根治的化学放射線療法と比較した導入療法後手術の優越性は証明されていないのが現状である。しかし、切除可能なN2非小細胞肺癌で、特に肺葉切除術が可能な場合には、導入化学放射線療法後の手術の有用性が示唆されており、治療の選択肢として考慮すべきである。また、最近では新しい治療薬として免疫チェックポイント阻害剤が登場し、切除不能III期非小細胞肺癌に対して、化学放射線療法との逐次併用による有用性が示され、治療の選択肢が増えている。本稿では、N2非小細胞肺癌に対する導入療法後手術の臨床試験を概説し、当院における導入放射線化学療法後手術の周術期管理や手術の工夫を述べるとともに、今後の展望について述べる。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J01244&link_issn=&doc_id=20200109370001&doc_link_id=130007775582&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130007775582&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Dose-volume parameters predict radiation pneumonitis after induction chemoradiotherapy followed by surgery for non-small cell lung cancer: a retrospective analysis. International journal

Kuniaki Katsui, Takeshi Ogata, Kenta Watanabe, Norihisa Katayama, Junichi Soh, Masahiro Kuroda, Katsuyuki Kiura, Yoshinobu Maeda, Shinichi Toyooka, Susumu Kanazawa

BMC cancer 19 ( 1 ) 1144 - 1144 2019.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The relationship between lung dose-volume histogram (DVH) parameters and radiation pneumonitis (RP) associated with induction concurrent chemoradiotherapy (CCRT) followed by surgery in patients with non-small cell lung cancer (NSCLC) is unclear, particularly when concerning irradiation of the whole lung prior to resection. We performed this study to identify factors associated with grade ≥ 2 RP in such patients. METHODS: Patients who received induction CCRT (chemotherapy: cisplatin and docetaxel; radiotherapy: 46 Gy/23 fractions) between May 2003 and May 2017 were reviewed. The mean lung dose (MLD) and the percentage of the lung volume that received ≥5 Gy (V5) and ≥ 20 Gy (V20) were calculated. Factors associated with the development of grade ≥ 2 RP were analyzed. RESULTS: One hundred and eight patients were included in this study, 34 (31.5%) of whom experienced grade ≥ 2 RP. A V20 ≥ 21%, an MLD ≥10 Gy, and a lower lobe tumor location were significant predictors of grade ≥ 2 RP on univariate analysis (p = 0.007, 0.002, and 0.004, respectively). Moreover, an MLD ≥10 Gy and lower lobe location were significant predictors of grade ≥ 2 RP on multivariate analysis (p = 0.026 and 0.0043, respectively). The cumulative incidence rates of grade ≥ 2 RP at 6 months were 15.7 and 45.6% in patients with MLDs < 10 Gy and ≥ 10 Gy, respectively, and were 23.5 and 55.6% in patients with upper/middle lobe- vs. lower lobe-located tumors, respectively. CONCLUSIONS: MLD and lower lobe location were predictors of grade ≥ 2 RP in patients who received induction CCRT. It is necessary to reduce the MLD to the greatest extent possible to prevent the occurrence of this adverse event.

DOI： 10.1186/s12885-019-6359-9

Mortality from extrathymic malignancy after thymic tumour resections: incidences and risk factors. Reviewed International journal

Masatsugu Hamaji, Takashi Sozu, Ryunosuke Machida, Shun-Ichi Watanabe, Kazuo Yoshida, Shinichi Toyooka, Masayuki Tanahashi, Kazuya Kondo, Hirotoshi Horio, Meinoshin Okumura, Hiroshi Date

Interactive cardiovascular and thoracic surgery 29 ( 5 ) 729 - 736 2019.11

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: To identify risk factors associated with extrathymic malignancy-related mortality after thymic epithelial tumour resection. METHODS: The Japanese Association for Research on the Thymus database registered the records of 2835 patients collected from 32 Japanese institutions from 1991 to 2010. The cumulative incidence function of death due to extrathymic malignancies or recurrence was calculated, with other causes of death as competing risks. Relevant risk factors associated with extrathymic malignancy-related deaths in patients with thymoma were evaluated using the Fine and Gray model. RESULTS: In total, 2701 patients were eligible for the analysis (thymoma, 2374; thymic carcinoma, 273; thymic neuroendocrine tumour, 54). The median follow-up period was 4.6 years. The cumulative incidence function of death due to extrathymic malignancies at 10 years was 2.2% (3.2% due to recurrence) in patients with thymoma, 1.6% (38.6% due to recurrence) in patients with thymic carcinoma and 0% (36.6% due to recurrence) in patients with thymic neuroendocrine tumour. In the multivariable analysis, age (every 10 years) at thymectomy [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.53-3.14; P < 0.001], male gender (HR 2.62, 95% CI 1.19-5.77; P = 0.017) and previous malignancies (HR 3.09, 95% CI 1.18-8.11; P = 0.022) were significant factors for death due to extrathymic malignancies after thymectomy. CONCLUSIONS: Continued management and early detection of extrathymic malignancies may improve survival of patients with thymoma who are male, of advanced age, or have previous malignancies. Prospective studies are required to further investigate the management of extrathymic malignancies.

DOI： 10.1093/icvts/ivz177

Impact of pathological stage and histological subtype on clinical outcome of adjuvant chemotherapy of paclitaxel plus carboplatin versus oral uracil-tegafur for non-small cell lung cancer: subanalysis of SLCG0401 trial.

Junichi Soh, Shinichi Toyooka, Norihito Okumura, Hiroshige Nakamura, Masao Nakata, Motohiro Yamashita, Junichi Sakamoto, Motoi Aoe, Katsuyuki Hotta, Satoshi Morita, Hiroshi Date

International journal of clinical oncology 24 ( 11 ) 1367 - 1376 2019.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Pathological stage (pStage) and histological subtype are strong determinants of the treatment strategy for non-small cell lung cancer (NSCLC). Setouchi Lung Cancer study Group (SLCG) recently reported the results of a multicenter trial (SLCG0401) indicating that paclitaxel plus carboplatin (CBDCA/PTX) as adjuvant chemotherapy does not yield better survival than uracil-tegafur (UFT) in NSCLC patients with pStage IB-IIIA disease, while stratified analyses considering the pStage and histological subtype have not been performed. METHODS: We reanalyzed the overall survival (OS) and relapse-free survival (RFS) in 402 patients who had been randomly assigned to receive CBDCA/PTX or UFT by multivariate analysis with adjustments for the pStage and histological subtype. RESULTS: There were no significant differences in the OS or RFS between the two treatment settings either in the entire cohort (n = 402) and in some of subsets: pStage IB (n = 228), pStage II (n = 117), adenocarcinoma (AD, n = 265), and squamous cell carcinoma (SQ, n = 101). In pStage IIIA patients (n = 57), CBDCA/PTX yielded superior RFS to UFT [hazard ratio (HR) 0.44; P = 0.016]. Among the patients with non-AD and non-SQ histology (n = 36), UFT yielded both superior OS and RFS to CBDCA/PTX (HRs 0.16 and 0.23; P = 0.046 and 0.011, respectively). CONCLUSIONS: There are subsets of patients in which one or the other between UFT and CBDCA/PTX is significantly more effective. Selection of adjuvant therapy for NSCLC patients needs to be made taking into consideration the pStage and histological subtype.

DOI： 10.1007/s10147-019-01508-9

臨床的疑問より発した研究-Reverse translational research High tumor mutation burdenのALK陽性肺癌におけるアレクチニブ早期耐性について

槇本剛, 大橋圭明, 冨田秀太, 二宮貴一朗, 久保寿夫, 頼冠名, 市原英基, 堀田勝幸, 田端雅弘, 豊岡伸一, 木浦勝行

肺癌 59 ( 6 ) 571 - 571 2019.11

Warm retrograde perfusion can remove more fat from lung grafts with fat embolism in a porcine model. Reviewed

Irie M, Otani S, Kurosaki T, Tanaka S, Ohki T, Miyoshi K, Sugimoto S, Yamane M, Oto T, Toyooka S

General thoracic and cardiovascular surgery 2019.11

Favorable survival even with high disease-specific complication rates in lymphangioleiomyomatosis after lung transplantation - long-term follow-up of a Japanese center. Reviewed

Kurosaki T, Otani S, Miyoshi K, Okazaki M, Sugimoto S, Suno M, Yamane M, Kobayashi M, Oto T, Toyooka S

The clinical respiratory journal 2019.11

c-I期非小細胞肺癌における予後因子としてのスリガラス様陰影第7次全国肺癌登録

朝倉啓介, 新谷康, 岡見次郎, 奥村明之進, 伊藤宏之, 大塚崇, 豊岡伸一, 森毅, 渡辺俊一, 伊達洋至, 横井香平, 淺村尚生, 永安武, 宮岡悦良, 吉野一郎, 肺癌登録合同委員会

肺癌 59 ( 6 ) 696 - 696 2019.11

Bリンパ球過形成を伴う小結節性胸腺腫瘍の1切除例

上山廉起, 岡崎幹生, 塩谷俊雄, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

肺癌 59 ( 6 ) 923 - 923 2019.11

肺癌との鑑別が困難であった肺結節性リンパ過形成の1例

富岡泰章, 山本寛斉, 松原慧, 山本治慎, 塩谷俊雄, 難波圭, 諏澤憲, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

肺癌 59 ( 6 ) 878 - 878 2019.11

サルベージ治療・オリゴ再発に対する局所治療戦略術前化学放射線療法後手術を行った局所進行肺癌術後再発症例の臨床経過

諏澤憲, 枝園和彦, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

肺癌 59 ( 6 ) 586 - 586 2019.11

腹臥位による後方アプローチ併用ロボット支援下ダンベル型神経鞘腫摘出術

岡崎幹生, 諏澤憲, 塩谷俊雄, 三好健太郎, 大谷真二, 山本寛斉, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

肺癌 59 ( 6 ) 745 - 745 2019.11

定型カルチノイドを伴うびまん性特発性肺神経内分泌過形成の1例

富岡泰章, 山本寛斉, 松原慧, 山本治慎, 塩谷俊雄, 難波圭, 諏澤憲, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

肺癌 59 ( 6 ) 878 - 878 2019.11

肉腫多発肺転移に対する肺切除術

山本寛斉, 諏澤憲, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

肺癌 59 ( 6 ) 684 - 684 2019.11

頭頸部癌治療歴を有する非小細胞肺がん患者に対する手術症例の検討

高津史明, 諏澤憲, 枝園和彦, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

肺癌 59 ( 6 ) 711 - 711 2019.11

完全切除II-IIIA期の非扁平上皮非小細胞肺癌に対するPEM/CDDPとVNR/CDDPを比較する第III相試験(JIPANG)

駄賀晴子, 釼持広知, 山本信之, 山中竹春, 岡本勇, 光冨徹哉, 瀬戸貴司, 杉尾賢二, 豊岡伸一, 伊達洋至, 坂英雄, 横井香平, 岡本浩明, 滝口裕一, 坪井正博, JIPANG運営委員会

肺癌 59 ( 6 ) 594 - 594 2019.11

非小細胞肺癌II/IIIA期における術後CBDCA+S-1とS-1維持の忍容性試験SLCG1001 長期予後と分子マーカーの解析

吉岡弘鎮, 尾瀬功, 奥村典仁, 園部誠, 中村廣繁, 岡部和倫, 片岡正文, 山下素弘, 中田昌男, 片岡和彦, 山下芳典, 沖田千佳, 能登原憲司, 宗淳一, 堀田勝幸, 松尾恵太郎, 坂本純一, 山本寛斉, 豊岡伸一, 伊達洋至

肺癌 59 ( 6 ) 747 - 747 2019.11

人生100年時代の肺がん治療外科医の立場から

宗淳一, 富沢健二, 武本智樹, 小原秀太, 藤野智大, 古賀教将, 西野将矢, 濱田顕, 千葉眞人, 須田健一, 杉本誠一郎, 豊岡伸一, 光冨徹哉

肺癌 59 ( 6 ) 853 - 853 2019.11

肺門部浸潤肺癌手術例の検討多施設共同データ結果

山下素弘, 豊岡伸一, 伊達洋至, 奥村仁典, 中村宏繁, 岡部和倫, 牧祐歩, 宗淳一

肺癌 59 ( 6 ) 742 - 742 2019.11

ゲフィチニブを用いた化学療法の効果を比較した第III相試験WJTOG3405の全生存期間に関する最終解析(Final overall survival results of WJTOG3405, a phase III trial comparing gefitinib with chemotherapy)

Yoshioka Hiroshige, Shimokawa Mototsugu, Seto Takashi, Morita Satoshi, Yatabe Yasushi, Okamoto Isamu, Tsurutani Junji, Satouchi Miyako, Hirashima Tomonori, Atagi Shinji, Shibata Kazuhiko, Saito Hiroshi, Toyooka Shinichi, Yamamoto Nobuyuki, Nakagawa Kazuhiko, Mitsudomi Tetsuya

肺癌 59 ( 6 ) 629 - 629 2019.11

SPECT/CTを用いて切除範囲を評価した左肺底動脈大動脈起始症の1例

山本諒, 杉本誠一郎, 中田憲太郎, 塩谷俊雄, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 山根正修, 大藤剛宏, 豊岡伸一, 末澤孝徳

肺癌 59 ( 5 ) 509 - 509 2019.10

新規臨床試験最新情報完全切除非扁平上皮非小細胞肺癌に対する術後補助化学療法第III相試験 JIPANG試験

上野剛, 釼持広知, 山本信之, 山中竹春, 杉尾賢二, 瀬戸貴司, 豊岡伸一, 伊達洋至, 光冨徹哉, 岡本勇, 横井香平, 坂英雄, 岡本浩明, 滝口裕一, 坪井正博

日本癌治療学会学術集会抄録集 57回 SSY14 - 2 2019.10

バイオバンクでの長期保存生体試料の品質管理標準化のための予備的検討

山本英喜, 松原岳大, 森田瑞樹, 冨田秀太, 豊岡伸一, 平沢晃

臨床病理 67 ( 補冊 ) 283 - 283 2019.10

Correction to: Risk assessments for broncho-pleural fistula and respiratory failure after lung cancer surgery by National Clinical Database Japan. Reviewed

Endo S, Ikeda N, Kondo T, Nakajima J, Kondo H, Shimada Y, Sato M, Toyooka S, Okada Y, Sato Y, Yoshino I, Okada M, Okumura M, Chida M, Fukuchi E, Miyata H

General thoracic and cardiovascular surgery 67 ( 10 ) 904 - 906 2019.10

非小細胞肺癌におけるモネンシン併用療法によるEMT関連薬剤耐性の克服(Overcoming EMT-mediated drug resistance with Monensin-based combined therapy in non-small cell lung cancer)

大智宏祐, 諏澤憲, 冨田秀太, 荒木恒太, 宮内俊策, 三浦章博, 武田達明, 難波圭, 枝園和彦, 山本寛斉, 岡崎幹生, 枝園忠彦, 豊岡伸一

日本癌学会総会記事 78回 P - 1139 2019.9

ネラチニブ耐性乳がんにおけるYES1の重要性(The importance of YES1 in neratinib-resistant breast cancer)

武田達明, 山本寛斉, 諏澤憲, 北村佳久, 千堂年昭, 豊岡伸一

日本癌学会総会記事 78回 P - 3157 2019.9

ドナー胸腔内所見により再斡旋によるレシピエント変更後に肺移植を行った1例

松原慧, 大谷真二, 山本治慎, 塩谷俊雄, 難波圭, 二萬英斗, 諏澤憲, 三好健太郎, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

移植 54 ( 総会臨時 ) 315 - 315 2019.9

妊婦に合併した縦隔成熟奇形腫に対して手術を行った1例

宮内俊策, 枝園和彦, 宗淳一, 山本寛斉, 山根正修, 豊岡伸一

日本呼吸器外科学会雑誌 33 ( 6 ) 624 - 628 2019.9

Language：Japanese Publisher：(NPO)日本呼吸器外科学会

縦隔成熟奇形腫は無症状で検診発見されることが多いが、時に急速に増大することがある。今回我々は、妊婦に合併し急速に増大したため妊娠中に手術を施行した症例を経験した。症例は27歳、女性。検診で胸部異常陰影を指摘され当科受診となった。初診時、患者は妊娠10週の妊婦であった。胸部X線写真で右上肺野中枢側に8cm大の腫瘤影、単純MRIで前縦隔に10cm大の多房性嚢胞性病変を認め、成熟奇形腫が疑われた。右前胸部痛が出現しており、腫瘍の急速な増大が考えられ手術の方針とした。手術は妊娠15週に胸骨正中切開で縦隔腫瘍摘出術、右肺上葉・心膜合併部分切除術を施行した。腫瘍は成熟奇形腫の診断で未熟成分や悪性所見は認めなかった。術後経過は良好で、妊娠40週で正常分娩に至った。妊娠と急速増大との因果関係は不明であるが、本症例のような場合でも術前検査や手術時期・方法に注意すれば妊娠中でも安全に手術が行えると考える。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J02256&link_issn=&doc_id=20190920300008&doc_link_id=10.2995%2Fjacsurg.33.624&url=https%3A%2F%2Fdoi.org%2F10.2995%2Fjacsurg.33.624&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

肺移植後移植片慢性機能不全の予防と治療-本邦における肺移植開始後20年での現状- 肺移植後移植片慢性機能不全(CLAD)における血中micro-RNA発現量の検討 Reviewed

塩谷俊雄, 杉本誠一郎, 松原慧, 山本治慎, 二萬英斗, 三好健太郎, 大谷真二, 岡崎幹生, 山根正修, 大藤剛宏, 豊岡伸一

移植 54 ( 総会臨時 ) 189 - 189 2019.9

生体・脳死肺移植における予後予測因子としてのPrognostic Nutrition Index(PNI)の有用性 Reviewed

山本治慎, 杉本誠一郎, 塩谷俊雄, 三好健太郎, 大谷真二, 岡崎幹生, 山根正修, 大藤剛宏, 豊岡伸一

移植 54 ( 総会臨時 ) 215 - 215 2019.9

ハイリスク症例に対する肺移植高度の胸膜癒着を認めたレシピエントに対する肺移植 Reviewed

杉本誠一郎, 塩谷俊雄, 山本治慎, 大河知世, 三好健太郎, 大谷真二, 岡崎幹生, 山根正修, 大藤剛宏, 豊岡伸一

移植 54 ( 総会臨時 ) 174 - 174 2019.9

転移がんに有効なS100A8/A9阻害薬の開発(Novel therapeutic approach based on S100A8/A9-mediated organ tropic cancer metastasis)

木下理恵, 友信奈保子, 山内明, 枝園和彦, 冨田秀太, 村田等, 二見淳一郎, 近藤英作, 豊岡伸一, 阪口政清

日本癌学会総会記事 78回 P - 2252 2019.9

バイオバンキングが切り拓く新しいがん研究わが国におけるクリニカルバイオバンクネットワークの構築(Innovative cancer research based on biobanking Clinical biobank network in Japan)

武藤学, 金井雅史, 鶴山竜昭, 松本繁巳, 豊岡伸一, 秋田弘俊, 松原久裕, 西原広史, 末岡榮三朗, 池田貞勝

日本癌学会総会記事 78回 S11 - 4 2019.9

Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts. Reviewed International journal

Yosuke Mitsui, Nahoko Tomonobu, Masami Watanabe, Rie Kinoshita, I Wayan Sumardika, Chen Youyi, Hitoshi Murata, Ken-Ichi Yamamoto, Takuya Sadahira, Acosta Gonzalez Herik Rodrigo, Hitoshi Takamatsu, Kota Araki, Akira Yamauchi, Masahiro Yamamura, Hideyo Fujiwara, Yusuke Inoue, Junichiro Futami, Ken Saito, Hidekazu Iioka, Eisaku Kondo, Masahiro Nishibori, Shinichi Toyooka, Yasuhiko Yamamoto, Yasutomo Nasu, Masakiyo Sakaguchi

Oncology research 27 ( 8 ) 945 - 956 2019.8

Language：English Publishing type：Research paper (scientific journal)

S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11-RAGE-TPL2-COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.

DOI： 10.3727/096504019X15555408784978

Impact of chronic lung allograft dysfunction, especially restrictive allograft syndrome, on the survival after living-donor lobar lung transplantation compared with cadaveric lung transplantation in adults: a single-center experience. Reviewed

Seiichiro Sugimoto, Haruchika Yamamoto, Takeshi Kurosaki, Shinji Otani, Mikio Okazaki, Masaomi Yamane, Shinichi Toyooka, Takahiro Oto

Surgery today 49 ( 8 ) 686 - 693 2019.8

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: The differences in chronic lung allograft dysfunction (CLAD) between living-donor lobar lung transplantation (LDLLT) and cadaveric lung transplantation (CLT) remain unclear. We conducted this study to compare the impact of CLAD on the outcomes after LDLLT vs. CLT. METHODS: We conducted a retrospective review of the data of 97 recipients of bilateral lung transplantation, including 51 recipients of LDLLT and 46 recipients of CLT. RESULTS: The CLAD-free survival and overall survival after LDLLT were similar to those after CLT. CLAD and restrictive allograft syndrome (RAS), but not bronchiolitis obliterans syndrome (BOS), developed significantly later after LDLLT than after CLT (p = 0.015 and p = 0.035). Consequently, patients with CLAD and RAS, but not those with BOS, after LDLLT had a significantly better overall survival than those after CLT (p = 0.037 and p = 0.0006). Furthermore, after the diagnosis of CLAD, the survival of patients with RAS after LDLLT tended to be better than that after CLT (p = 0.083). CONCLUSION: CLAD, especially RAS, appears to develop later after LDLLT than after CLT and seems to have a lower impact on the overall survival after LDLLT than that after CLT.

DOI： 10.1007/s00595-019-01782-0

Acquired resistance mechanisms to afatinib in HER2-amplified gastric cancer cells. Reviewed International journal

Takahiro Yoshioka, Kazuhiko Shien, Tatsuaki Takeda, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Hidejiro Torigoe, Hiroki Sato, Shuta Tomida, Hiromasa Yamamoto, Junichi Soh, Toshiyoshi Fujiwara, Shinichi Toyooka

Cancer science 110 ( 8 ) 2549 - 2557 2019.8

Language：English Publishing type：Research paper (scientific journal)

Cancer treatment, especially that for breast and lung cancer, has entered a new era and continues to evolve, with the development of genome analysis technology and the advent of molecular targeted drugs including tyrosine kinase inhibitors. Nevertheless, acquired drug resistance to molecular targeted drugs is unavoidable, creating a clinically challenging problem. We recently reported the antitumor effect of a pan-HER inhibitor, afatinib, against human epidermal growth factor receptor 2 (HER2)-amplified gastric cancer cells. The purpose of the present study was to identify the mechanisms of acquired afatinib resistance and to investigate the treatment strategies for HER2-amplified gastric cancer cells. Two afatinib-resistant gastric cancer cell lines were established from 2 HER2-amplified cell lines, N87 and SNU216. Subsequently, we investigated the molecular profiles of resistant cells. The activation of the HER2 pathway was downregulated in N87-derived resistant cells, whereas it was upregulated in SNU216-derived resistant cells. In the N87-derived cell line, both MET and AXL were activated, and combination treatment with afatinib and cabozantinib, a multikinase inhibitor that inhibits MET and AXL, suppressed the cell growth of cells with acquired resistance both in vitro and in vivo. In the SNU216-derived cell line, YES1, which is a member of the Src family, was remarkably activated, and dasatinib, a Src inhibitor, exerted a strong antitumor effect in these cells. In conclusion, we identified MET and AXL activation in addition to YES1 activation as novel mechanisms of afatinib resistance in HER2-driven gastric cancer. Our results also indicated that treatment strategies targeting individual mechanisms of resistance are key to overcoming such resistance.

DOI： 10.1111/cas.14089

災害ボランティア活動に参加した喘息患者の血痰精査中に発見された右胸部異常陰影の一例

鹿谷芳伸, 黒崎毅史, 大谷真二, 中田憲太郎, 難波圭, 諏澤憲, 枝園和彦, 久保寿夫, 山本寛斉, 岡崎幹生, 杉本誠一郎, 宗淳一, 山根正修, 大藤剛宏, 豊岡伸一

岡山医学会雑誌 131 ( 2 ) 113 - 113 2019.8

IB〜IIIA期肺癌切除例に対するCBDCA/PTXとUFTによる術後補助療法のランダム化比較試験(SLCG0401試験)の病期・組織型別のサブ解析

宗淳一, 豊岡伸一, 奥村典仁, 中村廣繁, 中田昌男, 山下素弘, 青江基, 堀田勝幸, 吉岡弘鎮, 伊達洋至, 森田智視

肺癌 59 ( 4 ) 425 - 425 2019.8

Newly developed anti-S100A8/A9 monoclonal antibody efficiently prevents lung tropic cancer metastasis. Reviewed International journal

Rie Kinoshita, Hiroki Sato, Akira Yamauchi, Yuta Takahashi, Yusuke Inoue, I Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Kota Araki, Kazuhiko Shien, Shuta Tomida, Hidejiro Torigoe, Kei Namba, Eisuke Kurihara, Yusuke Ogoshi, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, Hiromasa Yamamoto, Junichi Soh, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

International journal of cancer 145 ( 2 ) 569 - 575 2019.7

Language：English Publishing type：Research paper (scientific journal)

The metastatic dissemination of cancer cells to remote areas of the body is the most problematic aspect in cancer patients. Among cancers, melanomas are notoriously difficult to treat due to their significantly high metastatic potential even during early stages. Hence, the establishment of advanced therapeutic approaches to regulate metastasis is required to overcome the melanoma disease. An accumulating mass of evidence has indicated a critical role of extracellular S100A8/A9 in melanoma distant metastasis. Lung S100A8/A9 is induced by melanoma cells from distant organs and it attracts these cells to its enriched lung environment since melanoma cells possess several receptors that sense the S100A8/A9 ligand. We hence aimed to develop a neutralizing antibody against S100A8/A9 that would efficiently block melanoma lung metastasis. Our protocol provided us with one prominent antibody, Ab45 that efficiently suppressed not only S100A8/A9-mediated melanoma mobility but also lung tropic melanoma metastasis in a mouse model. This prompted us to make chimeric Ab45, a chimera antibody consisting of mouse Ab45-Fab and human IgG2-Fc. Chimeric Ab45 also showed significant inhibition of the lung metastasis of melanoma. From these results, we have high hopes that the newly produced antibody will become a potential biological tool to block melanoma metastasis in future clinical settings.

DOI： 10.1002/ijc.31982

Tumour size determines both recurrence-free survival and disease-specific survival after surgical treatment for thymoma. Reviewed International journal

Meinoshin Okumura, Ichiro Yoshino, Motoki Yano, Shun-Ichi Watanabe, Masahiro Tsuboi, Kazuo Yoshida, Hiroshi Date, Kohei Yokoi, Jun Nakajima, Shin-Ichi Toyooka, Hisao Asamura, Etsuo Miyaoka

European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 56 ( 1 ) 174 - 181 2019.7

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: The tumour, node and the metastasis (TNM) staging system for thymic epithelial tumours was adopted by the Union for International Cancer Control (UICC) in 2016. Although the T factor is defined by the invasive nature of a thymoma, tumour size is not considered. The aim of this study was to examine the clinical importance of tumour size using a nationwide retrospective database of cases treated from 1991 to 2010 compiled by the Japanese Association for Research of the Thymus. METHODS: Tumour size was evaluated by the maximum diameter shown by computed tomography imaging prior to resection. Tumour size was available for 2083 thymoma patients undergoing upfront surgical treatment. The tumour size ranged from 0.6 to 19.4 cm (mean 5.1 cm, median 4.9 cm). Harrell's C-index was adopted to determine the cut-off value of the tumour size in 0.5-cm increments. RESULTS: The highest C-index value (0.7760) was obtained in terms of recurrence-free survival after the complete resection when the cut-off value was set at 5.0 cm. The 10-year recurrence-free survival rate was 93.8% in patients with a tumour ≤5.0 cm and 84.3% in patients with a tumour >5.0 cm (P < 0.0001). The highest C-index value (0.8885) in terms of disease-specific survival was obtained when the cut-off value was set at 8.0 cm. The 10-year disease-specific survival rate was 98.8% in patients with a tumour <8.0 cm and 90.1% in those with a tumour ≥8.0 cm (P < 0.0001). The Cox's proportional hazard model analysis showed that the tumour size and the TNM-based pathological stage were independent factors to determine both recurrence-free survival and disease-specific survival. CONCLUSIONS: Tumour size is an important prognostic factor and should be considered when determining the treatment strategy for thymoma patients.

DOI： 10.1093/ejcts/ezz001

Clinical outcome of patients with recurrent non-small cell lung cancer after trimodality therapy. Reviewed

Ken Suzawa, Junichi Soh, Yuta Takahashi, Hiroki Sato, Kazuhiko Shien, Hiromasa Yamamoto, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

Surgery today 49 ( 7 ) 601 - 609 2019.7

Language：English Publishing type：Research paper (scientific journal)

PURPOSES: The purpose of this study was to review the clinical course of patients with recurrence after induction chemoradiotherapy followed by surgery (trimodality therapy) for locally advanced non-small cell lung cancer (LA-NSCLC) and to identify the factors associated with favorable clinical outcome after recurrence. METHODS: We analyzed the records of 140 patients with LA-NSCLC who were treated with trimodality therapy between 1999 and 2014. RESULTS: Recurrence developed after trimodality therapy in 48 patients. A yp-N positive status was associated with a high risk of recurrence (HR, 2.05; P = 0.048). Of the 45 of these patients able to be assessed retrospectively, 18 had oligometastatic recurrence and 20 underwent local treatment with curative intent. Local treatment was most frequently given to patients with oligometastatic recurrence (P < 0.001). The median post-recurrence survival (PRS) was 41.4 months, and the 2-year PRS rate was 62%. Patients who received local treatment showed better PRS (P = 0.009). The presence of liver metastasis (P = 0.008), bone metastasis (P = 0.041), or dissemination (P < 0.0001) were associated with worse PRS. CONCLUSION: The survival of patients who received aggressive local treatment for postoperative recurrence after trimodality therapy for LA-NSCLC was better than that of patients who did not.

DOI： 10.1007/s00595-019-1774-8

Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness. Reviewed International journal

Youyi Chen, I Wayan Sumardika, Nahoko Tomonobu, Rie Kinoshita, Yusuke Inoue, Hidekazu Iioka, Yosuke Mitsui, Ken Saito, I Made Winarsa Ruma, Hiroki Sato, Akira Yamauchi, Hitoshi Murata, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Junichiro Futami, Miyoko Kubo, Endy Widya Putranto, Takashi Murakami, Ming Liu, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

Neoplasia (New York, N.Y.) 21 ( 7 ) 627 - 640 2019.7

Language：English Publishing type：Research paper (scientific journal)

Metastatic breast cancer is the leading cause of cancer-associated death in women. The progression of this fatal disease is associated with inflammatory responses that promote cancer cell growth and dissemination, eventually leading to a reduction of overall survival. However, the mechanism(s) of the inflammation-boosted cancer progression remains unclear. In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT) in cells, since we found that ETV4 transcriptionally upregulates ZEB1, a strong EMT inducer, at a very high level. In contrast, downregulation of either MCAM or ETV4 repressed EMT, resulting in greatly weakened tumor growth and lung metastasis. Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells. Thus, therapeutic strategies based on our findings might improve patient outcomes.

DOI： 10.1016/j.neo.2019.04.006

Prolonged warm ischemia exacerbated acute rejection after lung transplantation from donation after cardiac death in a mouse. Reviewed

Hirano Y, Sugimoto S, Yamamoto S, Okada M, Otani S, Ohara T, Yamane M, Matsukawa A, Oto T, Toyooka S

General thoracic and cardiovascular surgery 2019.7

Melanoma cell adhesion molecule is the driving force behind the dissemination of melanoma upon S100A8/A9 binding in the original skin lesion. Reviewed International journal

Youyi Chen, I Wayan Sumardika, Nahoko Tomonobu, I Made Winarsa Ruma, Rie Kinoshita, Eisaku Kondo, Yusuke Inoue, Hiroki Sato, Akira Yamauchi, Hitoshi Murata, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Ming Liu, Junichiro Futami, Kaori Sasai, Hiroshi Katayama, Miyoko Kubo, Endy Widya Putranto, Toshihiko Hibino, Bei Sun, Masahiro Nishibori, Shinichi Toyooka, Masakiyo Sakaguchi

Cancer letters 452 178 - 190 2019.6

Language：English Publishing type：Research paper (scientific journal)

Since metastasis accounts for the majority of cancer-associated deaths, studies on the mechanisms of metastasis are needed to establish innovative strategies for cancer treatment. We previously reported that melanoma cell adhesion molecule (MCAM) functions as a critical receptor for S100A8/A9, and binding of S100A8/A9 to MCAM results in the migration of melanoma cells to lung tissue. However, the critical role of MCAM in the original melanoma skin lesion is still not clear. In this study, we aimed to determine the importance of the S100A8/A9-MCAM axis in melanoma dissemination in a skin lesion as a critical early step for metastasis. Mechanistic studies revealed the downstream signaling of MCAM that signaled the induction of metastasis. S100A8/A9-MCAM binding activates mitogen-activated protein kinase kinase kinase 8 (MAP3K8), also termed TPL2, leading to strong activation of the transcription factor ETV4 and subsequent induction of matrix metalloproteinase-25 (MMP25), and finally to induction of melanoma lung tropic metastasis. Collectively, our results demonstrate a crucial role of the S100A8/A9-MCAM signaling axis in metastatic onset of melanoma cells and indicate that strategies targeting the identified pathway may be useful for the establishment of innovative anti-cancer therapies.

DOI： 10.1016/j.canlet.2019.03.023

Extracellular S100A11 Plays a Critical Role in Spread of the Fibroblast Population in Pancreatic Cancers. Reviewed International journal

Hitoshi Takamatsu, Ken-Ichi Yamamoto, Nahoko Tomonobu, Hitoshi Murata, Yusuke Inoue, Akira Yamauchi, I Wayan Sumardika, Youyi Chen, Rie Kinoshita, Masahiro Yamamura, Hideyo Fujiwara, Yosuke Mitsui, Kota Araki, Junichiro Futami, Ken Saito, Hidekazu Iioka, I Made Winarsa Ruma, Endy Widya Putranto, Masahiro Nishibori, Eisaku Kondo, Yasuhiko Yamamoto, Shinichi Toyooka, Masakiyo Sakaguchi

Oncology research 27 ( 6 ) 713 - 727 2019.6

Language：English Publishing type：Research paper (scientific journal)

The fertile stroma in pancreatic ductal adenocarcinomas (PDACs) has been suspected to greatly contribute to PDAC progression. Since the main cell constituents of the stroma are fibroblasts, there is crosstalking(s) between PDAC cells and surrounding fibroblasts in the stroma, which induces a fibroblast proliferation burst. We have reported that several malignant cancer cells including PDAC cells secrete a pronounced level of S100A11, which in turn stimulates proliferation of cancer cells via the receptor for advanced glycation end products (RAGE) in an autocrine manner. Owing to the RAGE+ expression in fibroblasts, the extracellular abundant S100A11 will affect adjacent fibroblasts. In this study, we investigated the significance of the paracrine axis of S100A11-RAGE in fibroblasts for their proliferation activity. In in vitro settings, extracellular S100A11 induced upregulation of fibroblast proliferation. Our mechanistic studies revealed that the induction is through RAGE-MyD88-mTOR-p70 S6 kinase upon S100A11 stimulation. The paracrine effect on fibroblasts is linked mainly to triggering growth but not cellular motility. Thus, the identified pathway might become a potential therapeutic target to suppress PDAC progression through preventing PDAC-associated fibroblast proliferation.

DOI： 10.3727/096504018X15433161908259

exSSSRs (extracellular S100 soil sensor receptors)-Fc fusion proteins work as prominent decoys to S100A8/A9-induced lung tropic cancer metastasis. Reviewed International journal

Rie Kinoshita, Hiroki Sato, Akira Yamauchi, Yuta Takahashi, Yusuke Inoue, I Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Kota Araki, Kazuhiko Shien, Shuta Tomida, Hidejiro Torigoe, Kei Namba, Eisuke Kurihara, Yusuke Ogoshi, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, Hiromasa Yamamoto, Junichi Soh, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

International journal of cancer 144 ( 12 ) 3138 - 3145 2019.6

Language：English Publishing type：Research paper (scientific journal)

Within the "seed and soil" theory of organ tropic cancer metastasis is a growing compilation of evidence that S100A8/A9 functions as a soil signal that attracts cancer cells to certain organs, which prove beneficial to their growth. S100A8/A9-sensing receptors including Toll-like receptor 4 (TLR4), advanced glycation end products (RAGE), and also important receptors we recently succeeded in identifying (EMMPRIN, NPTNβ, MCAM, and ALCAM) have the potential to become promising therapeutic targets. In our study, we prepared extracellular regions of these novel molecules and fused them to human IgG2-Fc to extend half-life expectancy, and we evaluated the anti-metastatic effects of the purified decoy proteins on metastatic cancer cells. The purified proteins markedly suppressed S100A8/A9-mediated lung tropic cancer metastasis. We hence expect that our novel biologics may become a prominent medicine to prevent cancer metastasis in clinical settings through cutting the linkage between "seed and soil".

DOI： 10.1002/ijc.31945

Droplet digital PCR as a novel system for the detection of microRNA‑34b/c methylation in circulating DNA in malignant pleural mesothelioma. Reviewed International journal

Hiroki Sato, Junichi Soh, Keisuke Aoe, Nobukazu Fujimoto, Shin Tanaka, Kei Namba, Hidejiro Torigoe, Kazuhiko Shien, Hiromasa Yamamoto, Shuta Tomida, Hiroyuki Tao, Kazunori Okabe, Takumi Kishimoto, Shinichi Toyooka

International journal of oncology 54 ( 6 ) 2139 - 2148 2019.6

Language：English Publishing type：Research paper (scientific journal)

Malignant pleural mesothelioma (MPM) is a rare malignancy arising from the pleura that is difficult to diagnose, contributing to its dismal prognosis. Previously, we reported that the degree of microRNA (miR)‑34b/c methylation in circulating DNA is associated with the development of MPM. Herein, we present a newly developed droplet digital PCR (ddPCR)‑based assay for the detection of miR‑34b/c methylation in circulating DNA in patients with MPM. We originally prepared two probes within a short amplicon of 60 bp, designing one from the positive strand and the other from the complementary strand. The two probes functioned cooperatively, and our established assay detected DNA methylation accurately in the preliminary validation. We subsequently verified this assay using clinical samples. Serum samples from 35 cases of MPM, 29 cases of pleural plaque and 10 healthy volunteers were collected from 3 different institutions and used in this study. We divided the samples into 2 groups (group A, n=33; group B, n=41). A receiver‑operating characteristic curve analysis using the samples in group A determined the optimal cut‑off value for the diagnosis of MPM, with a sensitivity of 76.9% and a specificity of 90%. On the other hand, the use of the same criterion yielded a sensitivity of 59.1% and a specificity of 100% in group B, and corresponding values of 65.7 and 94.9% for the entire cohort, indicating a moderate sensitivity and a high specificity. In addition, when the analysis was focused on stage II or more advanced MPM, the sensitivity improved to 81.8%, suggesting the possibility that the methylated allele frequency in MPM may be associated with the stage of disease progression. On the whole, the findings of this study indicate that miR‑34b/c methylation in circulating DNA is a promising biomarker for the prediction of disease progression in patients with MPM.

DOI： 10.3892/ijo.2019.4768

Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression. Reviewed International journal

I Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Rie Kinoshita, I Made Winarsa Ruma, Hiroki Sato, Eisaku Kondo, Yusuke Inoue, Akira Yamauchi, Hitoshi Murata, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Junichiro Futami, Endy Widya Putranto, Toshihiko Hibino, Masahiro Nishibori, Shinichi Toyooka, Masakiyo Sakaguchi

Molecular carcinogenesis 58 ( 6 ) 980 - 995 2019.6

Language：English Publishing type：Research paper (scientific journal)

Compiling evidence indicates an unusual role of extracellular S100A8/A9 in cancer metastasis. S100A8/A9 secreted from either cancer cells or normal cells including epithelial and inflammatory cells stimulates cancer cells through S100A8/A9 sensor receptors in an autocrine or paracrine manner, leading to cancer cell metastatic progression. We previously reported a novel S100A8/A9 receptor, neuroplastin-β (NPTNβ), which plays a critical role in atopic dermatitis when it is highly activated in keratinocytes by an excess amount of extracellular S100A8/A9 in the inflammatory skin lesion. Interestingly, our expression profiling of NPTNβ showed significantly high expression levels in lung cancer cell lines in a consistent manner. We hence aimed to determine the significance of NPTNβ as an S100A8/A9 receptor in lung cancer. Our results showed that NPTNβ has strong ability to induce cancer-related cellular events, including anchorage-independent growth, motility and invasiveness, in lung cancer cells in response to extracellular S100A8/A9, eventually leading to the expression of a cancer disseminative phenotype in lung tissue in vivo. Mechanistic investigation revealed that binding of S100A8/A9 to NPTNβ mediates activation of NFIA and NFIB and following SPDEF transcription factors through orchestrated upstream signals from TRAF2 and RAS, which is linked to anchorage-independent growth, motility and invasiveness. Overall, our results indicate the importance of the S100A8/A9-NPTNβ axis in lung cancer disseminative progression and reveal a pivotal role of its newly identified downstream signaling, TRAF2/RAS-NFIA/NFIB-SPDEF, in linking to the aggressive development of lung cancers.

DOI： 10.1002/mc.22987

術後肺瘻に対してEWSを用いた気管支充填術を施行した6例の検討

安東千裕, 西井和也, 頼冠名, 山本寛斎, 狩野裕久, 渡邉洋美, 妹尾賢, 原尚史, 久保寿夫, 豊岡伸一, 木浦勝行

気管支学 41 ( Suppl. ) S254 - S254 2019.6

Frequent mutations of genes predisposing to Rho GTPase signal activation and autophagy inhibition in metastatic soft tissue sarcoma unveiled by paired somatic and germline genomic analyses. Reviewed

Takahashi Katsuhito, Motoki Ayako, Yashima Jun, Masaki Noriyuki, Sano Hiroko, Yamamoto Hiromasa, Sou Junichi, Takahashi Yuko, Toyooka Shinichi, Oyama Yu, Nomori Hiroaki, Narahara Hiroyuki, Yotsumoto Junko, Ono Yasuo, Tonsho Makoto, Teraoka Satoshi

JOURNAL OF CLINICAL ONCOLOGY 37 ( 15 ) 2019.5

SOCS3 overexpression in T cells ameliorates chronic airway obstruction in a murine heterotopic tracheal transplantation model. Reviewed

Kumi Mesaki, Masaomi Yamane, Seiichiro Sugimoto, Masayoshi Fujisawa, Teizo Yoshimura, Takeshi Kurosaki, Shinji Otani, Shinichiro Miyoshi, Takahiro Oto, Akihiro Matsukawa, Shinichi Toyooka

Surgery today 49 ( 5 ) 443 - 450 2019.5

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Suppressor of cytokine signaling-3 (SOCS3) is a negative feedback inhibitor of cytokine signaling with T-cell-mediated immunosuppressive effects on obliterative bronchiolitis (OB). In this study, we aimed to investigate the impact of T-cell-specific overexpression of SOCS3 using a murine heterotopic tracheal transplantation (HTT) model. METHODS: Tracheal allografts from BALB/c mice were subcutaneously transplanted into wild-type C57BL/6J (B6; WT) mice and SOCS3 transgenic B6 (SOCS3TG) mice. Tracheal allografts were analyzed by immunohistochemistry and quantitative polymerase chain reaction assays at days 7 and 21. RESULTS: At day 21, allografts in SOCS3TG mice showed significant amelioration of airway obstruction and epithelial loss compared with allografts in WT mice. The intragraft expression of IFN-γ and CXCL10 was suppressed, while that of IL-4 was enhanced in SOCS3TG mice at day 7. The T-bet levels were lower in SOCS3TG allografts than in WT allografts at day 7. CONCLUSION: We revealed that the overexpression of SOCS3 in T cells effectively ameliorates OB development in a murine HTT model by inhibiting the Th1 phenotype in the early phase. Our results suggest that the regulation of the T-cell response, through the modulation of SOCS expression, has potential as a new therapeutic strategy for chronic lung allograft dysfunction.

DOI： 10.1007/s00595-018-1753-5

A Prospective Cohort Study to Define the Clinical Features and Outcome of Lung Cancers Harboring HER2 Aberration in Japan (HER2-CS STUDY). Reviewed

Ninomiya K, Hata T, Yoshioka H, Ohashi K, Bessho A, Hosokawa S, Ishikawa N, Yamasaki M, Shibayama T, Aoe K, Kozuki T, Harita S, Ueda Y, Murakami T, Fujimoto N, Yanai H, Toyooka S, Takata M, Hotta K, Kiura K, HER2-CS Network

Chest 156 ( 2 ) 357 - 366 2019.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER

BACKGROUND: Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined.METHODS: Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations.RESULTS: Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26%]) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively.CONCLUSIONS: This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations.

DOI： 10.1016/j.chest.2019.01.011

Ganetespib in Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-resistant Non-small Cell Lung Cancer. Reviewed International journal

Eisuke Kurihara, Kazuhiko Shien, Hidejiro Torigoe, Tatsuaki Takeda, Yuta Takahashi, Yusuke Ogoshi, Takahiro Yoshioka, Kei Namba, Hiroki Sato, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Mikio Okazaki, Tadahiko Shien, Shuta Tomida, Shinichi Toyooka

Anticancer research 39 ( 4 ) 1767 - 1775 2019.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The 90-kDa heat-shock protein (HSP90) is a chaperone protein expressed at high levels in cancer cells and is involved in the folding or stabilization of several client proteins, including epidermal growth factor receptor (EGFR). Ganetespib is a second-generation HSP90 inhibitor with a potent antitumor effect against various cancer types. MATERIALS AND METHODS: This study examined the antitumor effect of ganetespib in EGFR-mutant non-small cell lung cancer (NSCLC) cells and experimentally established EGFR-tyrosine kinase inhibitor (TKI)-resistant cells harboring various resistance mechanisms, including EGFR T790M mutation, met proto-oncogene amplification, and epithelial-mesenchymal transition. RESULTS: Ganetespib showed a potent antitumor effect at low concentrations, suppressing EGFR-related downstream pathway molecules and inducing cleavage of poly ADP-ribose polymerase in all examined EGFR-TKI-resistant cell lines in vitro. Ganetespib also inhibited in vivo tumor growth in resistant cells harboring EGFR T790M. CONCLUSION: Ganetespib might be a promising therapeutic option for the treatment of patients with EGFR-TKI-resistant NSCLC.

DOI： 10.21873/anticanres.13283

EGFR-TKI耐性NSCLCに対するHSP90阻害剤ganetespibの有用性の検討

栗原英祐, 枝園和彦, 鳥越英次郎, 武田達明, 荒木恒太, 宮内俊策, 三浦章博, 高橋優太, 諏澤憲, 山本寛斉, 宗淳一, 冨田秀太, 豊岡伸一

日本呼吸器外科学会雑誌 33 ( 3 ) O17 - 4 2019.4

第7次事業2010年肺癌外科切除18972例の報告

岡見次郎, 新谷康, 奥村明之進, 伊藤宏之, 大塚崇, 豊岡伸一, 森毅, 渡辺俊一, 中西良一, 永安武, 伊達洋至, 淺村尚生, 遠藤俊輔, 千田雅之, 横井香平, 宮岡悦良, 吉野一郎, 肺癌登録合同委員会

日本呼吸器外科学会雑誌 33 ( 3 ) np10 - np10 2019.4

IB-IIIA期肺癌切除例に対する術後補助療法第三相試験(SLCG0401) 病期・組織型別のサブ解析

宗淳一, 豊岡伸一, 奥村典仁, 中村廣繁, 中田昌男, 山下素弘, 青江基, 伊達洋至

日本呼吸器外科学会雑誌 33 ( 3 ) RO21 - 2 2019.4

Risk assessments for broncho-pleural fistula and respiratory failure after lung cancer surgery by National Clinical Database Japan. Reviewed

Shunsuke Endo, Norihiko Ikeda, Takashi Kondo, Jun Nakajima, Haruhiko Kondo, Yoshihisa Shimada, Masami Sato, Shinichi Toyooka, Yoshinori Okada, Yukio Sato, Ichiro Yoshino, Morihito Okada, Meinoshin Okumura, Masayuki Chida, Eriko Fukuchi, Hiroaki Miyata

General thoracic and cardiovascular surgery 67 ( 3 ) 297 - 305 2019.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Broncho-pleural fistula (BPF) and respiratory failure (RF) are life-threatening complications after lung cancer surgery and can result in long-term hospitalization and decreased quality of life. Risk assessments for BPF and RF in addition to mortality and major morbidities are indispensable in surgical decision-making and perioperative care. METHODS: The characteristics and operative data of 80,095 patients who had undergone lung cancer surgery were derived from the 2014 and 2015 National Clinical Database (NCD) of Japan datasets. After excluding 1501 patients, risk models were developed from these data and validated by another dataset for 42,352 patients derived from the 2016 NCD dataset. Receiver operating characteristic curves were generated for postoperative BPF and RF development. The concordance-index was used to assess the discriminatory ability and validity of the model. RESULTS: BPF and RF occurred in 259 (0.3%) and 420 patients (0.5%), respectively, in the model development dataset and in 129 (0.3%) and 198 patients (0.5%), respectively, in the model validation dataset. Characteristic variables including types of surgery and comorbidities were identified as risk factors for BPF and RF, respectively. The concordance indexes of assessments for BPF and RF were 0.847 (p < 0.001) and 0.848 (p < 0.001), respectively, for the development dataset and 0.850 (p < 0.001) and 0.844 (p < 0.001), respectively, for the validation dataset. CONCLUSIONS: These models are satisfactory for predicting BPF and RF after lung cancer surgery in Japan and could guide preoperative assessment and optimal measures for preventing BPF and RF.

DOI： 10.1007/s11748-018-1022-y

Anti-tumor effect of neratinib against lung cancer cells harboring HER2 oncogene alterations. Reviewed International journal

Yusuke Ogoshi, Kazuhiko Shien, Takahiro Yoshioka, Hidejiro Torigoe, Hiroki Sato, Masakiyo Sakaguchi, Shuta Tomida, Kei Namba, Eisuke Kurihara, Yuta Takahashi, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka

Oncology letters 17 ( 3 ) 2729 - 2736 2019.3

Language：English Publishing type：Research paper (scientific journal)

Human epidermal growth factor receptor 2 (HER2) is a member of the ErbB family of receptor tyrosine kinases. Numerous studies have reported the amplification and overexpression of HER2 in several types of cancer, including non-small cell lung cancer (NSCLC). However, the benefits of HER2-targeted therapy have not been fully established. In the present study, the anti-tumor effect of neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), against NSCLC cells harboring HER2 alterations was investigated. The sensitivity of normal bronchial epithelial cells (BEAS-2B) ectopically overexpressing wild-type or mutant HER2 to neratinib was assessed. Furthermore, the anti-tumor activity of neratinib in several NSCLC cell lines harboring HER2 alterations was determined in vitro and in vivo, and the association between their genetic alterations and sensitivity to neratinib treatment was investigated. BEAS-2B cells ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, G660D and S310F) exhibited constitutive autophosphorylation of HER2, as determined by western blotting. While these BEAS-2B cells were sensitive to neratinib, they were insensitive to erlotinib, a first-generation epidermal growth factor receptor-TKI. Neratinib also exerted anti-proliferative effects on HER2-altered (H2170, Calu-3 and H1781) NSCLC cell lines. Neratinib was also demonstrated to exert strong tumor growth inhibitory activity in mouse xenograft models using HER2-altered lung cancer cells. The results of the present study strongly suggest that neratinib has potential as a promising therapeutic option for the treatment of HER2-altered NSCLC.

DOI： 10.3892/ol.2019.9908

Feasibility of lung transplantation from donors mechanically ventilated for prolonged periods. Reviewed

Seiichiro Sugimoto, Takeshi Kurosaki, Shinji Otani, Shin Tanaka, Yukiko Hikasa, Masaomi Yamane, Shinichi Toyooka, Motomu Kobayashi, Takahiro Oto

Surgery today 49 ( 3 ) 254 - 260 2019.3

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: When patients are mechanically ventilated for more than 5 days, they are usually declined as donors for lung transplantation (LTx); thus, the long-term outcomes of LTx from such donors remain unclear. We investigated the feasibility of LTx from donors that had been mechanically ventilated for prolonged periods. METHODS: The subjects of this retrospective comparative investigation were 31 recipients of LTx from donors who had been mechanically ventilated for < 5 days (short-term group) and 50 recipients of LTx from donors who had been mechanically ventilated for ≥ 5 days (long-term group). RESULTS: The median duration of donor mechanical ventilation was 3 days in the short-term group and 8.5 days in the long-term group. However, other than the difference in the duration of donor ventilation, there were no significant differences in the clinical characteristics of the donors or recipients between the groups. The overall survival rate after LTx was comparable between the long-term group and short-term group (5-year survival rate, 66.6% vs. 75.2%). CONCLUSION: The potential inclusion of donors who have been on mechanical ventilation for more than 5 days could be a feasible strategy to alleviate donor organ shortage.

DOI： 10.1007/s00595-018-1730-z

Lung transplant candidates with idiopathic pulmonary fibrosis and long-term pirfenidone therapy: Treatment feasibility influences waitlist survival. Reviewed International journal

Shin Tanaka, Kentaroh Miyoshi, Hisao Higo, Takeshi Kurosaki, Shinji Otani, Seiichiro Sugimoto, Masaomi Yamane, Katsuyuki Kiura, Shinichi Toyooka, Takahiro Oto

Respiratory investigation 57 ( 2 ) 165 - 171 2019.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronically progressive lung disease with exceptionally poor prognosis. While lung transplantation (LTx) is considered the last-resort therapeutic option, dismal waitlist mortality still hampers the salvage of patients with IPF. Pirfenidone, originally designed for IPF treatment, has increasingly been utilized. This study aimed to evaluate whether Pirfenidone could influence outcomes of patients with IPF on the Japanese LTx waitlist. METHODS: This retrospective single-center cohort study included 25 consecutive patients with IPF who were registered as LTx candidates at our institution between July 1999 and August 2016. Patients with a history of pretransplant Pirfenidone therapy (Pirfenidone group) were compared with those with no history (non-Pirfenidone group). RESULTS: In total, 6 (24%) patients received Pirfenidone as pretransplant therapy for 45.2 (range, 18.6-66.8) months. During the treatment period, the Pirfenidone group achieved a significant reduction in the decline rate of the forced vital capacity (-6.2% vs. -0.3%, p = 0.04) and a lower lung allocation score (31 vs. 41, p = 0.013) compared with the non-Pirfenidone group. The Pirfenidone group exhibited 100% waitlist survival three years after registration that was comparable to other indications, and 66% of the patients were still alive at the time of organ availability. No patient in the Pirfenidone group developed Pirfenidone-related surgical complications postoperatively. CONCLUSIONS: Patients with IPF successfully managed with long-term Pirfenidone therapy achieved favorable outcomes after LTx registration, comparable to other patients with LTx indications. The tolerability to antifibrotic therapy can be a predictor of waitlist survival.

DOI： 10.1016/j.resinv.2018.12.002

A single-nucleotide polymorphism in a gene modulating glucocorticoid sensitivity is associated with the decline in total lung capacity after lung transplantation. Reviewed

Haruchika Yamamoto, Seiichiro Sugimoto, Shin Tanaka, Takeshi Kurosaki, Shinji Otani, Masaomi Yamane, Naruto Taira, Takahiro Oto, Shinichi Toyooka

Surgery today 49 ( 3 ) 268 - 274 2019.3

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Glucocorticoids are used to prevent chronic lung allograft dysfunction (CLAD) after lung transplantation (LT). Our study was aimed at assessing the association between the glucocorticoid-induced transcript 1 gene (GLCCI1) variant, which modulates glucocorticoid sensitivity, and the postoperative lung function and development of CLAD after LT. METHODS: A total of 71 recipients of LT were genotyped for the GLCCI1 variant (rs37972) and divided into three groups: the homozygous mutant allele (TT) group, the heterozygous mutant allele (CT) group, and the wild-type allele (CC) group. The results of pulmonary function tests were compared with the postoperative baseline values. RESULTS: The total lung capacity (TLC) in the TT group was significantly lower than that in the CC group at 3 years after LT (P = 0.029). In the recipients of cadaveric LT, the TLC and forced expiratory volume in 1 s in the TT group were significantly lower than those in the CC groups, resulting in a significant worse CLAD-free survival at 3 years after LT (P = 0.016). CONCLUSION: The GLCCI1 variant was associated with a significant decrease of the TLC at 3 years after LT and the development of CLAD at 3 years, especially in patients undergoing cadaveric LT.

DOI： 10.1007/s00595-018-1717-9

チームアプローチで実現するゲノム医療と薬剤師の役割ゲノム医療におけるデータサイエンティストの役割と育成

冨田秀太, 森田瑞樹, 山下範之, 平沢晃, 豊岡伸一

日本薬学会年会要旨集 139年会 ( 1 ) 264 - 264 2019.3

肺癌患者に対する化学放射線療法は大動脈石灰化を増悪させる(Chemoradiation Therapy to Patients with Lung Cancer Exacerbates Aortic Calcification)

三木崇史, 三好亨, 市川啓之, 宮内俊策, 宗淳一, 豊岡伸一, 中村一文, 森田宏, 伊藤浩

日本循環器学会学術集会抄録集 83回 OJ33 - 4 2019.3

Application of amplicon-based targeted sequencing with the molecular barcoding system to detect uncommon minor EGFR mutations in patients with treatment-naïve lung adenocarcinoma. Reviewed International journal

Kei Namba, Shuta Tomida, Takehiro Matsubara, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Takahiro Yoshioka, Tatsuaki Takeda, Hidejiro Torigoe, Hiroki Sato, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Kazunori Tsukuda, Shinichi Toyooka

BMC cancer 19 ( 1 ) 175 - 175 2019.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: In lung cancer, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor sensitizing mutations co-existing with rare minor EGFR mutations are known as compound mutations. These minor EGFR mutations can lead to acquired resistance after EGFR tyrosine kinase inhibitor treatment, so determining the mutation status of patients is important. However, using amplicon-based targeted deep sequencing based on next-generation sequencing to characterize mutations is prone to sequencing error. We therefore assessed the benefit of incorporating molecular barcoding with high-throughput sequencing to investigate genomic heterogeneity in treatment-naïve patients who have undergone resection of their non-small cell lung cancer (NSCLC) EGFR mutations. METHODS: We performed amplicon-based targeted sequencing with the molecular barcoding system (MBS) to detect major common EGFR mutations and uncommon minor mutations at a 0.5% allele frequency in fresh-frozen lung cancer samples. RESULTS: Profiles of the common mutations of EGFR identified by MBS corresponded with the results of clinical testing in 63 (98.4%) out of 64 cases. Uncommon mutations of EGFR were detected in seven cases (10.9%). Among the three types of major EGFR mutations, patients with the G719X mutation had a significantly higher incidence of compound mutations than those with the L858R mutation or exon 19 deletion (p = 0.0052). This was validated in an independent cohort from the Cancer Genome Atlas dataset (p = 0.018). CONCLUSIONS: Our findings demonstrate the feasibility of using the MBS to establish an accurate NSCLC patient genotype. This work will help understand the molecular basis of EGFR compound mutations in NSCLC, and could aid the development of new treatment modalities.

DOI： 10.1186/s12885-019-5374-1

Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment in EGFR-Mutant Non-Small Cell Lung Cancer Cells. Reviewed International journal

Kei Namba, Kazuhiko Shien, Yuta Takahashi, Hidejiro Torigoe, Hiroki Sato, Takahiro Yoshioka, Tatsuaki Takeda, Eisuke Kurihara, Yusuke Ogoshi, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Shinichi Toyooka

Molecular cancer research : MCR 17 ( 2 ) 499 - 507 2019.2

Language：English Publishing type：Research paper (scientific journal)

Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR-mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib-resistant cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multigene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib. IMPLICATIONS: Upregulation of AXL is one of the mechanisms of acquired resistance to osimertinib, and combination of osimertinib and cabozantinib might be a key treatment for overcoming osimertinib resistance.

DOI： 10.1158/1541-7786.MCR-18-0628

Demographics, Safety and Quality, and Prognostic Information in Both the Seventh and Eighth Editions of the TNM Classification in 18,973 Surgical Cases of the Japanese Joint Committee of Lung Cancer Registry Database in 2010. Reviewed International journal

Okami J, Shintani Y, Okumura M, Ito H, Ohtsuka T, Toyooka S, Mori T, Watanabe SI, Date H, Yokoi K, Asamura H, Nagayasu T, Miyaoka E, Yoshino I, Japanese Join, Committee of Lung, Cancer Registry

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 14 ( 2 ) 212 - 222 2019.2

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: The Japanese Joint Committee of Lung Cancer Registry performed the fourth nationwide registry study of surgical cases. Demographics, safety and quality, prognostic information, and correlations between the seventh and the eighth editions of the TNM classification were investigated. The principal results were compared with those of previous Japanese Joint Committee of Lung Cancer Registry studies. METHODS: The clinicopathologic profiles, staging, and prognosis of patients who had an operation for primary lung cancer in 2010 were retrospectively collected in 2016 and analyzed. RESULTS: The cohort consisted of 18,973 patients from 297 hospitals (11,771 males, mean age 68.3 years). Tumor smaller than 2.0 cm was seen in 39.0% of patients, and limited resection was performed in 22.7%. The 30- and 90-day mortality rates were 0.43 and 1.26%, respectively. The overall and disease-free survival rates at 5 years were 74.7 and 67.8%, respectively. The respective 5-year survival rates by pathological stage in the seventh edition in the present study (2010) and in the previous study (2004) were 88.9% and 86.8% for stage IA, 76.7% and 73.9% for stage IB, 64.1% and 61.6% for stage IIA, 56.1% and 49.8% for stage IIB, 47.9% and 40.9% for stage IIIA, 30.2% and 27.8% for stage IIIB, and 36.1% and 27.9% for stage IV. The 5-year survival rates by clinical stage in the eighth edition in the present study were 97.0% for stage 0, 91.6% for stage IA1, 81.4% for stage IA2, 74.8% for stage IA3, 71.5% for stage IB, 60.2% for stage IIA, 58.1% for stage IIB, 50.6% for stage IIIA, 40.5% for stage IIIB, 37.5% for stage IIIC, and 36.0% for IVA/B. With restaging, the overall survival rates of clinical stage IA and IB in the seventh edition were stratified into stages 0 to IA3 and stages IA1 to IIA in the eighth edition, respectively. CONCLUSIONS: This study demonstrates improved surgical results for lung cancer in Japan. The TNM revision for the eighth edition was supported by the assessment of stage migration from the previous edition and the prognostic stratification.

DOI： 10.1016/j.jtho.2018.10.002

NEUROPLASTIN-β MEDIATES S100A8/A9-INDUCED LUNG CANCER DISSEMINATIVE PROGRESSION Reviewed

Sumardika IW, Chen Y, Tomonobu N, Kinoshita R, Ruma IMW, Sato H, Kondo E, Inoue Y, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Putranto EW, Hibino T, Nishibori M, Toyooka S, Sakaguchi M

Molecular Carcinogenesis 2019.2

Language：English Publishing type：Research paper (scientific journal)

Compiling evidence indicates an unusual role of extracellular S100A8/A9 in cancer metastasis. S100A8/A9 secreted from either cancer cells or normal cells including epithelial and inflammatory cells stimulates cancer cells through S100A8/A9 sensor receptors in an autocrine or paracrine manner, leading to cancer cell metastatic progression. We previously reported a novel S100A8/A9 receptor, neuroplastin-β (NPTNβ), which plays a critical role in atopic dermatitis when it is highly activated in keratinocytes by an excess amount of extracellular S100A8/A9 in the inflammatory skin lesion. Interestingly, our expression profiling of NPTNβ showed significantly high expression levels in lung cancer cell lines in a consistent manner. We hence aimed to determine the significance of NPTNβ as an S100A8/A9 receptor in lung cancer. Our results showed that NPTNβ has strong ability to induce cancer-related cellular events, including anchorage-independent growth, motility and invasiveness, in lung cancer cells in response to extracellular S100A8/A9, eventually leading to the expression of a cancer disseminative phenotype in lung tissue in vivo. Mechanistic investigation revealed that binding of S100A8/A9 to NPTNβ mediates activation of NFIA and NFIB and following SPDEF transcription factors through orchestrated upstream signals from TRAF2 and RAS, which is linked to anchorage-independent growth, motility and invasiveness. Overall, our results indicate the importance of the S100A8/A9-NPTNβ axis in lung cancer disseminative progression and reveal a pivotal role of its newly identified downstream signaling, TRAF2/RAS-NFIA/NFIB-SPDEF, in linking to the aggressive development of lung cancers. This article is protected by copyright.

DOI： 10.1002/mc.22987

Detection of lung cancer cells using a terahertz chemical microscope

Kosuke Sato, Masahiro Iida, Hirofumi Inoue, Toshihiko Kiwa, Shinichi Toyooka, Keiji Tsukada

Optics InfoBase Conference Papers Part F146-JSAP 2019 2019

Long-term spontaneous remission with active surveillance in IgG4-related pleuritis: A case report and literature review. Reviewed

Makimoto G, Ohashi K, Taniguchi K, Soh J, Taniguchi A, Miyahara N, Toyooka S, Yoshino T, Maeda Y, Kiura K

Respiratory medicine case reports 28 100938 2019

Multiple gastrointestinal stromal tumors of the small intestine in a patient with neurofibromatosis type 1: a case report

Mori Yoshiko, Fujiwara Toshiyoshi, Shigeyasu Kunitoshi, Yoshioka Takahiro, Nagasaka Takeshi, Haraga Junko, Kagawa Shunsuke, Teraishi Fuminori, Toyooka Shinichi, Hirasawa Akira

JOURNAL OF FAMILIAL TUMORS 19 ( 2 ) 77 - 82 2019

Language：Japanese Publisher：The Japanese Society for Familial Tumors

Neurofibromatosis type 1 (NF1) is a complex autosomal dominant disorder caused by germline variants in the NF1 tumor suppressor gene characterized by multiple caféau lait spots and cutaneous neurofibromas. Therefore, NF1 predisposes patients to benign and malignant tumor development. We report a 54-year-old NF1 male with multiple gastrointestinal stromal tumors (GIST) in the small intestine. We resected a part of the small intestine with larger tumors, but left the part with small tumors to avoid short bowel syndrome. Histological examination revealed spindle cells with eosinophilic cytoplasm. The tumors were positive for KIT on immunopathological examination. They were smaller than 3.5 cm and their mitotic activity was less than 5/50 in high-power fields. We left 17 GIST that were smaller than 10 mm, but no progression has been detected to date. (<250 words)

DOI： 10.18976/jsft.19.2_77

SPRED2 deficiency may lead to lung ischemia-reperfusion injury via ERK1/2 signaling pathway activation. Reviewed

Masanori Okada, Masaomi Yamane, Sumiharu Yamamoto, Shinji Otani, Kentaroh Miyoshi, Seiichiro Sugimoto, Akihiro Matsukawa, Shinichi Toyooka, Takahiro Oto, Shinichiro Miyoshi

Surgery today 48 ( 12 ) 1089 - 1095 2018.12

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Inflammatory changes during lung ischemia-reperfusion injury (IRI) are related to the activation of the extracellular signal-regulated kinase (ERK)1/2 signaling pathway. Sprouty-related EVH1 (enabled/vasodilator-stimulated phosphoprotein homology 1)-domain-containing proteins (SPREDs) are known inhibitors of ERK1/2 signaling. The role of SPRED2 in lung IRI was examined in a left hilar clamp mouse model. METHODS: C57BL/6 wild-type (WT) and Spred2-/- mice were used in the left hilar clamp model. Experimental groups underwent 30 min of left hilar clamping followed by 1 h of reperfusion. U0126, an ERK1/2 inhibitor, was administered to Spred2-/- mice with reperfused lungs. RESULTS: The partial pressures of oxygen of the Spred2-/- mice after reperfusion were significantly worse than those of WT mice (p < 0.01). Spred2-/- mice displayed more severe injuries than WT mice with increased neutrophil infiltration observed by a histological evaluation and flow cytometry (p < 0.001). This severe inflammation was inhibited by U0126. In addition, the rate of ERK1 activation was significantly higher in the lungs of Spred2-/- mice after reperfusion than in WT mice according to a Western blot analysis (p < 0.05). CONCLUSION: The activation of the ERK1/2 signaling pathway influences the severity of lung IRI, causing inflammation with neutrophil infiltration. SPRED2 may be a promising target for the suppression of lung IRI.

DOI： 10.1007/s00595-018-1696-x

Comparative mutational evaluation of multiple lung cancers by multiplex oncogene mutation analysis. Reviewed International journal

Yuta Takahashi, Kazuhiko Shien, Shuta Tomida, Shinsuke Oda, Takehiro Matsubara, Hiroki Sato, Ken Suzawa, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Takahiro Yoshioka, Hidejiro Torigoe, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka

Cancer science 109 ( 11 ) 3634 - 3642 2018.11

Language：English Publishing type：Research paper (scientific journal)

In patients presenting with synchronous or metachronous multiple lung cancer (MLC), it is important to distinguish between multiple primary lung cancer (MP) and intrapulmonary metastasis (IM). The present study was aimed at investigating the mutational profiles of synchronous/metachronous MLC and to compare the classification of paired tumors by multiplex gene mutation analysis with the histopathological evaluation. We carried out targeted sequencing of 20 lung cancer-related oncogenes using next-generation sequencing (NGS) in 82 tumors from 37 MLC patients who underwent surgical resection at our department. The patients were diagnosed as MP or IM cases based on the Martini and Melamed criteria, histopathological and gene mutational evaluations. Matching mutations between paired tumors was observed in 20 (54%) patients, who were diagnosed as IM cases by mutational evaluation. Patients who could not be clearly diagnosed by histopathological evaluation were classified as equivocal cases. Among the histopathological IM cases (n = 7), six (86%) were confirmed as IM cases also by mutational evaluation, and most of the paired tumors of these cases (n = 5) harbored multiple matching mutations. Among the histopathological MP cases (n = 17), mutational evaluation yielded a discordant diagnosis in eight (47%) cases. Of these, the paired tumors of four cases harbored multiple matching mutations, suggesting that the mutational diagnosis might be more suitable in these patients. Our findings suggest that multiplex mutational analysis could be a useful complementary tool for distinguishing between MP and IM in addition to histopathological evaluation.

DOI： 10.1111/cas.13797

Study Protocol: Phase-Ib Trial of Nivolumab Combined With Metformin for Refractory/Recurrent Solid Tumors. Reviewed International journal

Kubo T, Ninomiya T, Hotta K, Kozuki T, Toyooka S, Okada H, Fujiwara T, Udono H, Kiura K

Clinical lung cancer 19 ( 6 ) e861 - e864 2018.11

Language：English Publishing type：Research paper (scientific journal)

Although immune checkpoint inhibitors have shown significant survival benefits in the treatment of several cancers, optimal outcomes have been limited to certain subsets of patients. In a previous study, we found that the addition of metformin to nivolumab, an anti-programmed cell death protein 1 (PD-1) antibody, yielded substantial tumor regression in mouse models. Further analysis revealed that the number of tumor-infiltrating CD8 T cells had increased markedly. Based on this result, we have launched an investigator-initiated open-label phase-Ib clinical trial. The objectives of this trial are to investigate the safety, efficacy, and pharmacokinetics of a metformin-nivolumab combination treatment. This study consists of 2 parts. The recommended dose of metformin combined with nivolumab is determined in part 1. The safety and efficacy of the optimal dose of metformin to be delivered in conjunction with nivolumab are examined in part 2. Patient eligibility is based on the following criteria: pathologic diagnosis of refractory/recurrent solid tumor (part 1), and non-small-cell lung cancer or pancreatic cancer refractory to standard primary treatment (part 2); no prior use of immune checkpoint inhibitor; performance status 0 or 1; age ≥ 20 years; and adequate organ function. The primary endpoints are safety in part 1 and safety and pharmacokinetics in part 2. The maximum tolerated dose and recommended dose are determined in part 1 by the 3 + 3 cohort method, and the dose-limiting toxicity evaluation period for each patient is 4 weeks from the start of administration. In part 2, metformin is administered at the optimal dose determined in part 1. Total enrollment is 9 to 18 patients for part 1 and 30 patients for part 2. Enrollment began in 2017, and will be completed by 2019. The University Hospital Medical Information Network registration number for this study is 000028405.

DOI： 10.1016/j.cllc.2018.07.010

Donor-derived cell-free DNA is associated with acute rejection and decreased oxygenation in primary graft dysfunction after living donor-lobar lung transplantation. Reviewed International journal

Shin Tanaka, Seiichiro Sugimoto, Takeshi Kurosaki, Kentaroh Miyoshi, Shinji Otani, Ken Suzawa, Shinsuke Hashida, Masaomi Yamane, Takahiro Oto, Shinichi Toyooka

Scientific reports 8 ( 1 ) 15366 - 15366 2018.10

Language：English Publishing type：Research paper (scientific journal)

Donor-derived cell-free DNA (dd-cf-DNA) has been shown to be an informative biomarker of rejection after lung transplantation (LT) from deceased donors. However, in living-donor lobar LT, because small grafts from blood relatives are implanted with short ischemic times, the detection of dd-cf-DNA might be challenging. Our study was aimed at examining the role of dd-cf-DNA measurement in the diagnosis of primary graft dysfunction and acute rejection early after living-donor lobar LT. Immediately after LT, marked increase of the plasma dd-cf-DNA levels was noted, with the levels subsequently reaching a plateau with the resolution of primary graft dysfunction. Increased plasma levels of dd-cf-DNA were significantly correlated with decreased oxygenation immediately (p = 0.022) and at 72 hours (p = 0.046) after LT. Significantly higher plasma dd-cf-DNA levels were observed in patients with acute rejection (median, 12.0%) than in those with infection (median, 4.2%) (p = 0.028) or in a stable condition (median, 1.1%) (p = 0.001). Thus, measurement of the plasma levels of dd-cf-DNA might be useful to monitor the severity of primary graft dysfunction, and plasma dd-cf-DNA could be a potential biomarker for the diagnosis of acute rejection after LT.

DOI： 10.1038/s41598-018-33848-3

Dose-Volume Parameters Predict Radiation Pneumonitis after Surgery with Induction Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer. Reviewed

Ogata T, Katsui K, Yoshio K, Ihara H, Katayama N, Soh J, Kuroda M, Kiura K, Maeda Y, Toyooka S, Kanazawa S

Acta medica Okayama 72 ( 5 ) 507 - 513 2018.10

Language：English Publishing type：Research paper (scientific journal)

To clarify the relationship between dose-volume histogram (DVH) parameters and radiation pneumonitis (RP) after surgery in cases of non-small cell lung cancer (NSCLC) treated with induction concurrent chemoradiotherapy (CCRT). Patients with NSCLC treated with induction CCRT (chemotherapy: cisplatin and docetaxel; radiotherapy: 2.0 Gy fractions once daily for a total of 46 Gy) before surgery were reviewed. We calculated the percentage of lung volume receiving at least 20 Gy (V20) and the mean lung dose (MLD) for the total lung volume and the lung remaining after resection. Factors affecting the incidence of RP at grade 2 or higher (≥ G2 RP) were analyzed. Eighteen of 49 patients (37%) experienced ≥G2 RP. The V20 and MLD for the lung remaining after resection (V20r and MLDr) were significant predictors according to the multivariate analysis (p=0.007 and 0.041, respectively). The incidence of ≥G2 RP was 8% in patients with V20r<10%, and 13% in patients with MLDr<5.6 Gy, respectively. The optimal approach to reduce the rate of postoperative RP in patients with induction CCRT for NSCLC is to keep the V20r below 10% and/or the MLDr below 5.6 Gy in the radiotherapy planning.

DOI： 10.18926/AMO/56249

Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions. Reviewed International journal

Kato Y, Ninomiya K, Ohashi K, Tomida S, Makimoto G, Watanabe H, Kudo K, Matsumoto S, Umemura S, Goto K, Ichihara E, Ninomiya T, Kubo T, Sato A, Hotta K, Tabata M, Toyooka S, Maeda Y, Kiura K

Cancer science 109 ( 10 ) 3149 - 3158 2018.10

Language：English Publishing type：Research paper (scientific journal)

The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2-ROS1 and ABC-20 harboring CD74-ROS1, were used as cell line-based resistance models. Crizotinib-resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor-receptor tyrosine kinase array and RNA sequence analysis by next-generation sequencing. HCC78R cells showed upregulation of HB-EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB-EGF or EGF rendered HCC78 cells or ABC-20 cells resistant to crizotinib. RNA sequence analysis by next-generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR-TKI or anti-EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR-TKI were more effective against HCC78R cells than monotherapy with an EGFR-TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB-EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR-TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.

DOI： 10.1111/cas.13752

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer. Reviewed International journal

Hiroki Sato, Hiromasa Yamamoto, Masakiyo Sakaguchi, Kazuhiko Shien, Shuta Tomida, Tadahiko Shien, Hirokuni Ikeda, Minami Hatono, Hidejiro Torigoe, Kei Namba, Takahiro Yoshioka, Eisuke Kurihara, Yusuke Ogoshi, Yuta Takahashi, Junichi Soh, Shinichi Toyooka

Cancer science 109 ( 10 ) 3183 - 3196 2018.10

Language：English Publishing type：Research paper (scientific journal)

Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non-small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide-3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR-TKI-resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single-agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal-epithelial transition factor amplification, induction of epithelial-to-mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long-term treatment with the combination therapy induced the conversion from EMT to mesenchymal-to-epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR-TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR-TKIs.

DOI： 10.1111/cas.13763

Low-risk donor lungs optimize the post-lung transplant outcome for high lung allocation score patients. Reviewed

Takeshi Kurosaki, Kentaroh Miyoshi, Shinji Otani, Kentaro Imanishi, Seiichiro Sugimoto, Masaomi Yamane, Motomu Kobayashi, Shinichi Toyooka, Takahiro Oto

Surgery today 48 ( 10 ) 928 - 935 2018.10

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: The lung allocation score (LAS) has been generally recognized as a contributor to the overall survival in lung transplant candidates. However, donor-related risks have never been taken into consideration in previous research that validated the LAS. This study aimed to determine whether or not the role of the LAS as a predictor of the posttransplant outcome is influenced by the quality of the donor lungs. METHODS: We retrospectively reviewed 108 patients who underwent lung transplantation at Okayama University Hospital since 1998. The cohort was divided into two groups based on the lung donor score (DS; ≤ 4/> 4). Correlations between the LAS and posttransplant outcomes were investigated in both groups. RESULTS: In the high-DS group, an elevated LAS was strongly associated with posttransplant PaO2/FiO2 (p = 0.018). However, in the low-DS group, no correlation was found between them. There was no significant difference in the long-term survival according to the LAS in the low-DS group. The LAS effectively predicted the posttransplant outcome only when lungs with DS > 4 were transplanted; the LAS was not reliable if high-quality lungs were transplanted. CONCLUSION: Lung transplantation can be feasible and provides a survival benefit even for high-LAS patients if lungs from a low-risk donor are transplanted.

DOI： 10.1007/s00595-018-1670-7

EMT化を示すAlectinib耐性後の患者由来新規ALK肺癌細胞株の樹立とその耐性化の克服

槇本剛, 大橋圭明, 佐藤晃子, 渡邉洋美, 二宮貴一朗, 二宮崇, 頼冠名, 久保寿夫, 市原英基, 片山英樹, 堀田勝幸, 田端雅弘, 豊岡伸一, 前田嘉信, 木浦勝行

肺癌 58 ( 6 ) 599 - 599 2018.10

デジタルPCR法による呼気濃縮液を用いたEGFR遺伝子診断法の検討

西井和也, 大橋圭明, 田村朋季, 妹尾賢, 狩野裕久, 渡邉洋美, 小田尚廣, 槇本剛, 肥後寿夫, 二宮貴一朗, 加藤有加, 南大輔, 二宮崇, 久保寿夫, 堀田勝幸, 田端雅弘, 冨田秀太, 豊岡伸一, 前田嘉信, 木浦勝行

肺癌 58 ( 6 ) 597 - 597 2018.10

肺癌におけるPrecision Medicineの現状と今後の展開肺癌のゲノム異常と治療の課題

豊岡伸一, 枝園和彦, 山本寛斉, 宗淳一, 冨田秀太

日本癌治療学会学術集会抄録集 56回 PD3 - 2 2018.10

非小細胞肺癌完全切除例に対する術後補助化学療法におけるERCC1の効果予測因子としての意義

中田昌男, 最相晋輔, 宗淳一, 奥村典仁, 中村廣繁, 山下素弘, 多田弘人, 森田智視, 豊岡伸一, 伊達洋至, 瀬戸内肺癌研究会

肺癌 58 ( 6 ) 516 - 516 2018.10

Myoepithelioma occurring in the posterior mediastinum harboring EWSR1 rearrangement: a case report. Reviewed International journal

Tomohiro Habu, Junichi Soh, Tomohiro Toji, Kazuhiko Shien, Eito Niman, Kei Namba, Hiroki Sato, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka

Japanese journal of clinical oncology 48 ( 9 ) 851 - 854 2018.9

Language：English Publishing type：Research paper (scientific journal)

Myoepithelioma is a rare neoplasm usually occurring in the salivary glands or the mammary glands but also, more rarely, in the thoracic cavity. The diagnosis of myoepithelioma is based on the presence of histological and immunohistochemical characteristics of myoepithelioma, but in unusual locations, the diagnosis is challenging. For such cases, cytogenetic approaches have been developed as helpful tools for the diagnosis. We report a surgical case of 51-year-old woman with myoepithelioma occurring in the posterior mediastinum that harbored the Ewing sarcoma breakpoint region1 (EWSR1) gene rearrangement. To the best of our knowledge, this is the first report of a myoepithelioma occurring in the posterior mediastinum. In this case, the patient underwent the thoracoscopic surgery for a diagnostic tumorectomy and was diagnosed as myoepithelioma based on the following immunohistological findings. Considering the unusual location, we additionally performed a cytogenetic analysis to confirm the presence of the EWSR1 gene rearrangement, which is a genetic characteristic of myoepithelioma.

DOI： 10.1093/jjco/hyy100

Airway complications have a greater impact on the outcomes of living-donor lobar lung transplantation recipients than cadaveric lung transplantation recipients. Reviewed

Seiichiro Sugimoto, Masaomi Yamane, Shinji Otani, Takeshi Kurosaki, Shuji Okahara, Yukiko Hikasa, Shinichi Toyooka, Motomu Kobayashi, Takahiro Oto

Surgery today 48 ( 9 ) 848 - 855 2018.9

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Airway complications (ACs) after living-donor lobar lung transplantation (LDLLT) could have different features from those after cadaveric lung transplantation (CLT). We conducted this study to compare the characteristics of ACs after LDLLT vs. those after CLT and investigate their impact on outcomes. METHODS: We reviewed, retrospectively, data on 163 recipients of lung transplantation, including 83 recipients of LDLLT and 80 recipients of CLT. RESULTS: The incidence of ACs did not differ between LDLLT and CLT. The initial type of AC after LDLLT was limited to stenosis in all eight patients, whereas that after CLT consisted of stenosis in three patients and necrosis in ten patients (p = 0.0034). ACs after LDLLT necessitated significantly earlier initiation of treatment than those after CLT (p = 0.032). The overall survival rate of LDLLT recipients with an AC was significantly lower than that of those without an AC (p = 0.030), whereas the overall survival rate was comparable between CLT recipients with and those without ACs (p = 0.25). CONCLUSION: ACs after LDLLT, limited to bronchial stenosis, require significantly earlier treatment and have a greater adverse impact on survival than ACs after CLT.

DOI： 10.1007/s00595-018-1663-6

HER増幅胃癌におけるアファチニブ耐性機序(Acquired resistant mechanism to afatinib in HER2 amplified gastric cancer cells)

吉岡貴裕, 枝園和彦, 難波圭, 冨田秀太, 山本寛斉, 宗淳一, 藤原俊義, 豊岡伸一

日本癌学会総会記事 77回 1449 - 1449 2018.9

EGFR変異陽性肺癌におけるLRIG1の抗腫瘍効果(Tumor-suppressive effect of LRIG1 in non-small cell lung cancer harboring mutant EGFR)

鳥越英次郎, 山本寛斉, 阪口政清, 難波圭, 佐藤博紀, 枝園和彦, 諏澤憲, 宗淳一, 冨田秀太, 佃和憲, 三好新一郎, 豊岡伸一

日本癌学会総会記事 77回 940 - 940 2018.9

がん転移抑制剤としての効果を有するS100A8/A9中和抗体の開発(Development of a novel S100A8/A9 neutralizing monoclonal antibody for suppression of cancer metastasis)

木下理恵, 山内明, 枝園和彦, 冨田秀太, 村田等, 豊岡伸一, 近藤英作, 阪口政清

日本癌学会総会記事 77回 1608 - 1608 2018.9

Inherited lung cancer syndromes targeting never smokers. Reviewed

Yamamoto H, Yatabe Y, Toyooka S

Translational lung cancer research 7 ( 4 ) 498 - 504 2018.8

病理病期IB〜IIIA期非小細胞肺癌完全切除症例に対する術後補助化学療法無作為化比較第3相試験(SLCG0401)

井上啓爾, 福田実, 竹之内光広, 一瀬幸人, 高森信三, 奥村典仁, 松尾恵太郎, 宗淳一, 豊岡伸一, 伊達洋至

肺癌 58 ( 4 ) 303 - 303 2018.8

Embigin Promotes Prostate Cancer Progression by S100A4-Dependent and-Independent Mechanisms. Reviewed International journal

I Made Winarsa Ruma, Rie Kinoshita, Nahoko Tomonobu, Yusuke Inoue, Eisaku Kondo, Akira Yamauchi, Hiroki Sato, I Wayan Sumardika, Youyi Chen, Ken-Ichi Yamamoto, Hitoshi Murata, Shinichi Toyooka, Masahiro Nishibori, Masakiyo Sakaguchi

Cancers 10 ( 7 ) 2018.7

Language：English Publishing type：Research paper (scientific journal)

Embigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is involved in prostate and mammary gland development. As embigin's roles in cancer remain elusive, we studied its biological functions and interaction with extracellular S100A4 in prostate cancer progression. We found by a pull-down assay that embigin is a novel receptor for S100A4, which is one of the vital cancer microenvironment milleu. Binding of extracellular S100A4 to embigin mediates prostate cancer progression by inhibition of AMPK activity, activation of NF-κB, MMP9 and mTORC1 signaling, and inhibition of autophagy, which increase prostate cancer cell motility. We also found that embigin promotes prostate cancer growth, spheroid- and colony-forming ability, and survival upon chemotherapy independently of S100A4. An in vivo growth mouse model confirmed the importance of embigin and its cytoplasmic tail in mediating prostate tumor growth. Moreover, embigin and p21WAF1 can be used to predict survival of prostate cancer patients. Our results demonstrated for the first time that the S100A4-embigin/AMPK/mTORC1/p21WAF1 and NF-κB/MMP9 axis is a vital oncogenic molecular cascade for prostate cancer progression. We proposed that embigin and p21WAF1 could be used as prognostic biomarkers and a strategy to inhibit S100A4-embigin binding could be a therapeutic approach for prostate cancer patients.

DOI： 10.3390/cancers10070239

悪性胸膜中皮腫に対するREIC/Dkk-3遺伝子治療

山本寛斉, 諏澤憲, 枝園和彦, 宗淳一, 黒崎毅史, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 大藤剛宏, 豊岡伸一

日本がん免疫学会総会プログラム・抄録集 22回 146 - 146 2018.7

膵がん進展に導く膵がん細胞間質線維芽細胞クロストークを介在する分泌性S100A11 受容体RAGE連携の役割

光井洋介, 山本健一, Sumardika I Wayan, 木下理恵, 村田等, 二見淳一郎, 高松仁, 山本靖彦, 西堀正洋, 豊岡伸一, 渡部昌実, 那須保友, 阪口政清

日本がん免疫学会総会プログラム・抄録集 22回 156 - 156 2018.7

腫瘍浸潤リンパ球(TIL)を含んだ腫瘍解離細胞(DTC)の保存

渡邊元嗣, 高橋優太, 冨田秀太, 宗淳一, 松原岳大, 難波圭, 佐藤博紀, 森田瑞樹, 枝園和彦, 山本寛斉, 鵜殿平一郎, 豊岡伸一

日本がん免疫学会総会プログラム・抄録集 22回 161 - 161 2018.7

分泌性S100A11-受容体RAGEシグナルに着眼した膵がん間質増大のメカニズムの解明

山本健一, 高松仁, 光井洋介, 木下理恵, 村田等, 二見淳一郎, 山本靖彦, 西堀正洋, 豊岡伸一, 阪口政清

日本がん免疫学会総会プログラム・抄録集 22回 117 - 117 2018.7

難治性/再発性固形腫瘍に対するメトホルミンと併用したニボルマブ療法の第Ib相試験(Phase Ib trial of nivolumab combined with metformin for refractory/recurrent solid tumors)

久保寿夫, 堀田勝幸, 二宮崇, 加藤博也, 堀口繁, 高本篤, 上月稔幸, 野上尚之, 石井浩, 仁科智裕, 原田大二郎, 豊岡伸一, 岡田裕之, 藤原俊義, 鵜殿平一郎, 木浦勝行

日本がん免疫学会総会プログラム・抄録集 22回 141 - 141 2018.7

2型糖尿病治療薬メトホルミンのヒト末梢血CD8T細胞に対する影響の検討

渡邉元嗣, 榮川伸吾, 豊岡伸一, 鵜殿平一郎

日本がん免疫学会総会プログラム・抄録集 22回 74 - 74 2018.7

Is Surgery after Chemoradiotherapy Feasible in Lung Cancer Patients with Superior Vena Cava Invasion? Reviewed

Sato H, Soh J, Hotta K, Katsui K, Kanazawa S, Kiura K, Toyooka S

Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia 24 ( 3 ) 131 - 138 2018.6

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: The purpose of this study is to explore the possibility of surgery after chemoradiotherapy (CRT) for locally advanced-non-small-cell lung cancer (LA-NSCLC) with superior vena cava (SVC) resection in terms of prognosis and early and late postoperative course. METHODS: The medical records of NSCLC patients who underwent surgery after CRT at our institution between January 2001 and March 2016 were reviewed. We evaluated the feasibility of surgery with SVC resection after CRT. RESULTS: A total of 8 LA-NSCLC patients were enrolled in this study. The SVC management included a graft replacement in two patients, pericardial patch repair in two, and direct suture closure in four. A complete resection was achieved in seven of the eight patients (87.5%). Postoperative early and late complication rate (Clavien-Dindo classification ≥ grade III) was 25%. All the complications were manageable, and no treatment-related deaths occurred in this series. Although seven out of eight patients showed good patency of reconstructed SVC, one patient exhibited the SVC occlusion during long-term follow-up period. Regarding the prognosis, the 5-year overall survival (OS) rate was 60.0%, and the 2-year recurrence-free survival (RFS) rate was 75.0%. CONCLUSION: Our results suggest that surgery with SVC resection after CRT is a feasible procedure in terms of clinical outcomes and postoperative course.

DOI： 10.5761/atcs.oa.18-00027

Inherited BRCA2 mutations and tumor hemi/homozygosity of metastatic soft tissue sarcoma in up to one-third of the 55 patients with shorter survival time. Reviewed

Takahashi Katsuhito, Mizumoto Atsushi, Yashima Jun, Kutsunai Keiko, Yamamoto Hiromasa, Sou Junichi, Toyooka Shinichi, Oyama Yu, Nomori Hiroaki, Narahara Hiroyuki, Yotsumoto Junko, Ono Yasuo, Tonsho Makoto, Teraoka Satoshi

JOURNAL OF CLINICAL ONCOLOGY 36 ( 15 ) 2018.5

Tumor-suppressive effect of LRIG1, a negative regulator of ErbB, in non-small cell lung cancer harboring mutant EGFR. Reviewed International journal

Hidejiro Torigoe, Hiromasa Yamamoto, Masakiyo Sakaguchi, Chen Youyi, Kei Namba, Hiroki Sato, Kazuhiko Shien, Junichi Soh, Ken Suzawa, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

Carcinogenesis 39 ( 5 ) 719 - 727 2018.5

Language：English Publishing type：Research paper (scientific journal)

Epidermal growth factor receptor (EGFR) is a member of the ErbB (HER) family that is known to play important roles in the pathogenesis of various human cancers. Mutations of the EGFR gene are commonly found as oncogenic driver mutations and have been targeted for treatment of non-small cell lung cancer (NSCLC). Leucine-rich repeat and immunoglobulin-like domain protein-1 (LRIG1) is a cell-surface protein that is known as a negative regulator of the ErbB (HER) family. In this study, we first confirmed that the expression levels of LRIG1 were much lower in NSCLC than in non-malignant cells or tissues. Next, we focused on the effect of LRIG1 in NSCLC. For this purpose, we established clones stably overexpressing LRIG1, using EGFR-mutant (HCC827, HCC4011 and NCI-H1975) and wild-type (A549) cells. Transfection of LRIG1 was associated with a decrease in the expression and phosphorylation levels of EGFR in the HCC827, HCC4011 and NCI-H1975 cells. It was also associated with strong suppression of the cell proliferative, invasive, migratory and tumorigenic potential of the HCC827 cells. On the other hand, no such effects were observed in the A549 cells. In addition, LRIG1 also downregulated the expression and phosphorylation levels of other tyrosine kinase receptors, such as HER2, HER3, MET and IGF-1R, and prevented the epithelial-to-mesenchymal transition induced by TGF-β in the HCC827 cells. These findings suggest that LRIG1 exerts important tumor-suppressive effects in EGFR-mutant NSCLC and has the potential to become a novel therapeutic target for EGFR-mutant NSCLC.

DOI： 10.1093/carcin/bgy044

Preoperative short hookwire placement for small pulmonary lesions: evaluation of technical success and risk factors for initial placement failure Reviewed

Toshihiro Iguchi, Takao Hiraki, Yusuke Matsui, Hiroyasu Fujiwara, Yoshihisa Masaoka, Takashi Tanaka, Takuya Sato, Hideo Gobara, Shinichi Toyooka, Susumu Kanazawa

European Radiology 28 ( 5 ) 2194 - 2202 2018.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Verlag

Objectives: To retrospectively evaluate the technical success of computed tomography fluoroscopy-guided short hookwire placement before video-assisted thoracoscopic surgery and to identify the risk factors for initial placement failure. Methods: In total, 401 short hookwire placements for 401 lesions (mean diameter 9.3 mm) were reviewed. Technical success was defined as correct positioning of the hookwire. Possible risk factors for initial placement failure (i.e., requirement for placement of an additional hookwire or to abort the attempt) were evaluated using logistic regression analysis for all procedures, and for procedures performed via the conventional route separately. Results: Of the 401 initial placements, 383 were successful and 18 failed. Short hookwires were finally placed for 399 of 401 lesions (99.5%). Univariate logistic regression analyses revealed that in all 401 procedures only the transfissural approach was a significant independent predictor of initial placement failure (odds ratio, OR, 15.326
95% confidence interval, CI, 5.429–43.267
p &lt
0.001) and for the 374 procedures performed via the conventional route only lesion size was a significant independent predictor of failure (OR 0.793, 95% CI 0.631–0.996
p = 0.046). Conclusions: The technical success of preoperative short hookwire placement was extremely high. The transfissural approach was a predictor initial placement failure for all procedures and small lesion size was a predictor of initial placement failure for procedures performed via the conventional route. Key points: • Technical success of preoperative short hookwire placement was extremely high. • The transfissural approach was a significant independent predictor of initial placement failure for all procedures. • Small lesion size was a significant independent predictor of initial placement failure for procedures performed via the conventional route.

DOI： 10.1007/s00330-017-5176-2

Therapeutic strategies for afatinib-resistant lung cancer harboring HER2 alterations Reviewed

Hidejiro Torigoe, Kazuhiko Shien, Tatsuaki Takeda, Takahiro Yoshioka, Kei Namba, Hiroki Sato, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Masakiyo Sakaguchi, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

Cancer Science 109 ( 5 ) 1493 - 1502 2018.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Blackwell Publishing Ltd

Human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of various cancers. HER2 alterations have been suggested to be a therapeutic target in non-small-cell lung cancer (NSCLC), just as in breast and gastric cancers. We previously reported that the pan-HER inhibitor afatinib could be a useful therapeutic agent as HER2-targeted therapy for patients with NSCLC harboring HER2 alterations. However, acquired resistance to afatinib was observed in the clinical setting, similar to the case for other HER inhibitors. Thus, elucidation of the mechanisms underlying the development of acquired drug resistance and exploring means to overcome acquired drug resistance are important issues in the treatment of NSCLC. In this study, we experimentally established afatinib-resistant cell lines from NSCLC cell lines harboring HER2 alterations, and investigated the mechanisms underlying the acquisition of drug resistance. The established cell lines showed several unique afatinib-resistance mechanisms, including MET amplification, loss of HER2 amplification and gene expression, epithelial-to-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. The afatinib-resistant cell lines showing MET amplification were sensitive to the combination of afatinib plus crizotinib (a MET inhibitor), both in vitro and in vivo. The resistant cell lines which showed EMT or had acquired CSC-like features remained sensitive to docetaxel, like the parental cells. These findings may provide clues to countering the resistance to afatinib in NSCLC patients with HER2 alterations.

DOI： 10.1111/cas.13571

A Multicenter Randomized Controlled Study of Paclitaxel plus Carboplatin versus Oral Uracil-Tegafur as the Adjuvant Chemotherapy in Resected Non-Small Cell Lung Cancer. Reviewed International journal

Shinichi Toyooka, Norihito Okumura, Hiroshige Nakamura, Masao Nakata, Motohiro Yamashita, Hirohito Tada, Shinsuke Kajiwara, Naoki Watanabe, Morihito Okada, Junichi Sakamoto, Motoi Aoe, Junichi Soh, Shinichiro Miyoshi, Katsuyuki Hotta, Keitaro Matsuo, Hiroshi Date

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 13 ( 5 ) 699 - 706 2018.5

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: We conducted a randomized controlled study to compare the survival benefit of paclitaxel plus carboplatin and oral uracil-tegafur (UFT) as adjuvant chemotherapy in resected NSCLC. METHODS: In an open-label multicenter trial, patients with pathological stage IB to IIIA NSCLC were randomized into a group receiving paclitaxel (175 mg/m2) plus carboplatin (area under the curve 5) every 3 weeks for four cycles (arm A) or a group receiving orally administered UFT (250 mg/m2) daily for 2 years (arm B). The primary and secondary end points were overall survival and relapse-free survival and toxicity, respectively. RESULTS: Between November 2004 and November 2010, 402 patients from 40 institutions were included (201 in each arm). The median follow-up period was 6.5 years. The 5-year overall survival rate was 70% (95% confidential interval [CI]: 63-76] in arm A versus 73% (95% CI: 66-78) in arm B (hazard ratio = 0.92, 95% CI: 0.55-1.41, p = 0.69). There was no significant difference in the 5-year relapse-free survival rate between arms A and B (56% versus 57% [hazard ratio = 0.92, 95% CI: 0.63-1.34, p = 0.50]). Toxicities were well tolerated and there was no treatment-related death. Toxicities of any grade or grade 4 were significantly more frequent in the paclitaxel plus carboplatin group (95.7% and 22.1%, respectively) than in the UFT group (76.5% and 1.0%, respectively [p < 0.0001 in both]). CONCLUSIONS: As adjuvant chemotherapy, paclitaxel plus carboplatin was no better than UFT in terms of survival among patients with stage IB to IIIA NSCLC tumors who underwent complete resection (UMIN000000810).

DOI： 10.1016/j.jtho.2018.02.015

術後難治性有瘻性膿胸に対して気管支充填術により瘻孔閉鎖を行った一例

山本寛斉, 原尚史, 西井和也, 頼冠名, 木浦勝行, 豊岡伸一

気管支学 40 ( Suppl. ) S281 - S281 2018.5

β-1,3-Galactosyl-O-Glycosyl-Glycoprotein β-1,6-N-Acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility. Reviewed International journal

I Wayan Sumardika, Chen Youyi, Eisaku Kondo, Yusuke Inoue, I Made Winarsa Ruma, Hitoshi Murata, Rie Kinoshita, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiroki Sato, Akira Yamauchi, Junichiro Futami, Endy Widya Putranto, Toshihiko Hibino, Shinichi Toyooka, Masahiro Nishibori, Masakiyo Sakaguchi

Oncology research 26 ( 3 ) 431 - 444 2018.4

Language：English Publishing type：Research paper (scientific journal)

We previously identified novel S100A8/A9 receptors, extracellular matrix metalloproteinase inducer (EMMPRIN), melanoma cell adhesion molecule (MCAM), activated leukocyte cell adhesion molecule (ALCAM), and neuroplastin (NPTN) β, that are critically involved in S100A8/A9-mediated cancer metastasis and inflammation when expressed at high levels. However, little is known about the presence of any cancer-specific mechanism(s) that modifies these receptors, further inducing upregulation at protein levels without any transcriptional regulation. Expression levels of glycosyltransferase-encoding genes were examined by a PCR-based profiling array followed by confirmation with quantitative real-time PCR. Cell migration and invasion were assessed using a Boyden chamber. Western blotting was used to examine the protein level, and the RNA level was examined by Northern blotting. Immunohistochemistry was used to examine the expression pattern of β-1,3-galactosyl-O-glycosyl-glycoprotein β-1,6-N-acetylglucosaminyltransferase 3 (GCNT3) and MCAM in melanoma tissue. We found that GCNT3 is overexpressed in highly metastatic melanomas. Silencing and functional inhibition of GCNT3 greatly suppressed migration and invasion of melanoma cells, resulting in the loss of S100A8/A9 responsiveness. Among the novel S100A8/A9 receptors, GCNT3 favorably glycosylates the MCAM receptor, extending its half-life and leading to further elevation of S100A8/A9-mediated cellular motility in melanoma cells. GCNT3 expression is positively correlated to MCAM expression in patients with high-grade melanomas. Collectively, our results showed that GCNT3 is an upstream regulator of MCAM protein and indicate the possibility of a potential molecular target in melanoma therapeutics through abrogation of the S100A8/A9-MCAM axis.

DOI： 10.3727/096504017X15031557924123

Antitumor activity of pan-HER inhibitors in HER2-positive gastric cancer Reviewed

Takahiro Yoshioka, Kazuhiko Shien, Kei Namba, Hidejiro Torigoe, Hiroki Sato, Shuta Tomida, Hiromasa Yamamoto, Hiroaki Asano, Junichi Soh, Kazunori Tsukuda, Takeshi Nagasaka, Toshiyoshi Fujiwara, Shinichi Toyooka

Cancer Science 109 ( 4 ) 1166 - 1176 2018.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Blackwell Publishing Ltd

Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti-human epidermal growth factor receptor 2 (HER2) drugs have been developed, trastuzumab is still the only anti-HER2 drug presently available for gastric cancer. In this study, we propose novel treatment options for patients with HER2-positive gastric cancer. First, we determined the molecular profiles of 12 gastric cancer cell lines, and examined the antitumor effect of the pan-HER inhibitors afatinib and neratinib in those cell lines. Additionally, we analyzed HER2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs. In the drug sensitivity analysis, both afatinib and neratinib produced an antitumor effect in most of the HER2-amplified cell lines. However, some cells were not sensitive to the drugs. When the molecular profiles of the cells were compared based on the drug sensitivities, we found that cancer cells with lower mRNA expression levels of IGFBP7, a tumor suppressor gene that inhibits the activation of insulin-like growth factor-1 receptor (IGF-1R), were less sensitive to pan-HER inhibitors. A combination therapy consisting of pan-HER inhibitors and an IGF-1R inhibitor, picropodophyllin, showed a notable synergistic effect. Among 123 clinical samples, we found 19 cases of HER2 amplification and three cases of oncogenic mutations. In conclusion, afatinib and neratinib are promising therapeutic options for the treatment of HER2-amplified gastric cancer. In addition to HER2 amplification, IGFBP7 might be a biomarker of sensitivity to these drugs, and IGF-1R-targeting therapy can overcome drug insensitiveness in HER2-amplified gastric cancer.

DOI： 10.1111/cas.13546

Clinical implementation of precision medicine

Shuta Tomida, Shinichi Toyooka

Japanese Journal of Cancer and Chemotherapy 45 ( 4 ) 601 - 604 2018.4

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.

In the end of last year, the US Food and Drug Administration has announced the authorization of MSK-IMPACT™, clinical test based on multiplex cancer panel profiling for genetic mutations and other alterations in patients' tumors, while in Japan, NCC Oncopanel, domestic multiplex cancer panel, is scheduled to be clinically implemented as advanced medical care B in this coming spring, chasing the state of the art technology for cancer treatment. In this article, we outline a recently published roadmap for precision medicine in Japan, together with our years of experience on cancer diagnosis and treatment based on multiplex cancer panel at Okayama University Hospital and Okadai Biobank.

What factors determine the survival of patients with an acute exacerbation of interstitial lung disease after lung cancer resection? Reviewed

Masahiro Miyajima, Atsushi Watanabe, Toshihiko Sato, Satoshi Teramukai, Masahito Ebina, Kazuma Kishi, Yukihiko Sugiyama, Haruhiko Kondo, Satoru Kobayashi, Yutaka Takahashi, Hiroyuki Ito, Ryoji Yamamoto, Shigeki Sawada, Hideki Fujimori, Kazunori Okabe, Jun Arikura, Yasushi Shintani, Hiroshige Nakamura, Shinichi Toyooka, Tohru Hasumi, Takehiro Watanabe, Yoshinobu Hata, Hisashi Iwata, Minoru Aoki, Kazuhito Funai, Shuhei Inoue, Osamu Kawashima, Tomohiko Iida, Hiroshi Date

Surgery today 48 ( 4 ) 404 - 415 2018.4

Language：English Publishing type：Research paper (scientific journal)

PURPOSES: Acute exacerbation of interstitial pneumonia (AEIP) is a leading cause of death after lung cancer resection in patients with interstitial lung disease. METHODS: We retrospectively analyzed 1763 patients with non-small cell lung cancer with a clinical diagnosis of interstitial lung disease (ILD) who underwent lung cancer resection between 2000 and 2009 at 61 hospitals in Japan. AEIP occurred in 164 of 1763 (9.3%) patients with a mortality rate of 43.9% (72/164). Univariate and multivariate analyses were carried out to identify possible risk factors of fatal AEIP. We then analyzed the 164 patients who developed postoperative AEIP and identified the preoperative and postoperative risk factors. RESULTS: A multivariate regression analysis identified that the sex, percent vital capacity, neoadjuvant radiation, preoperative history of AEIP, preoperative use of steroids, usual interstitial pneumonia pattern on CT, and surgical procedures were independent preoperative risk factors for death due to AEIP. ILD patients with emphysema somehow showed a lower risk of fatal AEIP than those without emphysema in this study. CONCLUSIONS: This study revealed eight risk factors for fatal AEIP.

DOI： 10.1007/s00595-017-1605-8

[Induction Chemoradiotherapy for Locally Advanced Non-small Cell Lung Cancer]. Reviewed

Miura A, Soh J, Shien K, Yamamoto H, Toyooka S

Kyobu geka. The Japanese journal of thoracic surgery 71 ( 4 ) 270 - 277 2018.4

IV期肺癌における呼吸器外科の役割は拡大しているか? 手術を契機に診断した胸膜播種・悪性胸水を伴うIVA期肺癌は切除非適応か? 多施設共同後方視的解析

藤原俊哉, 松浦求樹, 宗淳一, 枝園和彦, 山本寛斉, 牧佑歩, 上野剛, 杉本龍士郎, 岡崎幹生, 田尾裕之, 葉山牧夫, 片岡正文, 佐野由文, 岡部和倫, 山下素弘, 川真田修, 片岡和彦, 森山重治, 豊岡伸一, 岡山大学呼吸器外科研究会

日本呼吸器外科学会雑誌 32 ( 3 ) PD3 - 1 2018.4

【肺癌の集学的治療の現況】局所進行肺癌における集学的治療局所進行非小細胞肺癌に対する術前導入化学放射線療法後手術

三浦章博, 宗淳一, 枝園和彦, 山本寛斉, 豊岡伸一

胸部外科 71 ( 4 ) 270 - 277 2018.4

肺腺がんにおけるSpred2の役割の解明

太田陽子, 藤澤真義, 吉村禎造, スマルディカ・イワヤン, 枝園和彦, 阪口政清, 豊岡伸一, 松川昭博

日本病理学会会誌 107 ( 1 ) 414 - 414 2018.4

肺癌登録合同委員会報告第7次事業「2010年肺癌手術症例に対する登録研究」の結果報告

岡見次郎, 新谷康, 奥村明之進, 伊藤宏之, 大塚崇, 豊岡伸一, 森毅, 渡辺俊一, 伊達洋至, 横井香平, 淺村尚生, 永安武, 高橋和久, 木浦勝行, 秋田弘俊, 滝口裕一, 宮岡悦良, 吉野一郎

日本呼吸器外科学会雑誌 32 ( 3 ) np4 - np4 2018.4

Second primary cancer in survivors of locally advanced non-small cell lung cancer treated with concurrent chemoradiation followed by surgery Reviewed

Go Makimoto, Toshio Kubo, Isao Oze, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Junichi Soh, Shinichi Toyooka, Kuniaki Katsui, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

Japanese Journal of Clinical Oncology 48 ( 3 ) 287 - 290 2018.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Oxford University Press

The standard treatment for patients with locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT), but surgical resection following induction CRT can extend overall survival in a select population. However, patients who survive longer are at risk of developing a second primary cancer (SPC). This is the first report to determine the incidence of SPC in survivors with LA-NSCLC after trimodal therapy. Between October 1997 and October 2013, 112 Stage III NSCLC patients underwent trimodal therapy in our hospital. The 5-year overall survival rate was 71.8%. SPC developed in 10 of the 112 patients 0.60-15.0 (median 5.49) years after initiating CRT. The observed incidence of SPC was 1.8 per 100 patient-years. Although trimodal therapy can prolong patient survival, the estimated incidence of SPC does not increase. A large prospective study with a longer follow-up time is required to determine the effects of trimodal therapy, including the development of SPC.

DOI： 10.1093/jjco/hyy003

Therapeutic Potential of Afatinib for Cancers with ERBB2 (HER2) Transmembrane Domain Mutations G660D and V659E Reviewed

Hiromasa Yamamoto, Shinichi Toyooka, Takashi Ninomiya, Shigemi Matsumoto, Masashi Kanai, Shuta Tomida, Katsuyuki Kiura, Manabu Muto, Ken Suzawa, Patrice Desmeules, Mark G. Kris, Bob T. Li, Marc Ladanyi

Oncologist 23 ( 2 ) 150 - 154 2018.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Wiley-Blackwell

We previously reported on a family with hereditary lung cancer, in which a germline mutation in the transmembrane domain (G660D) of avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2
human epidermal growth factor receptor 2 [HER2]) seemed to be responsible for the cancer predisposition. Although few data are available on treatment, anti-ERBB2 therapeutic agents may be effective for ERBB2-mutant cancers. The familial lung cancer patient in one of the authors’ institutes developed bone metastasis with enlarging lung tumors and was treated with the ERBB2 inhibitor afatinib. We also encountered a patient with ampullary adenocarcinoma with ERBB2 G660D and S310F comutations in another institute of the authors’, revealed by comprehensive genomic profiling. This patient was then treated with afatinib and also achieved transitory response. We also searched for ERBB2 transmembrane mutations in various types of cancers in PubMed, The Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) database. Besides our two cases, two patients with V659E mutations were found via PubMed. Three potential patients were found in TCGA. In addition, MSK-IMPACT allowed identification of three additional urothelial carcinomas with G660D mutations and two lung adenocarcinomas with V659E mutations. Our experience suggests that establishing a database of integrated information regarding the clinical genome and therapeutic outcome of patients with recurrent but less common mutations is essential to implement precision oncology. Key Points: Rare but targetable mutations such as avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2
human epidermal growth factor receptor 2 [HER2]) transmembrane domain (TMD) mutations can be detected by comprehensive genomic profiling. Afatinib may be effective for patients with cancer with ERBB2 (HER2) TMD mutations. In order to implement precision oncology, it is important to establish a database of integrated information regarding the clinical genomes and therapeutic outcomes of patients with recurrent but less common mutations.

DOI： 10.1634/theoncologist.2017-0345

A Phase II Study of Trastuzumab Emtansine in HER2-Positive Non–Small Cell Lung Cancer Reviewed

Katsuyuki Hotta, Keisuke Aoe, Toshiyuki Kozuki, Kadoaki Ohashi, Kiichiro Ninomiya, Eiki Ichihara, Toshio Kubo, Takashi Ninomiya, Kenichi Chikamori, Daijiro Harada, Naoyuki Nogami, Taizo Hirata, Shiro Hinotsu, Shinichi Toyooka, Katsuyuki Kiura

Journal of Thoracic Oncology 13 ( 2 ) 273 - 279 2018.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Inc

Trastuzumab emtansine (T-DM1), an anti–erb-b2 receptor tyrosine kinase 2 (HER2) antibody-drug conjugate, has been shown to significantly improve survival in HER2-positive breast cancer. We report a phase II trial of T-DM1 monotherapy in relapsed NSCLC with documented HER2 positivity (an immunohistochemistry [IHC] score of 3+, both an IHC score of 2+ and fluorescence in situ hybridization positivity, or exon 20 mutation). This study was terminated early because of limited efficacy. The demographic characteristics in the 15 assessable patients were as follows: median age, 67 years
male sex, 47%
performance status of 0 to 1, 80%
HER2 status IHC 3+, 33%
HER status IHC 2+/fluorescence in situ hybridization–positive, 20%
and exon 20 mutation, 47%. The median number of delivered cycles was 3 (range 1–11). One patient achieved a partial response with an objective response rate of 6.7% (90% confidence interval: 0.2–32.0). With a median follow-up time of 9.2 months, the median progression-free survival time and median survival time were 2.0 and 10.9 months, respectively. Grade 3 or 4 adverse events included thrombocytopenia (40%) and hepatotoxicity (20%) without any treatment-related deaths. T-DM1 had a limited efficacy for HER2-positive NSCLC in our cohort. Applying the concept of precision medicine to tumors appears challenging
thus, additional molecular approaches are warranted.

DOI： 10.1016/j.jtho.2017.10.032

Therapeutic potential of targeting S100A11 in malignant pleural mesothelioma Reviewed

Hiroki Sato, Masakiyo Sakaguchi, Hiromasa Yamamoto, Shuta Tomida, Keisuke Aoe, Kazuhiko Shien, Takahiro Yoshioka, Kei Namba, Hidejiro Torigoe, Junichi Soh, Kazunori Tsukuda, Hiroyuki Tao, Kazunori Okabe, Shinichiro Miyoshi, Harvey I. Pass, Shinichi Toyooka

Oncogenesis 7 ( 1 ) 11 2018.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Publishing Group

Malignant pleural mesothelioma (MPM) is an aggressive tumor with an unfavorable prognosis. The standard therapeutic approaches are limited to surgery, chemotherapy, and radiotherapy. Because the consequent clinical outcome is often unsatisfactory, a different approach in MPM treatment is required. S100A11, a Ca2+-binding small protein with two EF-hands, is frequently upregulated in various human cancers. Interestingly, it has been found that intracellular and extracellular S100A11 have different functions in cell viability. In this study, we focused on the impact of extracellular S100A11 in MPM and explored the therapeutic potential of an S100A11-targeting strategy. We examined the secretion level of S100A11 in various kinds of cell lines by enzyme-linked immunosorbent assay. Among them, six out of seven MPM cell lines actively secreted S100A11, whereas normal mesothelial cell lines did not secrete it. To investigate the role of secreted S100A11 in MPM, we inhibited its function by neutralizing S100A11 with an anti-S100A11 antibody. Interestingly, the antibody significantly inhibited the proliferation of S100A11-secreting MPM cells in vitro and in vivo. Microarray analysis revealed that several pathways including genes involved in cell proliferation were negatively enriched in the antibody-treated cell lines. In addition, we examined the secretion level of S100A11 in various types of pleural effusions. We found that the secretion of S100A11 was significantly higher in MPM pleural effusions, compared to others, suggesting the possibility for the use of S100A11 as a biomarker. In conclusion, our results indicate that extracellular S100A11 plays important roles in MPM and may be a therapeutic target in S100A11-secreting MPM.

DOI： 10.1038/s41389-017-0017-3

Development of novel biologics for cancer metastasis via prevention of extracellular S100A8/A9 function Reviewed

Kinoshita Rie, Yamauchi Akira, Shien Kazuhiko, Tomida Shuta, Toyooka Shinichi, Kondo Eisaku, Sakaguchi Masakiyo

CANCER SCIENCE 109 1017 2018.1

Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension. Reviewed International journal

Kazufumi Nakamura, Masakiyo Sakaguchi, Hiromi Matsubara, Satoshi Akagi, Toshihiro Sarashina, Kentaro Ejiri, Kaoru Akazawa, Megumi Kondo, Koji Nakagawa, Masashi Yoshida, Toru Miyoshi, Takeshi Ogo, Takahiro Oto, Shinichi Toyooka, Yuichiro Higashimoto, Kei Fukami, Hiroshi Ito

PloS one 13 ( 9 ) e0203046 2018

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Pulmonary vascular remodeling of pulmonary arterial hypertension (PAH) is characterized by an inappropriate increase of vascular cells. The receptor for advanced glycation end products (RAGE) is a type I single-pass transmembrane protein belonging to the immunoglobulin superfamily and is involved in a broad range of hyperproliferative diseases. RAGE is also implicated in the etiology of PAH and is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with PAH. We examined the role of RAGE in the inappropriate increase of PASMCs in patients with PAH. METHODS AND RESULTS: PASMCs were obtained from 12 patients with PAH including 9 patients with idiopathic PAH (IPAH) and 3 patients with heritable PAH (HPAH) (2 patients with BMPR2 mutation and one patient with SMAD9 mutation) who underwent lung transplantation. Western blot analysis and immunofluorescence staining revealed that RAGE and S100A8 and A9, ligands of RAGE, were overexpressed in IPAH and HPAH-PASMCs in the absence of any external growth stimulus. PDGF-BB (10 ng/mL) up-regulated the expression of RAGE in IPAH and HPAH-PASMCs. PAH-PASMCs are hyperplastic in the absence of any external growth stimulus as assessed by 3H-thymidine incorporation. This result indicates overgrowth characterized by continued growth under a condition of no growth stimulation in PAH-PASMCs. PDGF-BB stimulation caused a higher growth rate of PAH-PASMCs than that of non-PAH-PASMCs. AS-1, an inhibitor of TIR domain-mediated RAGE signaling, significantly inhibited overgrowth characterized by continued growth under a condition of no growth stimulation in IPAH and HPAH-PASMCs (P<0.0001). Furthermore, AS-1 significantly inhibited PDGF-stimulated proliferation of IPAH and HPAH-PASMCs (P<0.0001). CONCLUSIONS: RAGE plays a crucial role in the inappropriate increase of PAH-PASMCs. Inhibition of RAGE signaling may be a new therapeutic strategy for PAH.

DOI： 10.1371/journal.pone.0203046

Short hookwire placement under imaging guidance before thoracic surgery: A review Reviewed

T. Iguchi, T. Hiraki, Y. Matsui, H. Fujiwara, Y. Masaoka, M. Uka, H. Gobara, S. Toyooka, S. Kanazawa

Diagnostic and Interventional Imaging 99 ( 10 ) 591 - 597 2018

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Masson SAS

During video-assisted thoracic surgery (VATS), localization is sometimes needed to detect a target lesion that is too small and/or too far from the pleura. In 1995, Kanazawa et al. developed short hookwire and suture system. Since then, this system has been placed often for selected targets before VATS in Japan. This short hookwire and suture system is a representative preoperative localization method and the placement procedure is well-established. Its placement success rates are very high (range: 97.6%–99.6%), and dislodgement of this short hookwire rarely occurs with an incidence of 0.4%–2.5%. The most common complication of short hookwire placement is pneumothorax (incidence: 32.1%–68.1%), followed by pulmonary hemorrhage (incidence: 8.9%–41.6%). Complications are frequent
however, most complications are minor and asymptomatic.

DOI： 10.1016/j.diii.2018.04.001

β-1,3-Galactosyl-

Sumardika, I. W., Youyi, C., Kondo, E., Inoue, Y., Ruma, I. M. W., Murata, H., Kinoshita, R., Yamamoto, K. I., Tomida, S., Shien, K., Sato, H., Yamauchi, A., Futami, J., Putranto, E. W., Hibino, T., Toyooka, S., Nishibori, M., Sakaguchi, M.

Oncol Res 26 ( 3 ) 2018

Model of lung cancer surgery risk derived from a Japanese nationwide web-based database of 78 594 patients during 2014-2015 Reviewed

Shunsuke Endo, Norihiko Ikeda, Takashi Kondo, Jun Nakajima, Haruhiko Kondo, Kohei Yokoi, Masayuki Chida, Masami Sato, Shinichi Toyooka, Koichi Yoshida, Yoshinori Okada, Yukio Sato, Morihito Okada, Meinoshin Okumura, Koji Chihara, Eriko Fukuchi, Hiroaki Miyata

EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY 52 ( 6 ) 1182 - 1189 2017.12

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS INC

OBJECTIVES: Using data obtained from a Japanese nationwide annual database with web-based data entry, we developed a risk model of mortality and morbidity after lung cancer surgery.
METHODS: The characteristics and operative and postoperative data from 80 095 patients who underwent lung cancer surgery were entered into the annual National Clinical Database of Japan data sets for 2014 and 2015. After excluding 1501 patients, the development data set for risk models included 38 277 patients entering in 2014 and the validation data set included 40 317 patients entering in 2015. Receiver-operating characteristic curves were generated for the outcomes of mortality and composite mortality/major morbidity. The concordance index was used to assess the discriminatory ability and validity of the model.
RESULTS: The 30-day mortality and overall mortality rates, including in-hospital deaths, were 0.4% and 0.8%, respectively, in 2014, and 0.4% and 0.8%, respectively, in 2015. The rate of major morbidity was 5.6% in 2014 and 5.6% in 2015. Several risk factors were significantly associated with mortality, namely, male sex, performance status, comorbidities of interstitial pneumonia and liver cirrhosis, haemodialysis and the surgical procedure pneumonectomy. The concordance index for mortality and composite mortality/major morbidity was 0.854 (P < 0.001) and 0.718 (P < 0.001), respectively, for the development data set and 0.849 (P < 0.001) and 0.723 (P < 0.001), respectively, for the validation data set.
CONCLUSIONS: This model was satisfactory for predicting surgical outcomes after pulmonary resection for lung cancer in Japan and will aid preoperative assessment and improve clinical outcomes for lung cancer surgery.

DOI： 10.1093/ejcts/ezx190

胸膜外肺全摘術と放射線療法で、術後13年無再発生存中の悪性胸膜中皮腫の1例

岡部和倫, 山本寛斉, 宗淳一, 豊岡伸一

肺癌 57 ( 7 ) 895 - 895 2017.12

Restrictive ventilatory impairment is associated with poor outcome in patients with cT1aN0M0 peripheral squamous cell carcinoma of the lung Reviewed

Hiroyuki Tao, Junichi Soh, Hiromasa Yamamoto, Toshiya Fujiwara, Tsuyoshi Ueno, Makio Hayama, Mikio Okazaki, Ryujiro Sugimoto, Motohiro Yamashita, Yoshifumi Sano, Kazunori Okabe, Motoki Matsuura, Kazuhiko Kataoka, Shigeharu Moriyama, Shinichi Toyooka, Shinichiro Miyoshi

JOURNAL OF THORACIC DISEASE 9 ( 11 ) 4325 - 4335 2017.11

Language：English Publishing type：Research paper (scientific journal) Publisher：AME PUBL CO

Background: Patients with squamous cell carcinoma (SqCC) of the lung sometimes have a comorbid pulmonary disease such as pulmonary emphysema or an interstitial lung disease (ILD), both of which negatively affect patient outcome. The aim of this study was to determine the outcome of patients in a multicenter database who underwent surgery for cT1aN0M0 peripheral SqCC lung cancer.
Methods: The medical records of a total of 228 eligible patients from seven institutions were reviewed to evaluate the impact of concomitant impaired pulmonary function and other clinicopathological factors on overall survival (OS) and relapse-free survival (RFS).
Results: Six patients with positive or unclear tumor margins were excluded. Of the 222 remaining study patients, 42 (18.9%) and 97 (43.7%) patients were found to have coexisting restrictive or obstructive ventilatory impairment, respectively. Over a median follow-up period of 30.6 months, the 5-year OS and RFS were 69.0% and 62.6%, respectively. By multivariate analysis, ILDs identified on high-resolution computed tomography (HRCT), pulmonary function test results indicating a restrictive ventilatory impairment, and wedge resection were found to be independent risk factors for poor OS. An increased level of serum squamous cell carcinoma antigen (SCC-Ag) (> 1.5 ng/mL) and the same risk factors for poor OS were independent risk factors for recurrence. Among patients who underwent anatomical lung resection (lobectomy and segmentectomy, n=173), a restrictive ventilatory impairment was an independent risk factor for poor OS, and increased serum SCC-Ag level, ILDs on HRCT, and restrictive ventilatory impairment were independent risk factors for poor RFS by multivariate analysis. Factors such as visceral pleural invasion, and lymphatic or vascular invasion were not significantly associated with outcome.
Conclusions: A restrictive ventilatory impairment negatively affects the outcome of patients with cT1aN0M0 peripheral SqCC lung cancer.

DOI： 10.21037/jtd.2017.10.70

Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer Reviewed

Haiyang Chen, Kazuhiko Shien, Ken Suzawa, Kazunori Tsukuda, Shuta Tomida, Hiroki Sato, Hidejiro Torigoe, Mototsugu Watanabe, Kei Namba, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Shinichiro Miyoshi, Shinichi Toyooka

ONCOLOGY LETTERS 14 ( 4 ) 4349 - 4354 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Docetaxel is a third-generation chemotherapeutic drug that is widely used in the treatment of patients with non-small cell lung cancer (NSCLC). However, the majority of patients with NSCLC eventually acquire resistance to the treatment. In the present study, the mechanism of acquired resistance to docetaxel treatment in lung cancer cells was investigated. The three NSCLC cell lines, H1299 with wild-type epidermal growth factor receptor (EGFR), EGFR-mutant HCC4006 and HCC827, and experimentally established docetaxel-resistant (DR) cells, H1299-DR, HCC827-DR, and HCC4006-DR were used with stepwise increases in concentrations of docetaxel. It was demonstrated that the established cell lines showed resistance to docetaxel and EGFR-tyrosine kinase inhibitors (TKIs). Molecular analysis revealed that all of the resistant cell lines highly expressed ATP binding cassette subfamily B member 1 (ABCB1), which is also known as P-glycoprotein or MDR1. Furthermore, HCC827-DR and HCC4006-DR cells exhibited a cancer stem cell-like marker and epithelial-to-mesenchymal transition features, respectively. Elacridar (GF120918), a third-generation inhibitor of ABCB1, was able to overcome resistance to docetaxel. Additionally, knockdown of ABCB1 using small interfering RNA (si)-ABCB1 recovered sensitivity to docetaxel. However, elacridar and si-ABCB1 could not recover sensitivity to EGFR-TKIs in established resistant cells. The results of the present study revealed that docetaxelresis-tant NSCLC cells also acquired cross-resistance to EGFR-TKI therapy through mechanisms other than ABCB1, that ABCB1 serves an important role in acquired resistance to docetaxel in lung cancer, and that combination therapy with elacridar can overcome ABCB1-mediated docetaxel resistance.

DOI： 10.3892/ol.2017.6678

Postoperative pyoderma gangrenosum exacerbated by granulocyte-colony stimulating factor after lung cancer surgery Reviewed

Haruchika Yamamoto, Seiichiro Sugimoto, Shinji Otani, Shinichi Toyooka

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 47 ( 10 ) 991 - 992 2017.10

JAK1/STAT3 Activation through a Proinflammatory Cytokine Pathway Leads to Resistance to Molecularly Targeted Therapy in Non-Small Cell Lung Cancer Reviewed

Kazuhiko Shien, Vassiliki A. Papadimitrakopoulou, Dennis Ruder, Carmen Behrens, Li Shen, Neda Kalhor, Juhee Song, J. Jack Lee, Jing Wang, Ximing Tang, Roy S. Herbst, Shinichi Toyooka, Luc Girard, John D. Minna, Jonathan M. Kurie, Ignacio I. Wistuba, Julie G. Izzo

MOLECULAR CANCER THERAPEUTICS 16 ( 10 ) 2234 - 2245 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Molecularly targeted drugs have yielded significant therapeutic advances in oncogene-driven non-small cell lung cancer (NSCLC), but a majority of patients eventually develop acquired resistance. Recently, the relation between proinflammatory cytokine IL6 and resistance to targeted drugs has been reported. We investigated the functional contribution of IL6 and the other members of IL6 family proinflammatory cytokine pathway to resistance to targeted drugs in NSCLC cells. In addition, we examined the production of these cytokines by cancer cells and cancer-associated fibroblasts (CAF). We also analyzed the prognostic significance of these molecule expressions in clinical NSCLC samples. In NSCLC cells with acquired resistance to targeted drugs, we observed activation of the IL6-cytokine pathway and STAT3 along with epithelial-to-mesenchymal transition (EMT) features. In particular, IL6 family cytokine oncostatin-M (OSM) induced a switch to the EMT phenotype and protected cells from targeted drug-induced apoptosis in OSM receptors (OSMRs)/JAK1/STAT3-dependent manner. The crosstalk between NSCLC cells and CAFs also preferentially activated the OSM/STAT3 pathway via a paracrine mechanism and decreased sensitivity to targeted drugs. The selective JAK1 inhibitor filgotinib effectively suppressed STAT3 activation and OSMR expression, and cotargeting inhibition of the oncogenic pathway and JAK1 reversed resistance to targeted drugs. In the analysis of clinical samples, OSMR gene expression appeared to be associated with worse prognosis in patients with surgically resected lung adenocarcinoma. Our data suggest that the OSMRs/JAK1/STAT3 axis contributes to resistance to targeted drugs in oncogene-driven NSCLC cells, implying that this pathway could be a therapeutic target. (C) 2017 AACR.

DOI： 10.1158/1535-7163.MCT-17-0148

Effects of Cold Ischemia on RNA Stability and Quality of Lung Tissues Based on Standard PREanalytical Code Categorization Reviewed

Takehiro Matsubara, Shuta Tomida, Junichi Soh, Takahiro Uwabo, Yoshiko Mori, Mizuki Morita, Yasutomo Nasu, Susumu Kanazawa, Shinichi Toyooka

BIOPRESERVATION AND BIOBANKING 15 ( 5 ) 484 - 486 2017.10

臨床試験から視た肺癌手術瀬戸内肺癌研究会13年の活動

宗淳一, 奥村典仁, 山下芳典, 片岡和彦, 佐野由文, 片岡正文, 岡部和倫, 山下素弘, 青江基, 中田昌男, 根津賢司, 中村廣繁, 三好新一郎, 豊岡伸一, 伊達洋至

日本臨床外科学会雑誌 78 ( 増刊 ) 333 - 333 2017.10

Estimation of age-related DNA degradation from formalin-fixed and paraffin-embedded tissue according to the extraction methods Reviewed

Mototsugu Watanabe, Shinsuke Hashida, Hiromasa Yamamoto, Takehiro Matsubara, Tomoaki Ohtsuka, Ken Suzawa, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichi Toyooka, Shinichiro Miyoshi

EXPERIMENTAL AND THERAPEUTIC MEDICINE 14 ( 3 ) 2683 - 2688 2017.9

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Techniques for the extraction and use of nucleic acids from formalin-fixed and paraffin-embedded (FFPE) tissues, preserved over long time periods in libraries, have been developed. However, DNA extracted from FFPE tissues is generally damaged, and long-term storage may affect DNA quality. Therefore, it is important to elucidate the effect of long-term storage on FFPE tissues and evaluate the techniques used to extract DNA from them. In the present study, the yield, purity, and integrity of DNA in FFPE tissue samples was evaluated. Two DNA extraction techniques were used: A silica-binding DNA collection method using QIAamp DNA FFPE Tissue kit (QIA) and a total tissue DNA collection method using a WaxFree DNA extraction kit (WAX). A total of 25 FFPE tissues from lung adenocarcinomas were studied, which had been surgically resected and fixed at Okayama University Hospital prior to examination and subsequent storage at room temperature for 0.5, 3, 6, 9 and 12 years. Extracted DNA was quantified using ultraviolet absorbance, fluorescent dye, and quantitative polymerase chain reaction (qPCR). The quality of the DNA was defined by the absorbance ratio of 260 to 280 nm (A260/280) and Q-score, which is the quantitative value of qPCR product size ratio. The results demonstrated that the yield of total DNA extracted using WAX was significantly greater than when QIA was used (P<0.01); however, DNA extracted using WAX included more contaminants and was significantly more fragmented compared with DNA extracted using QIA (P<0.01). Aging had no significant effect on absolute DNA yield or DNA purity, although it did significantly contribute to increased DNA degradation for both QIA and WAX extraction (QIA P=0.02, WAX P=0.03; 0.5 years vs. 3 years, QIA P<0.01, WAX P=0.03; 9 years vs. 12 years). Both extraction methods are viable depending on whether high yield or high quality of extracted DNA is required. However, due to the increased degradation with age, storage time limits the available DNA in FFPE tissues regardless of the extraction method.

DOI： 10.3892/etm.2017.4797

Induction chemoradiotherapy using docetaxel and cisplatin with definitive-dose radiation followed by surgery for locally advanced non-small cell lung cancer Reviewed

Hidejiro Torigoe, Junichi Soh, Shuta Tomida, Kei Namba, Hiroki Sato, Kuniaki Katsui, Katsuyuki Hotta, Kazuhiko Shien, Hiromasa Yamamoto, Masaomi Yamane, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

JOURNAL OF THORACIC DISEASE 9 ( 9 ) 3076 - 3086 2017.9

Language：English Publishing type：Research paper (scientific journal) Publisher：AME PUBL CO

Background: Induction chemoradiotherapy (CRT) followed by surgery is a therapeutic option for locally advanced non-small cell lung cancer (LA-NSCLC). Typically, around 40-50 Gy of radiation is applied as the induction-dose; however, a definitive-dose (DD) of radiation (60 Gy or higher) is occasionally applied to increase local control. We investigated the impact of induction CRT with DD radiation in LA-NSCLC patients treated with a single regimen of docetaxel and cisplatin.
Methods: We reviewed 110 patients with LA-NSCLC who underwent induction CRT followed by surgery using a single regimen (docetaxel and cisplatin) between January 1999 and December 2014 at our hospital. The clinical outcomes of a DD group (60 Gy or higher, n= 11) and a non-DD group (less than 60 Gy, n= 99) were investigated using a propensity score (PS)-matched analysis.
Results: An advanced clinical stage was significantly more common in the DD group than in the nonDD group (P= 0.033). Before and after the PS-matching based on seven factors including clinical stage, there was no significant difference in the rates of postoperative (PO) complication, mortality, 5-year overall survival (OS), or 5-year recurrence-free survival (RFS) between the two groups. After the PS-matching, the pathological complete response (CR) rate was significantly higher in the DD group than in the non-DD group [50% (n= 5/10) vs. 0% (n= 0/10), P= 0.033].
Conclusions: Induction CRT followed by surgery using docetaxel and cisplatin with DD radiation can be performed safely and is associated with a higher pathological CR rate than that attained using non-DD radiation in LA-NSCLC patients.

DOI： 10.21037/jtd.2017.08.87

Advantage of Induction Chemoradiotherapy for Lung Cancer in Securing Cancer-Free Bronchial Margin Reviewed

Hiroki Sato, Shinichi Toyooka, Junichi Soh, Katsuyuki Hotta, Kuniaki Katsui, Kazuhiko Shien, Hiromasa Yamamoto, Takahiro Oto, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi

ANNALS OF THORACIC SURGERY 104 ( 3 ) 971 - 978 2017.9

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background. Bronchoplasty is a useful procedure for preserving pulmonary function. For this procedure, it is critical to secure the negative surgical margin for avoiding local recurrence. In this study, we examined the status of the surgical bronchial margin as well as the clinical outcomes in bronchoplasty with or without induction chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC).
Methods. The medical records of NSCLC patients who underwent bronchoplasty at our institution between January 1999 and September 2014 were reviewed. We compared the clinical outcomes of bronchoplasty with or without induction CRT.
Results. A total of 58 NSCLC patients were included in this study. Among these, 38 patients underwent primary surgical procedure with bronchoplasty and 20 patients underwent bronchoplasty after induction CRT. Intraoperative pathologic diagnosis for the surgical margin of the bronchus revealed that the patients in the primary surgical procedure group had a significantly higher rate of positive surgical margin than the induction CRT group (p = 0.023), requiring an additional bronchial resection to secure the negative margin. After additional resection of positive bronchial stumps, no significant difference was found in the rate of positive margin with postoperative histologic diagnosis between the two groups. In addition, no significant differences in the postoperative complication rate and overall and recurrence-free survivals were observed between the two groups.
Conclusions. Our results suggest that induction CRT before surgical procedure may help ensure the intraoperative negative surgical margin of the bronchus. Our study also indicates that bronchoplasty after induction CRT is feasible in comparison with bronchoplasty in primary surgical procedure. (C) 2017 by The Society of Thoracic Surgeons

DOI： 10.1016/j.athoracsur.2017.03.045

第3世代EGFR-TKI Osimertinib耐性肺癌細胞株における獲得耐性機構の解明

難波圭, 枝園和彦, 吉岡貴裕, 鳥越英次郎, 佐藤博紀, 山本寛斉, 宗淳一, 浅野博昭, 佃和憲, 豊岡伸一

肺癌 57 ( 5 ) 440 - 440 2017.9

分子標的薬への耐性機構の解明肺がんにおける分子標的薬耐性メカニズムの解明

枝園和彦, 佐藤博紀, 鳥越英次郎, 難波圭, 吉岡貴裕, 山本寛斉, 宗淳一, 豊岡伸一

肺癌 57 ( 5 ) 377 - 377 2017.9

抗HER2療法耐性におけるYes1の重要性

武田達明, 山本寛斉, 諏澤憲, 冨田秀太, 難波圭, 渡邉元嗣, 枝園和彦, 宗淳一, 佃和憲, 豊岡伸一

日本癌学会総会記事 76回 P - 3366 2017.9

肺がん新治療の展望 HER2異常肺癌に対する治療戦略

豊岡伸一, 諏澤憲, 二宮崇, 山本寛斉, 枝園和彦, 宗淳一, 冨田秀太, 木浦勝行

日本癌学会総会記事 76回 SST6 - 3 2017.9

分子バーコード技術を用いた低頻度多重変異の同定

難波圭, 冨田秀太, 枝園和彦, 山本寛斉, 宗淳一, 佃和憲, 豊岡伸一

日本癌学会総会記事 76回 P - 3052 2017.9

HER2陽性胃癌に対するアファチニブ・ネラチニブの抗腫瘍効果

吉岡貴裕, 枝園和彦, 高橋優太, 栗原英祐, 難波圭, 鳥越英次郎, 佐藤博紀, 山本寛斉, 宗淳一, 浅野博昭, 佃憲徳, 藤原俊義, 豊岡伸一

日本癌学会総会記事 76回 P - 2336 2017.9

HER2遺伝子異常肺癌に対するマルチキナーゼ阻害剤Afatinb耐性獲得機序の解明

鳥越英次郎, 枝園和彦, 吉岡貴裕, 難波圭, 佐藤博紀, 山本寛斉, 宗淳一, 浅野博昭, 冨田秀太, 佃和憲, 豊岡伸一

肺癌 57 ( 5 ) 441 - 441 2017.9

S100A8/A9とその受容体との結合遮断を目指した転移抑制タンパク質製剤の開発

木下理恵, 山内明, 枝園和彦, 富田秀太, 豊岡伸一, 近藤英作, 阪口政清

日本癌学会総会記事 76回 P - 3097 2017.9

Radiofrequency ablation of pulmonary tumors near the diaphragm Reviewed

T. Iguchi, T. Hiraki, H. Gobara, H. Fujiwara, J. Sakurai, Y. Matsui, T. Mitsuhashi, S. Toyooka, S. Kanazawa

DIAGNOSTIC AND INTERVENTIONAL IMAGING 98 ( 7-8 ) 535 - 541 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER MASSON

Purpose: To retrospectively evaluate the feasibility, safety, and efficacy of radiofrequency ablation (RFA) of lung tumors located near the diaphragm.
Materials and methods: A total of 26 patients (15 men, 11 women; mean age, 61.5 years +/- 13.0 [SD]) with a total of 29 lung tumors near the diaphragm (i.e., distance < 10 mm) were included. Mean tumor diameter was 11.0 mm +/- 5.3 (SD) (range, 2-23 mm). Efficacy of RFA, number of adverse events and number of adverse events with a grade >= 3, based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, were compared between patients with lung tumors near the diaphragm and a control group of patients with more distally located lung tumors (i.e., distance >= 10 mm).
Results: RFA was technically feasible for all tumors near the diaphragm. Four grade 3 adverse events (1 pneumothorax requiring pleurodesis and 3 phrenic nerve injuries) were observed. No grade >= 4 adverse events were reported. The median follow-up period for tumors near the diaphragm was 18.3 months. Local progression was observed 3.3 months after RFA in 1 tumor. The technique efficacy rates were 96.2% at 1 year and 96.2% at 2 years and were not different, from those observed in control subjects (186 tumors; P = 0.839). Shoulder pain (P < 0.001) and grade 1 pleural effusion (P < 0.001) were more frequently observed in patients with lung tumor near the diaphragm. The rates of grade >= 3 adverse events did not significantly differ between tumors near the diaphragm (4/26 sessions) and the controls (7/133 sessions) (P = 0.083).
Conclusion: RFA is a feasible and effective therapeutic option for lung tumors located near the diaphragm. However, it conveys a higher rate of shoulder pain and asymptomatic pleural effusion by comparison with more distant lung tumors. (C) 2017 Editions francaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

DOI： 10.1016/j.diii.2017.01.008

Erratum to “Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer” [Lung Cancer 76 (1) (2012) 32–38](S0169500211005150)(10.1016/j.lungcan.2011.10.002) Reviewed

Norimitsu Tanaka, Shinichi Toyooka, Junichi Soh, Takafumi Kubo, Hiromasa Yamamoto, Yuho Maki, Takayuki Muraoka, Kazuhiko Shien, Masashi Furukawa, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Keisuke Aoe, Shinichiro Miyoshi

Lung Cancer 76 ( 1 ) 32 - 38 2017.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Ireland Ltd

Small-cell lung cancer (SCLC) is an aggressive tumor with a dismal prognosis among primary lung cancers. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family is comprised of tumor-suppressive miRNAs, and its reduced expression by methylation has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the alteration and tumor-suppressive impact of miR-34s in SCLC. The methylation of miR-34a and miR-34b/c was observed in 4 (36%) and 7 (64%) of 11 SCLC cell lines, respectively. Among the 27 SCLC clinical specimens, miR-34a and miR-34b/c were methylated in 4 (15%) and 18 (67%), respectively. In contrast, 13 (28%) miR-34a methylated cases and 12 (26%) miR-34b/c methylated cases were found in 47 NSCLC primary tumors. The frequency of miR-34b/c methylation was significantly higher in SCLC than in NSCLC (p&lt
. 0.001). The expressions of miR-34s were reduced in methylated cell lines and tumors and restored after 5-aza-2'-deoxycytidine treatment, indicating that methylation was responsible for the reduced expression of miR-34s. Because the frequency of methylation was higher in miR-34b/c, we focused on miR-34b/c for a functional analysis. We examined the effect of miR-34b/c introduction on cell proliferation, migration and invasion. The transfection of miR-34b/c to two SCLC cell lines (H1048 and SBC5) resulted in the significant inhibition of cell growth, migration, and invasion, compared with control transfectants. Our results indicate that the aberrant methylation of miR-34b/c plays an important role in the pathogenesis of SCLC, implying that miR-34b/c may be a useful therapeutic target for SCLC. © 2011 Elsevier Ireland Ltd.

DOI： 10.1016/j.lungcan.2011.10.002

Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer (vol 76, pg 32, 2012) Reviewed

Norimitsu Tanaka, Shinichi Toyooka, Junichi Soh, Takafumi Kubo, Hiromasa Yamamoto, Yuho Maki, Takayuki Muraoka, Kazuhiko Shien, Masashi Furukawa, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Keisuke Aoe, Shinichiro Miyoshi

LUNG CANCER 108 254 - 255 2017.6

Optimal method for quantitative detection of plasma EGFR T790M mutation using droplet digital PCR system Reviewed

Ken Suzawa, Hiromasa Yamamoto, Kadoaki Ohashi, Shinsuke Hashida, Shuta Tomida, Toshio Kubo, Yuho Maki, Junichi Soh, Kazunori Tsukuda, Katsuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

ONCOLOGY REPORTS 37 ( 5 ) 3100 - 3106 2017.5

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Though patients with EGFR mutations are initially responsive to EGFR-tyrosine kinase inhibitors (TKIs), most tumors ultimately acquire resistance to EGFR-TKIs. The most frequently reported mechanism is EGFR T790M mutation. In this study, using a droplet digital PCR (ddPCR) system, we assessed optimal conditions for a mutation detection assay for EGFR T790M obtained from circulating cell-free DNA (cfDNA) in plasma. The advantages of locked nucleic acids (LNA) probe, short amplicon size, and blocking oligo using peptide nucleic acids (PNA) were assessed using control DNAs from cell lines to improve the sensitivity of mutation detection. T790M alleles were then analyzed using ddPCR in 59 plasma samples from 24 NSCLC patients with EGFR mutations, and compared to the T790M status which were determined thorough re-biopsies. The assessment of the optimal assay method revealed that the assay using the short amplicon can efficiently detect more fragmented-DNA. The LNA probe and PNA clamp contributed better separation between positive and negative droplets. This PNA-LNA-ddPCR clamp method can detect mutant alleles in the sample with a mutant allele content of 0.01%. In clinical plasma samples, T790M alleles were detected via ddPCR with a sensitivity of 42.8% and specificity of 97.3%. We established a highly-sensitive detection assay for the T790M allele using the PNA-LNA-ddPCR clamp method. ddPCR is a promising method for detecting non-invasive T790M mutation.

DOI： 10.3892/or.2017.5567

Is tumor location an independent prognostic factor in locally advanced non-small cell lung cancer treated with trimodality therapy? Reviewed

Kazuhiko Shien, Shinichi Toyooka, Junichi Soh, Hiromasa Yamamoto, Shinichiro Miyoshi

JOURNAL OF THORACIC DISEASE 9 ( 5 ) E489 - E491 2017.5

Early postoperative complications after middle lobe-preserving surgery for secondary lung cancer Reviewed

Yuho Maki, Shinichi Toyooka, Junichi Soh, Hiromasa Yamamoto, Seiichiro Sugimoto, Masaomi Yamane, Takahiro Oto, Shinichiro Miyoshi

SURGERY TODAY 47 ( 5 ) 601 - 605 2017.5

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Purpose Preservation of the middle lobe during lung surgery is traditionally avoided, because its presence in the hemithoracic cavity is considered a cause of complications. We report a series of lung cancer patients who underwent a secondary pulmonary resection with the preservation of the middle lobe to explore the complications and feasibility of these procedures.
Methods We reviewed the clinical courses of six patients who underwent surgery for metachronous lung cancers. Five patients underwent right upper lobectomy, including one sleeve lobectomy, after having undergone prior right lower lobectomy. The remaining patient underwent a right lower lobectomy after having undergone a prior right upper lobectomy.
Results There were no treatment-related deaths. One patient was readmitted for surgery to treat delayed air leakage progressing to pyothorax. One patient was treated for persistent air leakage. Two patients required intermittent drainage of pulmonary effusion, because of middle lobe atelectasis. The postoperative forced vital capacity and forced expiratory volume in 1 s were greater than the values predicted post-pneumonectomy in four evaluable patients.
Conclusions While postoperative complications after middle lobe-preserving surgery are manageable, their high incidence should be considered when performing this surgery.

DOI： 10.1007/s00595-016-1413-6

Diagnostic Value of Dual-time-point F-18 FDG PET/CT and Chest CT for the Prediction of Thymic Epithelial Neoplasms Reviewed

Takayoshi Shinya, Takashi Tanaka, Junichi Soh, Toshi Matsushita, Shuhei Sato, Shinichi Toyooka, Tadashi Yoshino, Shinichiro Miyoshi, Susumu Kanazawa

ACTA MEDICA OKAYAMA 71 ( 2 ) 105 - 112 2017.4

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

We retrospectively assessed the dual-time-point (DTP) F-18 FDG PET/CT findings of thymic epithelial neoplasms (TENs) and investigated the diagnostic capacity of PET/CT compared to that of CT for predicting carcinoma. We calculated the ratio of the standardized uptake value of the tumor and that of the aortic arch (T/M ratio) for both the 90-min early scan and the 2-h delayed scan in 56 TEN patients. We used a multivariate logistic regression (MLR) analysis to estimate the CT features of carcinoma. We compared the diagnostic capacities of PET/CT and chest CT using receiver operating characteristic (ROC) analyses. The ROC curve revealed that the appropriate cut-off T/M ratio value for the highest accuracy was 2.39 with 75.0% accuracy. The area under the curve (AUC) was 0.855. The statistical analyses for DTP scans of 35 TEN patients demonstrated 74.3% accuracy and 0.838 AUC for the early scan versus 82.9% and 0.825 for the delayed scan. The MLR analysis indicated that mediastinal fat infiltration was a predictor of carcinoma. The ROC curve obtained for the model yielded an AUC of 0.853. Delayed scanning could improve the diagnostic capacity for carcinoma. The T/M ratio and mediastinal fat infiltration are predictive of carcinoma with moderate diagnostic accuracy.

DOI： 10.18926/AMO/54978

Feasibility of adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 for completely resected non-small-cell lung cancer: results of the Setouchi Lung Cancer Group Study 1001 Reviewed

Norihito Okumura, Makoto Sonobe, Kazunori Okabe, Hiroshige Nakamura, Masafumi Kataoka, Motohiro Yamashita, Masao Nakata, Kazuhiko Kataoka, Yoshinori Yamashita, Junichi Soh, Hiroshige Yoshioka, Katsuyuki Hotta, Keitaro Matsuo, Junichi Sakamoto, Shinichi Toyooka, Hiroshi Date

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 22 ( 2 ) 274 - 282 2017.4

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

This multicenter study evaluated the feasibility of novel adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent, long-term maintenance with S-1 in patients with completely resected stage II-IIIA non-small-cell lung cancer (NSCLC).
Patients received four cycles of S-1 (80 mg/m(2)/day for 2 weeks, followed by 2 weeks rest) plus carboplatin (area under the curve 5, day 1) followed by S-1 (80 mg/m(2)/day for 2 weeks, followed by a 1-week rest). Patients unable to continue S-1 plus carboplatin because of severe toxicity converted to single-agent S-1 maintenance. The duration of adjuvant chemotherapy was 10 months in both situations. The primary endpoint was feasibility, defined as the proportion of patients who completed four cycles of S-1 plus carboplatin and single-agent S-1 maintenance for 10 months. The treatment completion rate was determined; treatment was considered feasible if the lower 90% confidence interval (CI) was 50%.
Eighty-nine patients were enrolled, of whom 87 were eligible and assessable. Seventy-eight patients (89.7%) completed four cycles of S-1 plus carboplatin and 55 (63.2%) completed the following S-1 maintenance therapy for a total of 10 months. The treatment completion rate was 63.2% (90% CI, 54.4-71.2%), indicating feasibility. There were no treatment-related deaths. Grade 3/4 toxicities included neutropenia (13.8%), thrombocytopenia (11.5%), and anorexia (4.6%). The 2-year relapse-free survival rate was 59.8%.
We concluded that adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 is feasible and tolerable in patients with completely resected NSCLC.
UMIN000005041.

DOI： 10.1007/s10147-016-1067-9

Lung Cancer Panelを用いた多発小型肺癌のマルチプレックス遺伝子変異解析

枝園和彦, 冨田秀太, 佐藤博紀, 高橋優太, 諏澤憲, 山本寛斉, 宗淳一, 三好新一郎, 豊岡伸一

日本呼吸器外科学会雑誌 31 ( 3 ) RO16 - 4 2017.4

Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer (vol 12, e0171356, 2017) Reviewed

T. Takeda, H. Yamamoto, H. Kanzaki, K. Suzawa, T. Yoshioka, S. Tomida

PLOS ONE 12 ( 3 ) e0171356 2017.3

同時化学放射線療法後の手術により治療した局所進行性NSCLCの生存者における第二原発性癌(Second primary cancer in survivors of locally advanced NSCLC treated with concurrent chemoradiation followed by surgery)

Makimoto Go, Kubo Toshio, Oze Isao, Ohashi Kadoaki, Hotta Katsuyuki, Takigawa Nagio, Toyooka Shinichi, Katsui Kuniaki, Tanimoto Mitsune, Kiura Katsuyuki

日本呼吸器学会誌 6 ( 増刊 ) 345 - 345 2017.3

Radiofrequency ablation of pulmonary metastases from sarcoma: single-center retrospective evaluation of 46 patients Reviewed

Takuya Sato, Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Jun Sakurai, Yusuke Matsui, Toshiharu Mitsuhashi, Junichi Soh, Shinichi Toyooka, Susumu Kanazawa

JAPANESE JOURNAL OF RADIOLOGY 35 ( 2 ) 61 - 67 2017.2

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

This retrospective, single-center study evaluated radiofrequency (RF) ablation for pulmonary metastases of sarcoma.
Forty-six patients with sarcoma (144 pulmonary metastases) underwent 88 RF ablation sessions. Data regarding local tumor progression, efficacy, procedural adverse events (AEs; National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0), overall survival (OS), and OS-associated prognostic factors were retrospectively evaluated using univariate analyses.
Local progression occurred in 22 of 144 tumors (15.3%). Primary and secondary efficacy rates were 83.5 and 90.0% at 1 year and 76.3 and 81.4% at 2 years, respectively. Seventy-three grade 1 AEs, 33 grade 2 AEs, and no grade >= 3 AEs were observed. Twenty-eight patients (60.9%) remained alive and 18 died, yielding 1-, 2-, and 3-year OS rates of 80.6, 70.1, and 47.1% (median survival time, 31.7 months). Univariate analysis revealed extrapulmonary metastasis (P = 0.005), noncurative RF ablation (P = 0.009), and a post-RF ablation disease-free interval of <= 12 months (P = 0.015) as significant negative prognostic factors.
RF ablation is safe, offers good local control, and may be a viable treatment option for pulmonary metastasis of sarcoma.

DOI： 10.1007/s11604-016-0601-z

Feasibility of Pulmonary Resection for Lung Cancer in Patients With Coronary Artery Disease or Atrial Fibrillation. Reviewed International journal

Yoshitaka Kitamura, Kenji Suzuki, Satoshi Teramukai, Makoto Sonobe, Shinichi Toyooka, Yoshihisa Nakagawa, Hiroyasu Yokomise, Hiroshi Date

The Annals of thoracic surgery 103 ( 2 ) 432 - 440 2017.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The aim of this study was to clarify the outcomes of lung resection for lung cancer in patients with cardiac disease, especially coronary artery disease, in a large-scale multi-institutional cohort. METHODS: We retrospectively analyzed the data on 1,254 patients who underwent major lung resection for lung cancer and had been diagnosed with coronary stenosis, atrial fibrillation, or both, in 58 institutions in Japan between January 2009 and December 2011. The primary outcome was 90-day postoperative mortality or in-hospital death. RESULTS: Among the 1,254 patients, 902 (71.9%) and 452 patients (36.0%) were preoperatively diagnosed with coronary stenosis and atrial fibrillation, respectively, and 951 patients (75.8%) received antiplatelet therapy. Among the patients with coronary stents (n = 532; 42.4%), 204 (16.3%) received drug-eluting stents. The 90-mortality or in-hospital death rate was 2.6% (n = 32), including stent thrombosis (n = 1), thromboembolic events without stent thrombosis (n = 2), and bleeding events (n = 2). In the multivariate analyses, blood transfusion, history of cerebrovascular disease, amount of bleeding, and history of congestive heart failure were associated with a higher independent risk of 90-day mortality or in-hospital death (odds ratio, 9.400, 3.574, 2.827, and 2.945, respectively). Preoperative discontinuation of antiplatelet therapy was not associated with an independent risk of 90-day mortality or in-hospital death on univariate analysis. CONCLUSIONS: Major lung resection for lung cancer in patients with coronary artery disease is feasible. Our study suggests that discontinuation of antiplatelet therapy may not increase postoperative complications in patients with coronary artery disease.

DOI： 10.1016/j.athoracsur.2016.08.077

Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer Reviewed

Tatsuaki Takeda, Hiromasa Yamamoto, Hirotaka Kanzaki, Ken Suzawa, Takahiro Yoshioka, Shuta Tomida, Xiaojiang Cui, Ramachandran Murali, Kei Namba, Hiroki Sato, Hidejiro Torigoe, Mototsugu Watanabe, Kazuhiko Shien, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Yoshihisa Kitamura, Shinichiro Miyoshi, Toshiaki Sendo, Shinichi Toyooka

PLOS ONE 12 ( 2 ) 2017.2

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Background
Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in approximately 15-23% of breast cancers and these cancers are classified as HER2-positive breast cancer. Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer and has improved patient overall survival. However, acquired resistance to trastuzumab is still a critical issue in breast cancer treatment. We previously established a trastuzumabresistant breast cancer cell line (named as BT-474-R) from a trastuzumab-sensitive HER2-amplified cell line BT-474. Lapatinib is also a molecular-targeted drug for HER2-positive breast cancer, which acquired the resistance to trastuzumab. Acquired resistance to lapatinib is also an issue to be conquered.
Methods
We established trastuzumab/lapatinib-dual resistant cell line (named as BT-474-RL2) by additionally treating BT-474-R with lapatinib. We analyzed the mechanisms of resistance to trastuzumab and lapatinib. Besides, we analyzed the effect of the detected resistance mechanism in HER2-positive breast cancer patients.
Results
Proto-oncogene tyrosine-protein kinase Yes1, which is one of the Src family members, was amplified, overexpressed and activated in BT-474-R and BT-474-RL2. Silencing of Yes1 by siRNA induced both BT-474-R and BT-474-RL2 to restore the sensitivity to trastuzumab and lapatinib. Pharmaceutical inhibition of Yes1 by the Src inhibitor dasatinib was also effective to restore the sensitivity to trastuzumab and lapatinib in the two resistant cell lines. Combination treatment with dasatinib and trastuzumab induced down-regulation of signaling molecules such as HER2 and Akt. Moreover, the combination treatments induced G1-phase cell-cycle arrest and apoptosis. Consistent with cell line data, high expression of Yes1 mRNA was correlated with worse prognosis in patients with HER2-positive breast cancer.
Conclusion
Yes1 plays an important role in acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancer. Our data suggest that pharmacological inhibition of Yes1 may be an effective strategy to overcome resistance to trastuzumab and lapatinib.

DOI： 10.1371/journal.pone.0171356

Targeting the miR-200c/LIN28B axis in acquired EGFR-TKI resistance non-small cell lung cancer cells harboring EMT features Reviewed

Hiroki Sato, Kazuhiko Shien, Shuta Tomida, Kazuhiro Okayasu, Ken Suzawa, Shinsuke Hashida, Hidejiro Torigoe, Mototsugu Watanabe, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

SCIENTIFIC REPORTS 7 40847 2017.1

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

MicroRNA (miR)-200 family members (miR-200s) are frequently silenced in advanced cancer and have been implicated in the process of epithelial-to-mesenchymal transition (EMT). We previously reported that miR-200s were silenced through promoter methylation in acquired EGFR-tyrosine kinase inhibitor (TKI) resistant non-small cell lung cancer (NSCLC) cells harboring EMT features. In this study, we examined the functional role of miR-200s in NSCLC cells and investigated a novel approach to overcoming acquired EGFR-TKI resistance. In the analysis of NSCLC cell lines, each of the miR-200s expression-silenced cell lines showed promoter methylation. Significant correlations between miR-200c silencing and several oncogenic pathway alterations, including EMT-changes and LIN28B overexpression, were observed in the database analysis. In addition, EGFR-wild type cell lines had lower miR-200s expression levels than EGFR-mutant cell lines. The introduction of miR-200c using pre-miR-200c caused LIN28B suppression in cells with acquired EGFR-TKI resistance that harbored EMT features. Interestingly, both the introduction of miR-200c and the knockdown of LIN28B produced an antitumor effect in acquired EGFR-TKI resistance cells, whereas these manipulations were not effective in parental cells. The miR-200c/LIN28B axis plays an important role in cells with acquired resistance to EGFR-TKI that harbor EMT features and might be a useful therapeutic target for overcoming resistance.

DOI： 10.1038/srep40847

Trastuzumab Emtansine in HER2+Recurrent Metastatic Non-Small-Cell Lung Cancer: Study Protocol Reviewed

Kadoaki Ohashi, Katsuyuki Hotta, Taizo Hirata, Keisuke Aoe, Toshiyuki Kozuki, Kiichiro Ninomiya, Hiroe Kayatani, Hiroyuki Yanai, Shinichi Toyooka, Shiro Hinotsu, Minoru Takata, Katsuyuki Kiura

CLINICAL LUNG CANCER 18 ( 1 ) 92 - 95 2017.1

Language：English Publishing type：Research paper (scientific journal) Publisher：CIG MEDIA GROUP, LP

The treatment outcome has been unsatisfactory for patients with non small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T-DM1 monotherapy for patientg with HER2+ lung cancers. The major eligibility criteria are as follows: age >= 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T-DM1 monotherapy is effective against HER2+ lung cancer. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.cllc.2016.06.014

Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies Reviewed

Ken Suzawa, Kazuhiko Shien, Huang Peng, Masakiyo Sakaguchi, Masami Watanabe, Shinsuke Hashida, Yuho Maki, Hiromasa Yamamoto, Shuta Tomida, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Hiromi Kumon, Shinichiro Miyoshi, Shinichi Toyooka

ANTICANCER RESEARCH 37 ( 1 ) 301 - 307 2017.1

Language：English Publishing type：Research paper (scientific journal) Publisher：INT INST ANTICANCER RESEARCH

Background: Reduced expression in immortalized cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and its overexpression by adenovirus vector (Ad-REIC) exhibits a remarkable therapeutic effect on various human cancer types through a mechanism triggered by endoplasmic reticulum stress. Materials and Methods: We examined the direct anti-tumor effect of Ad-REIC gene therapy on lung cancer and malignant mesothelioma cell lines in vitro, and the distant bystander effect using immunocompetent mouse allograft models with bilateral flank tumors. Results: Ad-REIC treatment showed antitumor effect in many lung cancer and malignant mesothelioma cell lines in vitro. In an in vivo model, Ad-REIC treatment inhibited the growth not only of directly treated tumors but also of distant untreated tumors. By immunohistochemical analysis, infiltration of T-cells and natural killer (NK) cells and expression of the major histocompatibility complex (MHC) class I molecules were observed in bilateral tumors. Conclusion: Ad-REIC treatment not only had a direct antitumor effect but also an indirect bystander effect through stimulation of the immune system.

DOI： 10.21873/anticanres.11321

Precision Medicine

Tomida Shuta, Toyooka Shinichi

Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 129 ( 1 ) 59 - 60 2017

Reconstruction of Anterior Chest Wall with Polypropylene Mesh: Two Primary Sternal Chondrosarcoma Cases Reviewed

Shinichi Kawana, Hiromasa Yamamoto, Yuho Maki, Seiichiro Sugimoto, Shinichi Toyooka, Shinichiro Miyoshi

ACTA MEDICA OKAYAMA 71 ( 3 ) 259 - 262 2017

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Primary sternal chondrosarcoma is a rare malignant tumor that is refractory to chemotherapy and radiation. Effective therapy is radical resection of the tumor. We present two patients with primary sternal chondrosarcoma who underwent a radical resection of the lower half of the sternum and bilateral ribs, followed by reconstruction with 2 sheets of polypropylene mesh layered orthogonally. The patients have maintained almost the same pulmonary function as preoperative values, with stability of the chest wall. Although there are various ways to reconstruct the anterior chest wall, reconstruction with polypropylene mesh layered orthogonally is an easy-to-use and sufficient method.

DOI： 10.18926/AMO/55210

Unique circulating microRNAs in relation to EGFR mutation status in Japanese smoker male with lung adenocarcinoma Reviewed

Sachio Ito, Yoshihiro Kamoto, Akiko Sakai, Kaori Sasai, Tatsuro Hayashi, Shinichi Toyooka, Hiroshi Katayama

Oncotarget 8 ( 70 ) 114685 - 114697 2017

Language：English Publishing type：Research paper (scientific journal) Publisher：Impact Journals LLC

The incidence of lung adenocarcinoma has been increasing recently in smokers. The molecular target therapy has been developed for lung adenocarcinoma patients harboring EGFR gene mutation. However, the treatment modalities for patients without mutation are currently limited. Thus, analysis of EGFR gene mutation status at early stage is important strategy to classify the patients for improving treatments and prognosis efficiently. This study aimed to identify microRNA (miRNA) signature in relation to mutation status in EGFR gene in early stage of lung adenocarcinoma male patients with smoking history. MiRNA profiles were assessed by microarray in paired plasma and tissue pooled from 10 EGFR wild type (EGFR-wt) and 10 EGFR mutated (EGFR-mut) patients. Expressions of selected miRNAs were verified further by real-time qRT-PCR in 83 plasma samples consisting of 55 EGFR-wt patients and 28 EGFR-mut patients and their correlation with clinicopathological parameters and EGFR gene mutation status were evaluated. We found that seven miRNAs (miR-16-5p, miR-23a-3p, miR-103a-3p, miR122-5p, miR-223-3p, miR-346 and miR-451a) were differentially expressed in stage I and stage I+II. Especially, miR-23a-3p was only miRNA shown higher expression in EGFR-wt patients than EGFR-mut patients. Thus, our findings could be useful non-invasive biomarkers to differentiate mutation status in EGFR gene in smoker lung adenocarcinoma male patients.

DOI： 10.18632/oncotarget.21425

ß-1,3-galactosyl-O-glycosyl-glycoprotein ß-1,6-N-acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility. Reviewed

Sumardika IW, Youyi C, Kondo E, Inoue Y, Ruma IMW, Murata H, Kinoshita R, Yamamoto KI, Tomida S, Shien K, Satoh H, Yamauchi A, Futami J, Putranto EW, Hibino T, Toyooka S, Nishibori M, Sakaguchi M

Oncol Res 2017

Role of surgery in N2 NSCLC: pros Reviewed

Kazuhiko Shien, Shinichi Toyooka

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 46 ( 12 ) 1168 - 1173 2016.12

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

The optimal management of clinical N2 Stage IIIA non-small cell lung cancer is still controversial. For a cure of locally advanced IIIA/N2 non-small cell lung cancer, the control of both local regions and possible distant micrometastases is crucial. Chemotherapy is generally expected to prevent distant recurrence. For local tumor control, radiotherapy or surgery has been adopted singly or in combination. If a complete resection can be safely performed, surgery remains the strongest modality for 'eradicating' local disease. Many retrospective studies have reported a possible survival benefit of induction treatment followed by surgery in selected patients with IIIA/N2 non-small cell lung cancer; however, randomized Phase III trials have failed to demonstrate the superiority of induction treatment followed by surgery over chemoradiotherapy, mainly because of the heterogeneity of the N2 status. IIIA/N2 non-small cell lung cancer consists of a heterogeneous group of disease ranging from microscopically single station to radiologically bulky ipsilateral multi-station mediastinal lymph node involvement. A recent definition proposed by the American College of Chest Physicians classified non-small cell lung cancer based on the N2 status, such as discrete or infiltrative type, and recommendations were made according to this N2 status, with definitive chemoradiotherapy recommended for infiltrative clinical N2 and definitive chemoradiotherapy or induction treatment followed by surgery recommended for other cases. Thus, the introduction of a multimodality treatment strategy seems to be necessary for the improved prognosis of non-small cell lung cancer patients with IIIA/N2 disease. In this review, we discuss the role of surgery and the optimal surgical management for patients with IIIA/N2 non-small cell lung cancer.

DOI： 10.1093/jjco/hyw125

Active Secretion of Dimerized S100A11 Induced by the Peroxisome in Mesothelioma Cells. Reviewed International journal

Satomi Saho, Hiroki Satoh, Eisaku Kondo, Yusuke Inoue, Akira Yamauchi, Hitoshi Murata, Rie Kinoshita, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, I Wayan Sumardika, Chen Youyi, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Yoshihiko Sakaguchi, Ken Saito, Hidekazu Iioka, Nam-Ho Huh, Shinichi Toyooka, Masakiyo Sakaguchi

Cancer microenvironment : official journal of the International Cancer Microenvironment Society 9 ( 2-3 ) 93 - 105 2016.12

Language：English Publishing type：Research paper (scientific journal)

S100A11, a small Ca2+ binding protein, acts extracellularly as a mediator of cancer progression. That raises the question of how a protein that lacks the classical secretory signal is able to be secreted outside cells without being damaged. Some insights into this question have been obtained, and there has been accumulating evidence indicating a pivotal role of a non-classical vesicle-mediated pathway using lysosomes or peroxisomes for the protein secretion. To obtain a more precise insight into the secretory mechanism of S100A11, we first screened representative cancer cells exhibiting significantly active secretion of S100A11. From the results of profiling, we turned our attention to aggressive cancer mesothelioma cells. In mesothelioma cells, we found that abundant dimeric S100A11 was produced selectively in the peroxisome after transportation of monomeric S100A11 through an interaction with PEX14, a peroxisome membrane protein, resulting in peroxisomal secretion of dimerized S100A11. In an extracellular environment in vitro, dimerized S100A11 promoted mesothelial cell invasion indirectly with the help of fibroblast cells. Overall, the results indicate that the peroxisome functions as an essential vesicle for the production of dimerized S100A11 and the subsequent secretion of the protein from mesothelioma cells and that peroxisome-mediated secretion of dimerized S100A11 might play a critical role in mesothelioma progression in a tumor microenvironment.

DOI： 10.1007/s12307-016-0185-2

Usefulness of Thoracoscopic Debridement for Chronic Empyema after an Extrapleural Pneumonectomy Reviewed

Hidejiro Torigoe, Shinichi Toyooka, Hiromasa Yamamoto, Junichi Soh, Shinichiro Miyoshi

ACTA MEDICA OKAYAMA 70 ( 6 ) 507 - 510 2016.12

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

We present the case of a 65-year-old Japanese man diagnosed with chronic empyema (without a bronchopleural fistula) that occurred 7 months after he underwent an extrapleural pneumonectomy for right malignant pleural mesothelioma (MPM). Following thoracic drainage and irrigation for 1 month, we performed surgery by a thoracoscopic approach, in light of his general condition. We performed debridement and removal of the Gore-Tex polytetralluoroethylene (PTFE) patch that had been used for the reconstruction of the diaphragm and the pericardium. The empyema had not relapsed when he died from recurrence of the MPM at 4 months after the thoracoscopic surgery. This patient's case suggests that thoracoscopic debridement and patch removal can be a therapeutic option for not only early-stage (exudative or fibrinopurulent) empyema but also late-stage (organized and chronic) empyema without a bronchopleural fistula, particularly for patients in poor general condition.

DOI： 10.18926/AMO/54816

Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway Reviewed

Tomoaki Ohtsuka, Masakiyo Sakaguchi, Hiromasa Yamamoto, Shuta Tomida, Katsuyoshi Takata, Kazuhiko Shien, Shinsuke Hashida, Tomoko Miyata-Takata, Mototsugu Watanabe, Ken Suzawa, Junichi Soh, Chen Youyi, Hiroki Sato, Kei Namba, Hidejiro Torigoe, Kazunori Tsukuda, Tadashi Yoshino, Shinichiro Miyoshi, Shinichi Toyooka

SCIENTIFIC REPORTS 6 39557 2016.12

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

HER2 is a receptor tyrosine kinase and its upregulation via activating mutations or amplification has been identified in some malignant tumors, including lung cancers. Because HER2 can be a therapeutic target in HER2-driven malignancies, it is important to understand the molecular mechanisms of HER2 activation. In the current study, we identified that cytokeratin 19 (KRT19) binds to HER2 at the inside face of plasma membrane. HER2 and KRT19, which were concurrently introduced to a human embryonic kidney 293 T cells, revealed an association with each other and resulted in phosphorylation of HER2 with the subsequent activation of a downstream Erk-associated pathway. A binding assay revealed that both the NH2-terminal head domain of KRT19 and the COOH-terminal domain of HER2 were essential for their binding. To investigate the impact of the interaction between HER2 and KRT19 in lung cancer, we examined their expressions and localizations in lung cancers. We found that KRT19 was highly expressed in HER2-positive lung cancer cells, and KRT19 and HER2 were co-localized at the cell membrane. In conclusion, we found that KRT19 intracellularly binds to HER2, playing a critical role in HER2 activation.

DOI： 10.1038/srep39557

NSCLCにおける分子バーコードシークエンス分析による複数の低頻度変異の検出(Detection of multiple low-frequency mutations by molecular-barcode sequencing in NSCLC)

難波圭, 冨田秀太, 枝園和彦, 鳥越英次郎, 佐藤博紀, 山本寛斉, 宗淳一, 佃和憲, 三好新一郎, 豊岡伸一

肺癌 56 ( 6 ) 639 - 639 2016.11

腸型肺腺癌の1切除例

清水大, 三好健太郎, 目崎久美, 枝園和彦, 杉本誠一郎, 山本寛斉, 宗淳一, 豊岡伸一, 大藤剛宏, 三好新一郎

肺癌 56 ( 6 ) 682 - 682 2016.11

Development of an annually updated Japanese national clinical database for chest surgery in 2014 Reviewed

Shunsuke Endo, Norihiko Ikeda, Takashi Kondo, Jun Nakajima, Haruhiko Kondo, Kohei Yokoi, Masayuki Chida, Masami Sato, Shinichi Toyooka, Koichi Yoshida, Yoshinori Okada, Yukio Sato, Meinoshin Okumura, Munetaka Masuda, Koji Chihara, Hiroaki Miyata

General Thoracic and Cardiovascular Surgery 64 ( 10 ) 569 - 576 2016.10

Language：English Publisher：Springer-Verlag Tokyo

Objectives: A national clinical database (NCD) adopted an “Internet-based collection” in 2011. An NCD specializing in chest surgery was launched based on the NCD system in 2014. The system was linked to the board certification as the second level in the hierarchy of the specialty of chest surgery and accreditation of educational institutions for chest surgery. Here, we report the status of the NCD for chest surgery in 2014 and clarified its registration rate and its accuracy. Methods: Chest surgeries undertaken in Japan since January 1st, 2014 until the end of the same year were registered through an Internet-based system until April 8th, 2015. The registration rate was compared with the annual survey conducted by the Japanese Association for Thoracic Surgery (JATS) from 2011 to 2014. The rate of accurate inputting was measured by an Internet-based audit in reference to 563 anonymous operative notes of patients presented by 106 chest surgeons at the time of renewal for board certification for chest surgery. Results: A total of 88,112 chest-surgical procedures were registered from 1000 chest surgery units (CSUs). Distribution of procedures by thoracic disease was almost identical to that of the annual survey conducted by JATS. However, the NCD had 4260 more registered procedures compared with the annual survey. The Internet-based audit showed that inter-rater agreement between Internet-based data and operative notes in any item was &gt
94Â %. Conclusions: The NCD system can sustainably provide important and up-to-date information relating to preoperative status, oncology, and best practice for chest surgery in Japan.

DOI： 10.1007/s11748-016-0697-1

悪性胸膜中皮腫におけるS100A11の働き

佐藤博紀, 山本寛斉, 難波圭, 鳥越英次郎, 下田篤志, 吉岡貴裕, 枝園和彦, 宗淳一, 豊岡伸一

日本癌学会総会記事 75回 J - 1061 2016.10

Long-Term Survival after Radiofrequency Ablation of Lung Oligometastases from Five Types of Primary Lesions: A Retrospective Evaluation Reviewed

Kenichi Omae, Takao Hiraki, Hideo Gobara, Toshihiro Iguchi, Hiroyasu Fujiwara, Yusuke Matsui, Shinichi Toyooka, Takeshi Nagasaka, Susumu Kanazawa

JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 27 ( 9 ) 1362 - 1370 2016.9

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Purpose: To conduct a retrospective evaluation of long-term survival after radiofrequency (RF) ablation for lung oligometastases from 5 types of primary lesions.
Materials and Methods: The study population consisted of 123 patients with lung oligometastases from colorectal cancer (CRC), non small-cell lung cancer, hepatocellular carcinoma, esophageal cancer, and renal-cell carcinoma treated with RF ablation. Lung oligometastases were defined as 1-5 Metastases confined to the lung while the primary cancer and other metastases were eradicated. Overall survival (OS) and recurrence-free survival (RFS) were estimated for-the overall study population and for patients with each type of primary lesion. The OS and RFS rates were compared with those of the patients with any of the other four primary lesion types. Finally, various variables were analyzed to determine what factors influenced OS and RFS.
Results: The Median follow-up was 45.7 months; and the 5-year-OS and RFS rates for all 123 patients Were 62% and 25%, respectively, The OS :time for patients with metastases from. CRC was significantly longer (P = .042); it was significantly shorter (P = .022) in patients with metastases from esophageal cancer. Longer disease-free interval was significantly (P = .015) associated with better OS. There was no variable significantly associated with OS and RFS on multivariate analyses.
Conclusions: Data from this single-center study appear promising in terms of long-term survival after RF ablation of lung oligometastases from 5 primary lesions.

DOI： 10.1016/j.jvir.2016.05.017

The Feasibility of Median Sternotomy With or Without Thoracotomy for Locally Advanced Non-Small Cell Lung Cancer Treated With Induction Chemoradiotherapy Reviewed

Hiroki Sato, Shinichi Toyooka, Junichi Soh, Katsuyuki Hotta, Kuniaki Katsui, Hiromasa Yamamoto, Seiichiro Sugimoto, Takahiro Oto, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi

ANNALS OF THORACIC SURGERY 102 ( 3 ) 985 - 992 2016.9

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background. This study aimed to compare the morbidity and mortality of a median sternotomy approach and a lateral thoracotomy and to investigate the feasibility of a median sternotomy for locally advanced non-small cell lung cancer (NSCLC) after induction chemoradiotherapy.
Methods. The medical records of patients with locally advanced NSCLC who underwent induction chemoradiotherapy followed by surgery at our institution between January 1999 and September 2014 were reviewed. We compared the morbidity and mortality of a median sternotomy approach and a lateral thoracotomy.
Results. A total of 102 NSCLC patients were the subjects of this study. Among them, 31 patients underwent surgery with a median sternotomy approach and 71 patients underwent surgery with a lateral thoracotomy. Patients in the median sternotomy group had a significantly higher rate of postoperative arrhythmia than those in the lateral thoracotomy group (p = 0.0028). However, all the complications were manageable, and no treatment-related deaths occurred in the median sternotomy group. Regarding the prognosis, the 5-year overall survival rate was 72.7%, and the 2-year recurrence-free survival rate was 66.5% in the entire population. No significant differences in overall survival or recurrence-free survival were observed between the 2 approaches.
Conclusions. Whereas the lateral thoracotomy approach is a standard procedure, our experience suggests that a median sternotomy approach for locally advanced NSCLC after induction chemoradiotherapy is a feasible procedure and can be a surgical option. (C) 2016 by The Society of Thoracic Surgeons

DOI： 10.1016/j.athoracsur.2016.03.092

Study about the Efficacy of Metformin to Immune Function in Cancer Patients Reviewed

Mototsugu Watanabe, Hiromasa Yamamoto, Shingo Eikawa, Kazuhiko Shien, Tadahiko Shien, Junichi Soh, Katsuyuki Hotta, Jun Wada, Shiro Hinotsu, Toshiyoshi Fujiwara, Katsuyuki Kiura, Hiroyoshi Doihara, Shinichiro Miyoshi, Heiichiro Udono, Shinichi Toyooka

ACTA MEDICA OKAYAMA 70 ( 4 ) 327 - 330 2016.8

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

A study to evaluate the effect of metformin on the immune system was commenced in July 2014. Metformin is one of the most commonly prescribed drugs for type 2 diabetes, and previous studies have reported that metformin has an anti-tumor effect. The aim of this study is to evaluate the efficacy of metformin on the immune system in human cancer patients in vivo. The primary outcome parameter will be the rate change in the population of CD8(+) T cells, which produce multiple cytokines.

DOI： 10.18926/AMO/54514

Randomized feasibility study of S-1 for adjuvant chemotherapy in completely resected Stage IA non-small-cell lung cancer: results of the Setouchi Lung Cancer Group Study 0701 Reviewed

Junichi Soh, Norihito Okumura, Masao Nakata, Hiroshige Nakamura, Minoru Fukuda, Masafumi Kataoka, Shinsuke Kajiwara, Yoshifumi Sano, Motoi Aoe, Kazuhiko Kataoka, Katsuyuki Hotta, Keitaro Matsuo, Shinichi Toyooka, Hiroshi Date

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 46 ( 8 ) 741 - 747 2016.8

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Objective: The aim of this multicenter study was to determine the appropriate administration schedule for S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in patients with completely resected pathological-Stage IA ( tumor diameter, 2-3 cm) non-small-cell lung cancer.
Methods: Patients were randomly assigned to receive adjuvant chemotherapy consisting of either the 4-week oral administration of S-1 ( 80-120 mg/body/day) followed by a 2-week rest ( Group A), or the 2-week oral administration of S-1 ( 80-120mg/body/day) followed by a 1-week rest ( Group B). The duration of adjuvant chemotherapy was 1 year in both arms. The primary endpoint was compliance, namely drug discontinuation-free survival, which was calculated using the Kaplan-Meier method with log-rank test.
Results: Eighty patients were enrolled in this study, and 76 patients actually received S-1 treatment. The drug discontinuation-free survival rates at 1 year were 49.1% in Group A and 52.7% in Group B ( P = 0.373). The means of the relative dose intensities were 55.3% in Group A and 64.6% in Group B ( P = 0.237). There were no treatment-related deaths. Patients with grade 3/ 4 toxicities were significantly more frequent in Group A ( 40.5%) than in Group B ( 15.4%, P = 0.021). The 2-year relapse-free survival rates were 97.5% in Group A and 92.5% in Group B, and the 2-year overall survival rates were 100% in both groups.
Conclusions: The feasibility showed no significant difference between the two groups among patients with completely resected Stage IA ( tumor diameter, 2-3 cm) non-small-cell lung cancer.

DOI： 10.1093/jjco/hyw062

胸腔鏡下拡大胸腺摘除術を施行した重症筋無力症の1例

尾山貴徳, 野田卓男, 納所洋, 谷本光隆, 牧佑歩, 宗淳一, 豊岡伸一, 三好新一郎, 柴田敬, 井上拓志, 吉永治美

日本小児科学会雑誌 120 ( 7 ) 1142 - 1142 2016.7

Yesl is the key molecule for the resistance to trastuzumab in breast cancer, and dasatinib overcomes the resistance Reviewed

Yamamoto Hiromasa, Takeda Tatsuaki, Kanzaki Hirotaka, Suzawa Ken, Namba Kei, Sato Hiroki, Torigoe Hidejiro, Watanabe Mototsugu, Maki Yuho, Soh Junichi, Asano Hiroaki, Tsukuda Kazunori, Miyoshi Shinichiro, Kitamura Yoshihisa, Sendo Toshiaki, Toyooka Shinichi

CANCER RESEARCH 76 2016.7

The proliferative effects of asbestos-exposed peripheral blood mononuclear cells on mesothelial cells. Reviewed International journal

Yuho Maki, Yasumitsu Nishimura, Shinichi Toyooka, Junichi Soh, Kazunori Tsukuda, Kazuhiko Shien, Masashi Furukawa, Takayuki Muraoka, Tsuyoshi Ueno, Norimitsu Tanaka, Hiromasa Yamamoto, Hiroaki Asano, Megumi Maeda, Naoko Kumagai-Takei, Suni Lee, Hidenori Matsuzaki, Takemi Otsuki, Shinichiro Miyoshi

Oncology letters 11 ( 5 ) 3308 - 3316 2016.5

Language：English Publishing type：Research paper (scientific journal)

Malignant mesothelioma (MM) is thought to arise from the direct effect of asbestos on mesothelial cells. However, MM takes a long time to develop following exposure to asbestos, which suggests that the effects of asbestos are complex. The present study examined the effects of asbestos exposure on the cell growth of MeT-5A human mesothelial cells via cytokines produced by immune cells. Peripheral blood mononuclear cells (PBMCs) were stimulated with antibodies against cluster of differentiation (CD)3 and CD28 upon exposure to the asbestos chrysotile A (CA) or crocidolite (CR); the growth of MeT-5A cells in media supplemented with PBMC culture supernatants was subsequently examined. MeT-5A cells exhibited an increase in proliferation when grown in supernatant from the 7-day PBMC culture exposed to CA or CR. Analysis of cytokine production demonstrated increased levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1α, IL-1β, IL-3, IL-5, IL-13 and IL-17A in supernatants. Individual administration of these cytokines, excluding G-CSF and GM-CSF, led to an increase in cell growth of MeT-5A, whereas this effect was not observed following the combined administration of these cytokines. The results indicate that cytokines secreted by immune cells upon exposure to asbestos cause an increase in the growth activity of mesothelial cells, suggesting that alterations in the production of cytokines by immune cells may contribute to tumorigenesis in individuals exposed to asbestos.

DOI： 10.3892/ol.2016.4412

非小細胞肺癌術後補助化学療法におけるS-1+CBDCA併用療法とS-1維持療法の多施設共同認容性試験

中村廣繁, 奥村典仁, 園部誠, 岡部和倫, 片岡正文, 山下素弘, 中田昌男, 片岡和彦, 山下芳典, 宗淳一, 吉岡弘鎮, 堀田勝幸, 松尾恵太郎, 坂本純一, 豊岡伸一, 三好新一郎, 伊達洋至

日本呼吸器外科学会雑誌 30 ( 3 ) RO9 - 4 2016.4

小型肺癌に対する外科治療戦略肺野末梢型cT1aN0M0扁平上皮癌の予後因子

田尾裕之, 宗淳一, 藤原俊哉, 葉山牧夫, 岡崎幹生, 杉本龍士郎, 上野剛, 岡部和倫, 山下素弘, 佐野由文, 片岡和彦, 松浦求樹, 森山重治, 豊岡伸一, 三好新一郎

日本外科学会定期学術集会抄録集 116回 SY - 6 2016.4

メトホルミン服用における健常人および肺癌患者のCD8T細胞の多機能性調査

鵜殿平一郎, 豊岡伸一, 榮川伸吾

大和証券ヘルス財団研究業績集 ( 39 ) 96 - 100 2016.3

Language：Japanese Publisher：(公財)大和証券ヘルス財団

メトホルミン服用における健常人および肺癌患者のCD8T細胞の多機能性について検討した。末梢血単核球(PBMC)をメトホルミン存在下又は非存在下で培養し、メトホルミンを除去したものを、PMA/イオノマイシンで処理した細胞のCD8+ T細胞のうち、IFNγ、TNFα、IL-2を同時に産生できる細胞を検出した。がん患者のCD8T細胞はメトホルミン処理により多機能性の上昇を認める場合が多く、健常人では多機能性の上昇を認める場合は少なかった。

Genetic alterations in lung adenocarcinoma with a micropapillary component. Reviewed International journal

Masashi Furukawa, Shinichi Toyooka, Kouichi Ichimura, Hiromasa Yamamoto, Junichi Soh, Shinsuke Hashida, Mamoru Ouchida, Kazuhiko Shien, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

Molecular and clinical oncology 4 ( 2 ) 195 - 200 2016.2

Language：English Publishing type：Research paper (scientific journal)

Pulmonary adenocarcinoma (PA) with a micropapillary component (PA-MPC) is known as an aggressive subtype of PA. The molecular profiles of PA-MPC have not been well characterized. the pathological reports of patients who underwent surgical resection for lung cancer between April, 2004 and May, 2012 were reviewed. Of the 674 patients diagnosed with PA, 28 were found to have MPC. A total of 138 resected PAs without MPC were selected in the same period to serve as age-, gender- and smoking status-matched controls to the PA-MPC group. Mutational status was determined by the following two methods: SNaPshot assay based on multiplex polymerase chain reaction (PCR), primer extension and capillary electrophoresis that was designed to assess 38 somatic mutations in 8 genes [AKT1, BRAF, endothelial growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), mitogen-activated protein kinase kinase 1, neuroblastoma RAS viral oncogene homolog, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA) and phosphatase and tensin homolog]; and a PCR-based sizing assay that assesses EGFR exon 19 (deletions), EGFR exon 20 (insertions) and human epidermal growth factor receptor 2 exon 20 (insertions). echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene (EML4-ALK) was screened by ALK immunohistochemistry and confirmed using the reverse transcription PCR assay and the break-apart fluorescence in situ hybridization assay. Regarding genetic alterations, 13 (46.4%) of the 28 PA-MPCs harbored mutually exclusive mutations: 9 (32.1%) EGFR mutations, 1 (3.6%) KRAS mutation and 3 (10.7%) EML4-ALK fusion genes. PAs without MPC harbored 42 (30.4%) EGFR mutations, 17 (12.3%) KRAS mutations, 3 (2.2%) EML4-ALK fusion genes and 1 (0.7%) PIK3CA mutation. EML4-ALK fusion genes appeared to occur significantly more frequently in PA-MPCs compared with PAs without MPC (P=0.027). Although the sample size was small, our study suggests that the molecular pathogenesis of PA-MPC may be different from that of other adenocarcinomas.

DOI： 10.3892/mco.2015.690

Induction S-1+Concurrent Radiotherapy Followed by Surgical Resection of Locally Advanced Non-small-cell Lung Cancer in an Elderly Patient Reviewed

Hidejiro Torigoe, Shinichi Toyooka, Kuniaki Katsui, Junichi Soh, Yuho Maki, Katsuyuki Kiura, Shinichiro Miyoshi

ACTA MEDICA OKAYAMA 70 ( 1 ) 63 - 65 2016.2

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

We present the case of a 77 year-old Japanese man diagnosed with lung squamous cell carcinoma with mediastinal lymph node metastasis. He was treated with induction chemoradiotherapy for T1bN2M0 stage IIIA disease. Considering his age, we selected S-1 as the chemotherapeutic drug. Observing an objective response with no severe adverse events, we performed a left upper lobectomy with sleeve resection of the pulmonary artery. No residual tumor cells were found in the resected specimens, and no critical complication was observed in the clinical course. This case suggests that induction chemoradiotherapy using S-1 combined with concurrent radiation followed by surgery can he a therapeutic option for elderly patients with locally advanced non-small-cell lung cancer.

DOI： 10.18926/AMO/54007

放射線化学療法後に外科手術を行った局所進行非小細胞肺癌症例の長期フォローアップ解析

槇本剛, 久保寿夫, 南大輔, 大橋圭明, 堀田勝幸, 田端雅弘, 豊岡伸一, 勝井邦彰, 谷本光音, 木浦勝行

日本内科学会雑誌 105 ( Suppl. ) 192 - 192 2016.2

Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations Reviewed

Ken Suzawa, Shinichi Toyooka, Masakiyo Sakaguchi, Mizuki Morita, Hiromasa Yamamoto, Shuta Tomida, Tomoaki Ohtsuka, Mototsugu Watanabe, Shinsuke Hashida, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

Cancer Science 107 ( 1 ) 45 - 52 2016.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Blackwell Publishing Ltd

Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G1 arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations. In this study, we demonstrated the antitumor effect of afatinib, as a HER2-targeted therapy, in lung cancers harboring HER2 alterations in vitro and in vivo. Our results strongly suggest that afatinib is a promising therapeutic option for NSCLC patients with HER2-amplification or mutations.

DOI： 10.1111/cas.12845

Radiofrequency Ablation of Lung Tumors Using a Multitined Expandable Electrode: Impact of the Electrode Array Diameter on Local Tumor Progression Reviewed

Hiroki Ihara, Hideo Gobara, Takao Hiraki, Toshiharu Mitsuhashi, Toshihiro Iguchi, Hiroyasu Fujiwara, Yusuke Matsui, Junichi Soh, Shinichi Toyooka, Susumu Kanazawa

JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 27 ( 1 ) 87 - 95 2016.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Purpose: To retrospectively investigate the impact of the electrode array diameter on local tumor progression after lung radiofrequency ablation.
Materials and Methods: This study included 651 lung tumors treated using multitined expandable electrodes and followed for 6 months. The mean long-axis tumor diameter was 12 mm +/- 7 (range, 2-42 mm). The difference between electrode array diameter and tumor diameter (DAT) was used to investigate the impact of the electrode array diameter. All tumors were classified into 2 groups according to various variables including DAT (>= 10 mm or < 10 mm). The primary technique efficacy rates were calculated using Kaplan-Meier analysis and compared between the 2 groups of each variable using the log-rank test. In addition, crude and multivariate multilevel survival analyses were performed by sequentially including DAT and the other variables in 5 models.
Results: The median DAT for 651 tumors was 12 mm (range, 15 to 24 mm). The technique efficacy rate was significantly lower in the < 10 mm DAT group than in the >= 10 nun group (P < .001). In the crude and multivariate multilevel survival analyses, < 10 mm DAT was a significant risk factor for local progression in all models except model 5 (P = .067). In the >= 10 mm group, the technique efficacy rates were riot significantly different-between the 2 >= 10 min DAT subgroups (ICY to < 15 mm DAT vs >= 15 mm DAT).
Conclusions: DAT is an important risk factor for local progression. We recommend an electrode that is >= 10 mm larger than the tumor diameter.

DOI： 10.1016/j.jvir.2015.07.025

Establishment and molecular characterization of cell lines from Japanese patients with malignant pleural mesothelioma Reviewed

Ken Suzawa, Hiromasa Yamamoto, Tomoyuki Murakami, Hideki Katayama, Masashi Furukawa, Kazuhiko Shien, Shinsuke Hashida, Kazunori Okabe, Keisuke Aoe, Junichi Soh, Hiroaki Asan, Kazunori Tsukuda, Yusuke Mimura, Shinichi Toyooka, Shinichiro Miyoshi

ONCOLOGY LETTERS 11 ( 1 ) 705 - 712 2016.1

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Malignant pleural mesothelioma (MPM) is an aggressive disease that is resistant to conventional therapies. Cell lines are useful models for studying the biological characteristics of tumors; therefore, the establishment of MPM cell lines is valuable for exploring novel therapeutic strategies for MPM. In the present study, 4 MPM cell lines (YUMC8, YUMC44, YUMC63, and YUMC64) were established, which consisted of 2 epithelioid and 2 sarcomatoid mesothelioma histological subtypes, from Japanese patients with MPM. The DNA methylation status, mutations, copy number gains, protein expression of representative genes, and the sensitivity to several drugs were examined in these 4 cell lines. Methylation of P16 was demonstrated in 3/4 cell lines, in which the protein expression of p16 was lost. Methylation of RASSF1A was observed in 3/4 cell lines. Copy number gains of EGFR, HER2 or MET were not detected in the 4 cell lines. Mutations in various genes, including EGFR, KRAS,HER2,BRAF, and PIK3CA, which are frequently detected in non-small cell lung cancer, were not detected in the 4 cell lines. microRNA-34b/c is a direct transcriptional target of p53 and is often silenced in MPM by promoter methylation. In the present study, miR-34b/c was heavily methylated in 2/4 established MPM cell lines. For cell adhesion molecules, E-cadherin expression was detected in the 2 epithelioid MPM cell lines, whereas N-cadherin expression was detected in all 4 established cell lines by western blotting. Vimentin was strongly expressed in the 2 sarcomatoid MPM cell lines. None of the established MPM cell lines demonstrated significant responses to the drugs tested, including NVP-AUY922, 17-DMAG, Trichostatin A, and Vorinostat. Although novel molecular findings were not observed in the current characterization of these MPM cell lines, these lines will be useful for future extensive analyses of the biological behavior of MPM and the development of novel therapeutic strategies.

DOI： 10.3892/ol.2015.3955

[Cross-sectoral Approach of a Perioperative Management Center for General Thoracic Surgery]. Reviewed

Shimoda A, Soh J, Ashiba T, Murata N, Fukuda T, Kobayashi M, Torigoe H, Maki Y, Sugimoto S, Yamane M, Toyooka S, Oto T, Miyoshi S

Kyobu geka. The Japanese journal of thoracic surgery 69 ( 1 ) 20 - 24 2016.1

Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations Reviewed

Ken Suzawa, Shinichi Toyooka, Masakiyo Sakaguchi, Mizuki Morita, Hiromasa Yamamoto, Shuta Tomida, Tomoaki Ohtsuka, Mototsugu Watanabe, Shinsuke Hashida, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

CANCER SCIENCE 107 ( 1 ) 45 - 52 2016.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G(1) arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations.

DOI： 10.1111/cas.12845

Path and challenges of the clinical trial network construction of the cancer drug―Through the lung cancer registry tumor specimen banking in Chugoku and Shikoku district―

Kiura Katsuyuki, Hotta Katsuyuki, Toyooka Shiinichi

Neurological Therapeutics 33 ( 5 ) S99 - S99 2016

Low frequency of drug-resistant virus did not affect the therapeutic efficacy in daclatasvir plus asunaprevir therapy in patients with chronic HCV genotype-1 infection Reviewed

Hideaki Kinugasa, Fusao Ikeda, Kouichi Takaguchi, Chizuru Mori, Takehiro Matsubara, Hidenori Shiraha, Akinobu Takaki, Yoshiaki Iwasaki, Shinichi Toyooka, Kazuhide Yamamoto

ANTIVIRAL THERAPY 21 ( 1 ) 37 - 44 2016

Language：English Publishing type：Research paper (scientific journal) Publisher：INT MEDICAL PRESS LTD

Background: The efficacy of a direct-acting antiviral agent (DAA) is compromised by the development of drug resistance. The associations between resistance-associated virus (RAV) and therapeutic outcomes have not been well-understood.
Methods: A total of 30 patients with HCV genotype-1b were enrolled and treated for 24 weeks with asunaprevir (ASV) and daclatasvir (DCV). Viral sequences in non-structural (NS) regions 3 and 5A in serum and liver tissue before treatment were examined with direct sequencing, next-generation sequencing (NGS) and the PCR-invader method to evaluate the importance of drug-resistance in the prediction of the outcomes of ASV plus DCV therapy.
Results: Of 30 patients (22 treatment-naive patients, 2 interferon-intolerant patients and 6 non-responders), 25 patients (83.3%) achieved sustained virological response (SVR) 24 weeks after the treatment. Viral breakthrough occurred in three treatment-naive patients and one non-responder. One treatment-naive patient experienced viral relapse. Among 25 patients without RAV, 24 obtained SVR, whereas 5 patients had RAV with a 1.3 to 88% frequency, resulting in various therapeutic outcomes. As for HCV compartments, similar RAVs were detected in serum and liver tissue for a patient obtaining SVR despite HCV NS5A Y93H and another developed viral breakthrough although no RAV was detected. Direct sequencing could not detect RAVs in low frequency (1.3 to 12%) for three of four patients.
Conclusions: Low frequency of RAVs might not affect the outcomes of ASV plus DCV therapy. Deep sequencing and PCR-invader methods can detect clinically significant RAVs for ASV plus DCV therapy.

DOI： 10.3851/IMP2976

肺類上皮血管内皮腫の1例

田中晶平, 小田尚廣, 佐藤晃子, 宮原信明, 狩野裕久, 中西将元, 秦雄介, 槇本剛, 久保寿夫, 大橋圭明, 二宮崇, 堀田勝幸, 金廣有彦, 田端雅弘, 谷本光音, 木浦勝行, 牧佑歩, 宗淳一, 豊岡伸一, 三好新一郎

肺癌 55 ( 7 ) 1127 - 1127 2015.12

Fever after lung radiofrequency ablation: Prospective evaluation of its incidence and associated factors Reviewed

Yoshihisa Masaoka, Takao Hiraki, Hideo Gobara, Toshihiro Iguchi, Hiroyasu Fujiwara, Yusuke Matsui, Shinichi Toyooka, Junichi Soh, Katsuyuki Kiura, Susumu Kanazawa

EUROPEAN JOURNAL OF RADIOLOGY 84 ( 11 ) 2202 - 2209 2015.11

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Purpose: To prospectively investigate the incidence of post-lung radiofrequency (RF) ablation fever as well as its associated factors, according to the grade of fever.
Materials and Methods: A total of 56 patients who underwent 67 lung RF sessions were analyzed. Postablation fever (>= 37.0 degrees C) was graded according to the common toxicity criteria of adverse events v. 4.0. Fever >= 37.0 degrees C and <38.0 C was defined as grade 0 fever. The 67 RF sessions were divided into two groups according to the presence of post-ablation fever, and the factors associated with fever were determined using univariate and multivariate analyses. Subsequently, the RF sessions accompanied by post-ablation fever were further divided into two groups according to the grade of fever (grade 0 vs. grade >= 1), and the factors associated with the grade of fever were determined.
Results: Grade 0, 1, and 2 fever accompanied 36 (54%), 11(16%), and 2 (3%) sessions, respectively. Post-ablation fever was significantly associated with larger ablated parenchymal volume (P=0.001) and development of pulmonary infiltration (P=0.004). Additionally, development of pulmonary infiltration (P=0.048) was also significantly and independently associated with higher grade of fever in the multivariate analysis.
Conclusions: The incidences of grade 0, 1, and 2 post-ablation fever were 54%, 16%, and 3%, respectively. Larger ablated parenchymal volume and development of pulmonary infiltration were found to be associated with the development of post-ablation fever, with the latter being an independent factor associated with higher grade of fever. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.ejrad.2015.07.009

DNA copy number gains in malignant pleural mesothelioma Reviewed

Masashi Furukawa, Shinichi Toyooka, Tatsuro Hayashi, Hiromasa Yamamoto, Nobukazu Fujimoto, Junichi Soh, Shinsuke Hashida, Kazuhiko Shien, Hiroaki Asano, Keisuke Aoe, Kazunori Okabe, Harvey I. Pass, Kazunori Tsukuda, Takumi Kishimoto, Shinichiro Miyoshi

Oncology Letters 10 ( 5 ) 3274 - 3278 2015.11

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with an extremely poor prognosis. The incidence of MPM is increasing as a result of widespread exposure to asbestos. The molecular pathogenesis of MPM remains unclear. The present study analyzed the frequency of various genomic copy number gains (CNGs) in MPM using reverse transcription-quantitative polymerase chain reaction. A total of 83 primary MPMs and 53 primary lung adenocarcinomas were analyzed to compare the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2. In MPM, the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2 were detected in 12 (14.5%), 8 (9.6%), 5 (6.0%), 4 (4.8%) and 1 (1.2%) of the samples, respectively. In lung adenocarcinomas, the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2 were detected in 21 (39.6%), 12 (22.6%), 5 (9.4%), 10 (18.9%) and 0 (0.0%) of the samples, respectively. The CNGs of EGFR, KRAS and FGFR1 were significantly less frequent in the MPMs compared with the lung adenocarcinomas (P=0.0018, 0.048 and 0.018, respectively). Overall, the MPMs exhibited these CNGs less frequently compared with the lung adenocarcinomas (P=0.0002). The differences in CNGs between the two tumor types suggested that they are genetically different.

DOI： 10.3892/ol.2015.3652

Predicting pleural invasion using HRCT and F-18-FDG PET/CT in lung adenocarcinoma with pleural contact Reviewed

Takashi Tanaka, Takayoshi Shinya, Shuhei Sato, Toshiharu Mitsuhashi, Koichi Ichimura, Junichi Soh, Shinichi Toyooka, Mitsumasa Kaji, Shinichiro Miyoshi, Susumu Kanazawa

ANNALS OF NUCLEAR MEDICINE 29 ( 9 ) 757 - 765 2015.11

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

To evaluate the relevance of high-resolution computed tomography (HRCT) findings and fluorine-18-fluorodeoxyglucose (F-18-FDG) uptake for risk stratification of visceral pleural invasion by lung adenocarcinoma.
The HRCT findings and F-18-FDG uptake for lung adenocarcinomas with pleural contact on CT were retrospectively analyzed in 208 consecutive patients (94 females and 114 males; median age, 69.0 years) between January 2009 and December 2013, with institutional review board approval. The HRCT findings and maximum standardized uptake value (SUVmax) were recorded for each patient. Multivariate logistic regression was used for statistical analysis, and subgroup analysis stratified for whole tumor size a parts per thousand currency sign3 cm was also performed.
Multivariate analysis showed that SUVmax [odds ratio (OR) 1.09, 95 % confidence interval (CI) 1.02-1.16, P = 0.014] and obtuse angle (OR 4.14, 95 % CI 1.97-8.74, P < 0.001) were significant independent predictors for visceral pleural invasion. Receiver operating characteristic (ROC) analysis showed that, compared with the multivariate models [area under the curve (Az) 0.819-0.829], SUVmax alone (Az 0.815) was useful in predicting visceral pleural invasion. In the subgroup analysis, multivariate analysis showed that SUVmax (OR 1.29, 95 % CI 1.12-1.50, P = 0.001) and contact length with the pleura (OR 1.13, 95 % CI 1.05-1.22, P = 0.001) were significant independent predictors for visceral pleural invasion. ROC analysis showed that SUVmax alone (Az 0.844) showed similar diagnostic performance to the multivariate models (Az 0.845-0.857).
SUVmax alone and multivariate models including SUVmax are useful for the prediction of visceral pleural invasion by lung adenocarcinoma.

DOI： 10.1007/s12149-015-0999-x

[SIGNIFICANCE OF NONCODING RNA IN SURGERY: NONCODING RNA IN LUNG CANCER]. Reviewed

Yamamoto H, Toyooka S, Maki Y, Soh J, Miyoshi S

Nihon Geka Gakkai zasshi 116 ( 6 ) 374 - 377 2015.11

【ノンコーディングRNAの外科領域における意義】肺癌における意義

山本寛斉, 豊岡伸一, 牧佑歩, 宗淳一, 三好新一郎

日本外科学会雑誌 116 ( 6 ) 374 - 377 2015.11

Language：Japanese Publisher：(一社)日本外科学会

ノンコーディングRNA(non-coding RNA,ncRNA)はタンパク質へ翻訳されずに機能するRNAの総称であるが,近年ノンコーディングRNAの癌における異常が報告されている.特にマイクロRNA(micro-RNA,miRNA)と長鎖ノンコーディングRNA(longnon-coding RNA,lncRNA)はバイオマーカーとしての可能性が示唆されており,肺癌においてもmiRNA-21(miR-21),miR-34,miR-200などのmiRNAやMALAT1,HOTAIR,BANCRなどのlncRNAの発現異常が報告されている.そのため,ncRNAは肺癌の早期診断・予後予測・化学療法や放射線療法の感受性判定に使用されるバイオマーカーや,新規の治療標的として臨床応用することが期待されている.外科医の肺癌治療における役割は,確かな外科手技を手術適応のある肺癌患者に提供することであるが,肺癌治療成績の向上に更に大きく貢献するためには,より鋭敏なスクリーニングテストを用いて肺癌根治手術症例を増やすこと,肺癌手術症例において再発リスクの高い患者を漏らさず濃厚に観察することで再発症例を早期に確実に検出することが必要である.血液検体や肺癌切除検体においてncRNAの解析を行い,新たなバイオマーカーを探究することは一つの方法である.外科医は臨床検体へのアプローチが容易であることから,検体提供のみならず主体的な立場で研究を進めることが望まれる.(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J01065&link_issn=&doc_id=20151202110005&doc_link_id=110010006642&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F110010006642&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib Reviewed

Shinsuke Hashida, Hiromasa Yamamoto, Kazuhiko Shien, Yuichiro Miyoshi, Tomoaki Ohtsuka, Ken Suzawa, Mototsugu Watanabe, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

CANCER SCIENCE 106 ( 10 ) 1377 - 1384 2015.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Afatinib is an irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that is known to be effective against the EGFR T790M variant, which accounts for half of the mechanisms of acquired resistance to reversible EGFR-TKIs. However, acquired resistance to afatinib was also observed in clinical use. Thus, elucidating and overcoming the mechanisms of resistance are important issues in the treatment of non-small cell lung cancer. In this study, we established various afatinib-resistant cell lines and investigated the resistance mechanisms. EGFR T790M mutations were not detected using direct sequencing in established resistant cells. Several afatinib-resistant cell lines displayed MET amplification, and these cells were sensitive to the combination of afatinib plus crizotinib. As a further investigation, a cell line that acquired resistance to afatinib plus crizotinib, HCC827-ACR, was established from one of the MET amplified-cell lines. Several afatinib-resistant cell lines including HCC827-ACR displayed epithelial-to-mesenchymal transition (EMT) features and epigenetic silencing of miR-200c, which is a suppresser of EMT. In addition, these cell lines also exhibited overexpression of ALDH1A1 and ABCB1, which are putative stem cell markers, and resistance to docetaxel. In conclusion, we established afatinib-resistant cells and found that MET amplification, EMT, and stem cell-like features are observed in cells with acquired resistance to EGFR-TKIs. This finding may provide clues to overcoming resistance to EGFR-TKIs.

DOI： 10.1111/cas.12749

Downregulation of TBXAS1 in an iron-induced malignant mesothelioma model Reviewed

Daisuke Minami, Nagio Takigawa, Yuka Kato, Kenichiro Kudo, Hideko Isozaki, Shinsuke Hashida, Daijiro Harada, Nobuaki Ochi, Masanori Fujii, Toshio Kubo, Kadoaki Ohashi, Akiko Sato, Takehiro Tanaka, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Mitsune Tanimoto, Katsuyuki Kiura

CANCER SCIENCE 106 ( 10 ) 1296 - 1302 2015.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Malignant mesothelioma is an aggressive and therapy-resistant neoplasm arising from mesothelial cells. Evidence suggests that the major pathology associated with asbestos-induced mesothelioma is local iron overload. In the present study, we induced iron-induced mesothelioma in rats based on previous reports. Ten Wistar rats were given ferric saccharate and nitrilotriacetate i.p. for 5 days a week. Five of the ten rats exhibited widespread mesotheliomas in the peritoneum and tunica vaginalis. The tumor cells showed positive immunostaining for calretinin, wilms tumor-1, podoplanin and the oxidative DNA marker 8-hydroxy-2-deoxyguanosine. In three of the five rats with mesothelioma, array-based comparative genomic hybridization analysis identified a common chromosomal deletion mapped to the chromosomal 4q31 locus, which encompasses the TBXAS1 gene. Downregulation of the TBXAS1 gene was confirmed using quantitative PCR. TBXAS1 gene expression was also reduced in three of four human malignant pleural mesothelioma cell lines compared with normal bronchial epithelial cells. Immunohistochemistry revealed that TBXAS1 expression was weakly positive and positive in five and three out of eight human malignant mesothelioma samples, respectively. In conclusion, TBXAS1 gene expression was downregulated in rats with iron-induced mesothelioma. The relationship between iron overload and TBXAS1 downregulation should be pursued further.

DOI： 10.1111/cas.12752

ドセタキセル耐性非小細胞肺癌細胞はEGFR-TKIにも交差耐性を示す

Chen Haiyang, 諏澤憲, 橋田真輔, 大塚智明, 渡邉元嗣, 牧祐歩, 山本寛斉, 宗淳一, 佃和憲, 三好新一郎, 豊岡伸一

日本癌学会総会記事 74回 E - 1177 2015.10

REIC/Dkk-3遺伝子治療の胸部悪性腫瘍に対する免疫刺激を介する抗腫瘍効果

諏澤憲, 枝園和彦, 阪口政清, 渡部昌実, 橋田真輔, 宗淳一, 山本寛斉, 牧祐歩, 佃和憲, 那須保友, 公文裕巳, 三好新一郎, 豊岡伸一

日本癌学会総会記事 74回 J - 1224 2015.10

トランスレーショナルリサーチ基礎から臨床応用へ EGFRチロシンキナーゼ阻害剤に対する獲得耐性の機序

豊岡伸一, 諏澤憲, 冨田秀太, 牧佑歩, 山本寛斉, 宗淳一, 三好新一郎

肺癌 55 ( 5 ) 359 - 359 2015.10

鉄誘発ラット悪性中皮腫モデルにおけるTBXAS1遺伝子発現の抑制

南大輔, 瀧川奈義夫, 工藤健一郎, 加藤有加, 磯崎英子, 原田大二郎, 越智宣明, 二宮崇, 久保寿夫, 大橋圭明, 堀田勝幸, 田端雅弘, 豊岡伸一, 谷本光音, 木浦勝行

肺癌 55 ( 5 ) 502 - 502 2015.10

集学的治療非小細胞肺癌術後補助化学療法におけるS-1+CBDCA併用療法とS-1維持療法の多施設共同認容性試験 SLCG1001

岡部和倫, 田尾裕之, 宗淳一, 豊岡伸一, 奥村典仁, 山下素弘, 中田昌男, 片岡正文, 片岡和彦, 中村廣繁, 山下芳典, 園部誠, 吉岡弘鎮, 堀田勝幸, 坂本純一, 三好新一郎, 伊達洋至

肺癌 55 ( 5 ) 388 - 388 2015.10

集学的治療病理病期IA期非小細胞肺癌完全切除例に対するティーエスワン単剤による術後化学療法の無作為化忍容性試験

中田昌男, 宗淳一, 奥村典仁, 中村廣繁, 福田実, 片岡正文, 梶原伸介, 青江基, 片岡和彦, 堀田勝幸, 松尾恵太郎, 豊岡伸一, 伊達洋至

肺癌 55 ( 5 ) 388 - 388 2015.10

T790M変異を含むEGFR遺伝子変異を有する非小細胞肺癌細胞株に対するTAE226の抗腫瘍効果

山本寛斉, 阪口政清, 宗淳一, 佃和憲, 木浦勝行, 猶本良夫, 三好新一郎, 豊岡伸一

日本癌学会総会記事 74回 P - 2193 2015.10

鉄誘発ラット悪性中皮腫モデルにおけるTBXAS1遺伝子発現の抑制

南大輔, 瀧川奈義夫, 加藤有加, 工藤健一郎, 磯崎英子, 二宮崇, 久保寿夫, 大橋圭明, 堀田勝幸, 豊岡伸一, 谷本光音, 木浦勝行

日本癌学会総会記事 74回 P - 1040 2015.10

喀痰を用いたCpGのメチル化検出による非侵襲的なスクリーニングの開発

河合毅, 永坂岳司, 藤智和, 谷口文崇, 戸嶋俊明, 母里淑子, 豊岡伸一, 藤原俊義

日本癌学会総会記事 74回 P - 3314 2015.10

Extended sleeve lobectomy after induction chemoradiotherapy for non-small cell lung cancer Reviewed

Shinichi Toyooka, Junichi Soh, Hiromasa Yamamoto, Masaomi Yamane, Shigeru Hattori, Kazuhiko Shien, Kentaroh Miyoshi, Seiichiro Sugimoto, Takahiro Oto, Shinichiro Miyoshi

SURGERY TODAY 45 ( 9 ) 1121 - 1126 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Extended sleeve lobectomy is a challenging surgery. While induction chemoradiotherapy (ChRT) followed by surgery is one of the therapeutic strategies used for locally advanced non-small cell lung cancer (NSCLC), ChRT can impair the anastomotic healing potential. We herein present our experience with cases who underwent an extended sleeve lobectomy after induction ChRT.
The medical records of patients who underwent a surgery for NSCLC after ChRT were reviewed.
Between December 2007 and January 2013, nine patients underwent an extended sleeve lobectomy; the left lingular division and lower lobe in four patients, the right upper lobe and trachea in one patient, the carina and trachea in one patient, the right middle and lower lobes in one patient, the right upper and middle lobes and carina in one patient and the right upper lobe and superior segment of the lower lobe in one patient. While no postoperative 90-day deaths occurred, one case developed a bronchopleural fistula on postoperative day (POD) 25 and one case developed a bronchovascular fistula on POD 163. No cases of local recurrence developed.
Our experience suggests that an extended sleeve lobectomy after induction ChRT is feasible, but careful patient selection and perioperative management are mandatory.

DOI： 10.1007/s00595-014-1025-y

Ethnicity affects EGFR and KRAS gene alterations of lung adenocarcinoma Reviewed

Junichi Soh, Shinichi Toyooka, Keitaro Matsuo, Hiromasa Yamamoto, Ignacio I. Wistuba, Stephen Lam, Kwun M. Fong, Adi F. Gazdar, Shinichiro Miyoshi

ONCOLOGY LETTERS 10 ( 3 ) 1775 - 1782 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Mutations or copy number gains (CNGs) of the EGFR and KRAS genes are representative alterations in lung adenocarcinomas that are individually associated with patient characteristics such as ethnicity, smoking status and gender. However, the effects of combinations of these genetic alterations have not been statistically examined. The present study analyzed previously examined lung adenocarcinoma cases in Asian (n=166) and non-Asian (n=136) individuals in whom all four EGFR and KRAS alterations had been studied. The polynomial logistic regression models were used following adjustment for gender and smoking status, and using patients without any type of EGFR/KRAS alterations as a reference. Between the two ethnic groups, EGFR CNGs (gEGFR) occurred more frequently than EGFR mutations (mEGFR) (46 vs. 38% in Asians; 21 vs. 10% in non-Asians), whereas KRAS mutations (mKRAS) were more frequent than KRAS CNGs (gKRAS) (13 vs. 7% and 35 vs. 4%, respectively). Additionally, gEGFR and gKRAS occurred significantly more frequently in respective mutant cases, and all EGFR alterations were almost exclusive of all KRAS alterations. The polynomial logistic regression models confirmed that all types of EGFR alterations were significantly more frequent among Asian individuals than among non-Asian individuals, independent of gender and smoking status (odds ratios, 2.36-6.67). KRAS alterations occurred less frequently among Asian individuals than among non-Asian individuals, although a significant difference was not detected. The present study results indicated that the EGFR and KRAS profiles, including mutations and CNGs, differ between Asian and non-Asian individuals with lung adenocarcinoma, suggesting that ethnicity strongly affects the molecular characteristics of lung adenocarcinoma.

DOI： 10.3892/ol.2015.3414

Primary pulmonary melanoma: a report of two cases Reviewed

Mototsugu Watanabe, Hiromasa Yamamoto, Shinsuke Hashida, Junichi Soh, Seiichiro Sugimoto, Shinichi Toyooka, Shinichiro Miyoshi

WORLD JOURNAL OF SURGICAL ONCOLOGY 13 274 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Malignant melanoma is a refractory malignancy with a dismal prognosis. It generally arises from the skin in most cases, and cases of primary pulmonary malignant melanoma are rare and often behave aggressively. We have treated two cases of localized primary pulmonary malignant melanoma using surgical resection. Pulmonary malignant melanomas often metastasize to the brain and liver; one of our cases exhibited metastasis to the cecum at about 8 months after surgery. Because cutaneous melanomas often carry activating mutations in the BRAF gene (V600E), we performed a BRAF mutational analysis using direct sequencing for both of these tumors arising from the lung. However, no BRAF mutations were detected. We detected a p53 mutation, which was thought to be a potential somatic mutation, in one of the two cases using a sequencing panel targeting 20 lung cancer-related genes. Although we also checked the expression of programmed death ligand 1 (PD-L1) on the surface of the tumor cells by immunohistochemical testing, neither of our two cases expressed PD-L1. Further molecular analyses may uncover the characteristics of primary pulmonary malignant melanomas.

DOI： 10.1186/s12957-015-0695-2

TAE226, a Bis-Anilino Pyrimidine Compound, Shows Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells including T790M Mutant Reviewed

Hiromasa Yamamoto, Hiroki Otani, Munenori Takaoka, Masakiyo Sakaguchi, Junichi Soh, Masaru Jida, Tsuyoshi Ueno, Takafumi Kubo, Hiroaki Asano, Kazunori Tsukuda, Katsuyuki Kiura, Shinji Hatakeyama, Eiji Kawahara, Yoshio Naomoto, Shinichiro Miyoshi, Shinichi Toyooka

JOURNAL OF THORACIC ONCOLOGY 10 ( 9 ) S311 - S312 2015.9

Distant Bystander Effect of REIC/Dkk-3 Gene Therapy through Immune System Stimulation in a Murine Model of Thoracic Malignancies Reviewed

Suzawa Ken, Shien Kazuhiko, Huang Peng, Sakaguchi Masakiyo, Watanabe Masami, Hashida Shinsuke, Soh Junichi, Yamamoto Hiromasa, Maki Yuho, Asano Hiroaki, Tsukuda Kazunori, Nasu Yasutomo, Kumon Hiromi, Miyoshi Shinichiro, Toyooka Shinichi

JOURNAL OF THORACIC ONCOLOGY 10 ( 9 ) S599 2015.9

Anti-tumor effect of afatinib, an irreversible EGFR/HER2 dual inhibitor, in lung cancers harboring HER2 oncogene Reviewed

Suzawa Ken, Toyooka Shinichi, Sakaguchi Masakiyo, Ohtsuka Tomoaki, Watanabe Mototsugu, Hashida Shinsuke, Maki Yuho, Yamamoto Hiromasa, Soh Junichi, Asano Hiroaki, Tsukuda Kazunori, Miyoshi Shinichiro

CANCER RESEARCH 75 2015.8

Identification of a novel binding protein playing a critical role in HER2 activation in lung cancer cells Reviewed

Ohtsuka Tomoaki, Sakaguchi Masakiyo, Takata Katsuyoshi, Hashida Shinsuke, Watanabe Mototsugu, Suzawa Ken, Maki Yuho, Yamamoto Hiromasa, Soh Junichi, Asano Hiroaki, Tsukuda Kazunori, Miyoshi Shinichiro, Toyooka Shinichi

CANCER RESEARCH 75 2015.8

Anti-tumor effect of Dasatinib in HER2 positive breast cancer with Trastuzumab resistance Reviewed

Takeda Tatsuaki, Kanzaki Hirotaka, Toyooka Shinichi, Watanabe Mototsugu, Ohtsuka Tomoaki, Suzawa Ken, Hashida Shinsuke, Maki Yuho, Yamamoto Hiromasa, Soh Junichi, Asano Hiroaki, Tsukuda Kazunori, Miyoshi Shinichiro, Kitamura Yoshihisa, Sendo Toshiaki

CANCER RESEARCH 75 2015.8

Simultaneous Multiple Preoperative Localizations of Small Pulmonary Lesions Using a Short Hook Wire and Suture System Reviewed

Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Yusuke Matsui, Seiichiro Sugimoto, Shinichi Toyooka, Takahiro Oto, Shinichiro Miyoshi, Susumu Kanazawa

CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY 38 ( 4 ) 971 - 976 2015.8

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

The aim of the study was to retrospectively evaluate simultaneous multiple hook wire placement outcomes before video-assisted thoracoscopic surgery (VATS).
Thirty-eight procedures were performed on 35 patients (13 men and 22 women; mean age, 59.9 years) with 80 lung lesions (mean diameter 7.9 mm) who underwent simultaneous multiple hook wire placements for preoperative localizations. The primary endpoints were technical success, complications, procedure duration, and VATS outcome; secondary endpoints included comparisons between technical success rates, complication rates, and procedure durations of the 238 single-placement procedures performed. Complications were also evaluated.
In 35 procedures including 74 lesions, multiple hook wire placements were technically successful; in the remaining three procedures, the second target placement was aborted because of massive pneumothorax after the first placement. Although complications occurred in 34 procedures, no grade 3 or above adverse event was observed. The mean procedure duration was 36.4 +/- A 11.8 min. Three hook wires dislodged during patient transport to the surgical suite. Seventy-four successfully marked lesions were resected. Six lesions without hook wires were successfully resected after detection by palpation with an additional mini-thoracotomy or using subtle pleural changes as a guide. The complication rates and procedure durations of multiple-placement procedures were significantly higher (P = 0.04) and longer (P < 0.001) than those in the single-placement group, respectively, while the technical success rate was not significantly different (P = 0.051).
Simultaneous multiple hook wire placements before VATS were clinically feasible, but increased the complication rate and lengthened the procedure time.

DOI： 10.1007/s00270-014-1028-5

【家族性腫瘍学-家族性腫瘍の最新研究動向-】臓器・領域別家族性腫瘍の臨床家族性肺癌

山本寛斉, 牧佑歩, 宗淳一, 三好新一郎, 豊岡伸一

日本臨床 73 ( 増刊6 家族性腫瘍学 ) 433 - 436 2015.8

TAE226, a Bis-Anilino Pyrimidine Compound, Inhibits the EGFR-Mutant Kinase Including T790M Mutant to Show Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells Reviewed

Hiroki Otani, Hiromasa Yamamoto, Munenori Takaoka, Masakiyo Sakaguchi, Junichi Soh, Masaru Jida, Tsuyoshi Ueno, Takafumi Kubo, Hiroaki Asano, Kazunori Tsukuda, Katsuyuki Kiura, Shinji Hatakeyama, Eiji Kawahara, Yoshio Naomoto, Shinichiro Miyoshi, Shinichi Toyooka

PLOS ONE 10 ( 6 ) e0129838 2015.6

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

TAE226, a bis-anilino pyrimidine compound, has been developed as an inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR). In this study, we investigated the effect of TAE226 on non-small-cell lung cancer (NSCLC), especially focusing on the EGFR mutational status. TAE226 was more effective against cells with mutant EGFR, including the T790M mutant, than against cells with wild-type one. TAE226 preferentially inhibited phospho-EGFR and its downstream signaling mediators in the cells with mutant EGFR than in those with wild-type one. Phosphorylation of FAK and IGF-IR was not inhibited at the concentration at which the proliferation of EGFR-mutant cells was inhibited. Results of the in vitro binding assay indicated significant differences in the affinity for TAE226 between the wild-type and L858R (or delE746_A750) mutant, and the reduced affinity of ATP to the L858R (or delE746_A750) mutant resulted in good responsiveness of the L858R (or delE746_A750) mutant cells to TAE226. Of interest, the L858R/T790M or delE746_A750/T790M mutant enhanced the binding affinity for TAE226 compared with the L858R or delE746_A750 mutant, resulting in the effectiveness of TAE226 against T790M mutant cells despite the T790M mutation restoring the ATP affinity for the mutant EGFR close to that for the wild-type. TAE226 also showed higher affinity of about 15-fold for the L858R/T790M mutant than for the wild-type one by kinetic interaction analysis. The antitumor effect against EGFR-mutant tumors including T790M mutation was confirmed in mouse models without any significant toxicity. In summary, we showed that TAE226 inhibited the activation of mutant EGFR and exhibited anti-proliferative activity against NSCLCs carrying EGFR mutations, including T790M mutation.

DOI： 10.1371/journal.pone.0129838

Kissing-stents technique after living-donor lobar lung transplantation Reviewed

Seiichiro Sugimoto, Takahiro Oto, Shinichi Toyooka, Shinichiro Miyoshi

EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY 47 ( 6 ) 1105 - 1106 2015.6

Language：English Publisher：OXFORD UNIV PRESS INC

Stent placement has become common practice for bronchial stenosis (BS) after lung transplantation (LT). Especially, segmental BS after lobar LT requires a complex stenting technique. We describe a case of multiple segmental bronchial stenoses treated by the kissing-stents technique using balloon-expandable metallic stents after living-donor lobar LT. Based on the vascular kissing-stents technique, we simultaneously placed two stents, side by side, in the superior segmental bronchus and the basal segmental bronchus of the right transplanted lobar lung. This technique may represent a valuable option for complex segmental BS after lobar LT.

DOI： 10.1093/ejcts/ezu314

Clinicopathological characteristics and lymph node metastasis pathway of non-small-cell lung cancer located in the left lingular division Reviewed

Kazuhiko Shien, Shinichi Toyooka, Junichi Soh, Jiro Okami, Masahiko Higashiyama, Yoshihisa Kadota, Hajime Maeda, Makio Hayama, Masayuki Chida, Soichiro Funaki, Meinoshin Okumura, Shinichiro Miyoshi

INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY 20 ( 6 ) 791 - 797 2015.6

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

OBJECTIVES: The purpose of this study is to assess the clinicopathological characteristics of non-small-cell lung cancer (NSCLC) occurring in the left lingular division (LLD) in association with a proposal of the LLD-specific regional lymph node stations.
METHODS: Medical records of patients, who underwent complete tumour resection with mediastinal lymph node dissection (MLND) for LLD-NSCLC from 2000 to 2009 in multiple institutions, were retrospectively examined. We analysed patient clinicopathological characteristics and obtained the LLD-specific regional lymph node stations, and then the validity of intraoperative navigation in lymphadenectomy for LLD-NSCLC was investigated.
RESULTS: One hundred and eighty-four LLD-NSCLC patients (97 males and 87 females, and 128 adenocarcinomas and 56 non-adenocarcinomas) were studied. The 5-year overall survival (OS) and disease-free survival (DFS) rates for all LLD-NSCLC patients were 72.9 and 58.3%, respectively. We examined the lymph node metastasis patterns in 42 node-positive tumours. The frequent metastatic lymph node stations were #12u lobar node (n = 22), #5 subaortic node (n = 15) and #11 interlobar node (n = 13) in order. These three node stations were also single metastatic sites in some patients. Metastases to sub-carinal (#7) or inferior mediastinal nodes (#8) were rare. Thus, we assigned the three stations (#5, #11, #12u) as the regional lymph node stations for LLD-NSCLC. If these regional lymph node stations had been examined pathologically during surgery for a total of 160 LLD-NSCLC patients with c-T2N1M0 or lower stage disease, 125 p-N0 and 5 p-N1 patients diagnosed with no metastasis would have been subjected to selective MLND, while 14 p-N1 and all 16 p-N2 patients diagnosed with metastasis would have had complete MLND carried out. As a result, these regional lymph node stations could accurately predict the existence of p-N2 metastasis, and appropriately lead to a selective or complete MLND.
CONCLUSIONS: An intraoperative pathological examination using our proposed LLD-specific regional lymph node stations may accurately diagnose the status of node metastasis, and appropriately lead to selective or complete MLND in LLD-NSCLC patients with c-T2N1M0 or lower stage disease.

DOI： 10.1093/icvts/ivv062

Radiofrequency Ablation of Lung Metastases from Adenoid Cystic Carcinoma of the Head and Neck: Retrospective Evaluation of Nine Patients Reviewed

Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Yusuke Matsui, Shinichi Toyooka, Kazunori Nishizaki, Susumu Kanazawa

JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 26 ( 5 ) 703 - 708 2015.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Purpose: To retrospectively evaluate the outcomes of radiofrequency (RF) ablation of lung metastases from head and neck adenoid cystic carcinoma (ACC).
Materials and Methods: Nine patients (two men and seven women; mean age, 61.6 y) with 45 lung metastases (mean diameter, 1.1 cm; range, 0.4-2.7 cm) from head and neck ACC underwent RF ablation in 30 sessions. Primary endpoints were technical success, technique effectiveness, and procedural complications. Secondary endpoints included overall survival (OS).
Results: RF ablation was technically successful for all 45 metastases. The median tumor follow-up period was 37.1 months (range, 12.9-128.3 mo). Local progression occurred in six tumors, two of which were treated again and subsequently showed complete response. Major complications (pneumothorax requiring chest tube placement) occurred in five sessions (16.7%). The median patient follow-up period was 61.6 months (range, 20.5-134.5 mo). Two patients died of disease progression at 38.9 and 61.6 months after RF ablation, respectively, whereas the other seven remained alive at the end of the study. OS rates from the initial RF ablation were 100% at 3 years and 83.3% at 5 years (mean survival time, 106.4 mo). OS rates from the treatment of the primary site were 100% at 5 years and 62.5% at 10 years (mean survival time, 210.1 mo).
Conclusions: Radiofrequency ablation is an acceptable and effective local treatment for lung metastases from head and neck ACC. However, further study is needed to evaluate its effect on patient survival.

DOI： 10.1016/j.jvir.2014.11.040

Lower lobe origin is a poor prognostic factor in locally advanced non-small-cell lung cancer patients treated with induction chemoradiotherapy. Reviewed International journal

Kazuhiko Shien, Shinichi Toyooka, Junichi Soh, Katsuyuki Hotta, Kuniaki Katsui, Takahiro Oto, Susumu Kanazawa, Katsuyuki Kiura, Hiroshi Date, Shinichiro Miyoshi

Molecular and clinical oncology 3 ( 3 ) 706 - 712 2015.5

Language：English Publishing type：Research paper (scientific journal)

The AIM of this study was to identify prognostic factors in patients receiving trimodality therapy for locally advanced non-small-cell lung cancer (NSCLC). Among patients who underwent induction chemoradiotherapy (CRT) followed by surgery between 1999 and 2011 at our institution, 76 NSCLC patients with clinical (c) N2/3 stage III were enrolled in this retrospective study. Induction CRT consisted of docetaxel and cisplatin with concurrent 40-60 Gy radiation therapy. In total, 76 patients were assessed (53 men and 23 women) with 43 adenocarcinomas and 33 non-adenocarcinomas. Of the 76 patients, 44 had cStage IIIA and 32 had cStage IIIB disease. The primary tumors were located in the right upper lobe (N=33), right middle lobe (N=5), right lower lobe (N=11), left upper lobe (N=20s) and left lower lobe (N=7). For all 76 patients, lower lobe tumors were associated with a significantly shorter overall survival (OS) and disease-free survival (DFS) compared to non-lower lobe tumors (OS, P=0.022; and DFS, P=0.0007). When the analysis was limited to pathologically proven N2/3 disease prior to induction CRT (n=36), lower lobe location, compared to other locations, tended to be a poor prognostic factor (OS, P=0.068; and DFS, P=0.0075). Our results indicated that a lower lobe tumor origin is associated with unfavorable prognosis in NSCLC patients treated with induction CRT, strongly suggesting the significance of appropriate patient selection in order to maximize the benefits of trimodality therapy.

DOI： 10.3892/mco.2015.509

Percutaneous Radiofrequency Ablation of Lung Cancer Presenting as Ground-Glass Opacity Reviewed

Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Yusuke Matsui, Junichi Soh, Shinichi Toyooka, Katsuyuki Kiura, Susumu Kanazawa

CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY 38 ( 2 ) 409 - 415 2015.4

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

We retrospectively evaluated the outcomes of lung cancer patients presenting with ground-glass opacity (GGO) who received radiofrequency ablation (RFA).
Sixteen patients (5 men and 11 women; mean age, 72.6 years) with 17 lung cancer lesions showing GGO (mean long axis diameter, 1.6 cm) underwent a total of 20 percutaneous computed tomography (CT) fluoroscopy-guided RFA sessions, including three repeated sessions for local progression. Lung cancer with GGO was defined as a histologically confirmed malignant pulmonary lesion with a GGO component accounting for > 50 % of the lesion on high-resolution CT. Procedure outcomes were evaluated.
There were no major complications. Pneumothorax occurred in 15 of 20 treatment sessions: 14 were asymptomatic, and 1 required chest tube placement but resolved satisfactorily within 48 h. Minor pulmonary hemorrhage occurred in two and mild pneumonitis in one. The median tumor follow-up period was 61.5 (range 6.1-96.6) months. The effectiveness rates of the primary and secondary techniques were 100 and 100 % at 1 year, 93.3 and 100 % at 2 years, and 78.3 and 92.3 % at 3 years, respectively. The median patient follow-up period was 65.6 (range 6.1-96.6) months. One patient died owing to recurrent other cancer 11.7 months after RFA, whereas the other 15 remained alive. Overall survival and disease-specific survival rates were 93.3 and 100 % at 1 year and 93.3 and 100 % at 5 years, respectively.
RFA for lung cancer with GGO was safe and effective, and resulted in promising survival rates.

DOI： 10.1007/s00270-014-0926-x

悪性胸膜中皮腫におけるDNAコピー数の増加(DNA copy number gains in malignant pleural mesothelioma)

古川公之, 豊岡伸一, 林達朗, 山本寛斉, 宗淳一, 橋田真輔, 枝園和彦, 浅野博昭, 岡部和倫, 佃和憲, 三好新一郎

日本呼吸器外科学会雑誌 29 ( 3 ) O56 - 6 2015.4

局所進行性肺癌に対する胸骨正中切開アプローチの利用可能性(Feasibility of median sternotomy approach for locally advanced lung cancer)

佐藤博紀, 豊岡伸一, 岡田真典, 伊賀徳周, 牧佑歩, 三好健太郎, 山本寛斉, 杉本誠一郎, 宗淳一, 山根正修, 大藤剛宏, 三好新一郎

日本呼吸器外科学会雑誌 29 ( 3 ) O39 - 1 2015.4

胸腔鏡下拡大胸腺摘除術を施行した重症筋無力症の1例

尾山貴徳, 野田卓男, 谷本光隆, 牧佑歩, 宗淳一, 豊岡伸一, 三好新一郎, 柴田敬, 井上拓志, 吉永治美

日本小児外科学会雑誌 51 ( 2 ) 279 - 279 2015.4

局所進行非小細胞肺癌に対する根治的放射線化学療法後手術の治療成績

宗淳一, 豊岡伸一, 諏澤憲, 岡田真典, 牧佑歩, 伊賀徳周, 三好健太郎, 山本寛斉, 杉本誠一郎, 山根正修, 大藤剛宏, 伊達洋至, 三好新一郎

日本呼吸器外科学会雑誌 29 ( 3 ) RO2 - 2 2015.4

EGFR Mutation Testing Practices within the Asia Pacific Region Results of a Multicenter Diagnostic Survey Reviewed

Yasushi Yatabe, Keith M. Kerr, Ahmad Utomo, Pathmanathan Rajadurai, Van Khanh Tran, Xiang Du, Teh-Ying Chou, Ma. Luisa D. Enriquez, Geon Kook Lee, Jabed Iqbal, Shanop Shuangshoti, Jin-Haeng Chung, Koichi Hagiwara, Zhiyong Liang, Nicola Normanno, Keunchil Park, Shinichi Toyooka, Chun-Ming Tsai, Paul Waring, Li Zhang, Rose McCormack, Marianne Ratcliffe, Yohji Itoh, Masatoshi Sugeno, Tony Mok

JOURNAL OF THORACIC ONCOLOGY 10 ( 3 ) 438 - 445 2015.3

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Introduction: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR mutation-positive non-small-cell lung cancer (NSCLC) patients necessitates accurate, timely testing. Although EGFR mutation testing has been adopted by many laboratories in Asia, data are lacking on the proportion of NSCLC patients tested in each country, and the most commonly used testing methods.
Methods: A retrospective survey of records from NSCLC patients tested for EGFR mutations during 2011 was conducted in 11 Asian Pacific countries at 40 sites that routinely performed EGFR mutation testing during that period. Patient records were used to complete an online questionnaire at each site.
Results: Of the 22,193 NSCLC patient records surveyed, 31.8% (95% confidence interval: 31.2%-32.5%) were tested for EGFR mutations. The rate of EGFR mutation positivity was 39.6% among the 10,687 cases tested. The majority of samples were biopsy and/or cytology samples (71.4%). DNA sequencing was the most commonly used testing method accounting for 40% and 32.5% of tissue and cytology samples, respectively. A pathology report was available only to 60.0% of the sites, and 47.5% were not members of a Quality Assurance Scheme.
Conclusions: In 2011, EGFR mutation testing practices varied widely across Asia. These data provide a reference platform from which to improve the molecular diagnosis of NSCLC, and EGFR mutation testing in particular, in Asia.

DOI： 10.1097/JTO.0000000000000422

Pneumocephalus and Chylothorax Complicating Vertebrectomy for Lung Cancer Reviewed

Seiichiro Sugimoto, Masato Tanaka, Ken Suzawa, Hitoshi Nishikawa, Shinichi Toyooka, Takahiro Oto, Toshifumi Ozaki, Shinichiro Miyoshi

ANNALS OF THORACIC SURGERY 99 ( 4 ) 1425 - 1428 2015.3

Language：English Publisher：ELSEVIER SCIENCE INC

Pneumocephalus is a rare, but potentially fatal complication of thoracic surgery. We describe a case of successful management of pneumocephalus complicated by persistent chylothorax developing after en bloc partial vertebrectomy performed after induction chemoradiotherapy for lung cancer invading the spine. Surgical treatment should be considered for pneumocephalus complicated by any condition requiring persistent chest drainage. (C) 2015 by The Society of Thoracic Surgeons

DOI： 10.1016/j.athoracsur.2014.05.098

Hsp90 inhibitor NVP-AUY922 enhances the radiation sensitivity of lung cancer cell lines with acquired resistance to EGFR-tyrosine kinase inhibitors Reviewed

Shinsuke Hashida, Hiromasa Yamamoto, Kazuhiko Shien, Tomoaki Ohtsuka, Ken Suzawa, Yuho Maki, Masashi Furukawa, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Susumu Kanazawa, Shinichi Toyooka

ONCOLOGY REPORTS 33 ( 3 ) 1499 - 1504 2015.3

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is a critical issue that needs to be overcome in the treatment of patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. EGFR and AKT are client proteins of the 90-kDa heat shock protein (Hsp90). Therefore, it was hypothesized that the use of Hsp90 inhibitors might allow the resistance to EGFR-TKIs to be overcome. Furthermore, Hsp90 inhibitors are known to function as radiosensitizers in various types of cancer. In the present study, we evaluated the radiosensitizing effect of the novel Hsp90 inhibitor, NVP-AUY922 (AUY), on NSCLC cell lines harboring EGFR activating mutations and showing acquired resistance to EGFR-TKIs via any of several mechanisms. We used HCC827 and PC-9, which are NSCLC cell lines harboring EGFR exon 19 deletions, and gefitinib-resistant sublines derived from the same cell lines with T790M mutation, MET amplification or stem-cell like properties. AUY was more effective against the gefitinib-resistant sublines with T790M mutation and MET amplification than against the parental cell lines, although the subline with stem cell-like properties showed more than a 10-fold higher resistance to AUY than the parental cell line. AUY exerted a significant radiosensitizing effect on the parental cell line and the MET-amplified subline through inducing G(2)/M arrest and inhibition of non-homologous end joining (NHEJ). In contrast, the radiosensitizing effect of AUY was limited on the subline with stem cell-like properties, in which it did not induce G(2)/M arrest or inhibition of NHEJ. In conclusion, combined inhibition of Hsp90 plus radiation was effective, and therefore a promising treatment alternative for overcoming major EGFR-TKI resistance, such as that induced by T790M mutation or MET amplification. However, other approaches are required to overcome minor resistance to EGFR-TKIs, such as that observed in cells with stem cell-like properties.

DOI： 10.3892/or.2015.3735

Long-Term Survival following Percutaneous Radiofrequency Ablation of Colorectal Lung Metastases Reviewed

Yusuke Matsui, Takao Hiraki, Hideo Gobara, Toshihiro Iguchi, Hiroyasu Fujiwara, Takeshi Nagasaka, Shinichi Toyooka, Susumu Kanazawa

JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 26 ( 3 ) 303 - 310 2015.3

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Purpose: To retrospectively evaluate long-term survival outcomes of radiofrequency (RF) ablation of colorectal lung metastases and evaluate factors associated with improved survival.
Materials and Methods: Eighty-four patients (46 male and 38 female; median age, 65 y) with 172 colorectal lung metastases (median size, 1.2 cm) underwent 113 RF ablation sessions. Thirteen patients had viable extrapulmonary recurrences at the time of RF ablation. The primary endpoint was patient survival. Prognostic factors associated with survival were determined by univariate and multivariate analyses. Secondary endpoints were local tumor progression and adverse events (per National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0).
Results: During follow-up (median duration, 37.5 mo), 36 patients (42.9%) died. The estimated overall survival (OS) rates were 95.2%, 65.0%, and 51.6% at 1, 3, and 5 years, respectively (median OS time, 67.0 mo). Multivariate analysis revealed that a carcinoembryonic antigen (CEA) level of at least 5 ng/mL before RE ablation (P = .03) and the presence of viable extrapulmonary recurrences at the time of RF ablation (P = .001) were independent negative prognostic factors. The local tumor progression rate was 14.0% (24 of 172 tumors). Grade 3 adverse events were observed after two sessions (1.8%), and grade 415 adverse events were not observed.
Conclusions: RF ablation of colorectal lung metastases provided favorable long-term survival With a low incidence of severe adverse events. Independent prognostic factors were a high CEA level before RF ablation and the presence of viable extrapulmonary recurrences at the time of RF ablation.

DOI： 10.1016/j.jvir.2014.11.013

Transfissural Route Used for Preoperative Localization of Small Pulmonary Lesions with a Short Hook Wire and Suture System Reviewed

Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Yusuke Matsui, Seiichiro Sugimoto, Shinichi Toyooka, Takahiro Oto, Shinichiro Miyoshi, Susumu Kanazawa

CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY 38 ( 1 ) 222 - 226 2015.2

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

We retrospectively evaluated the results of the transfissural route for preoperative localization with a short hook wire and suture system for video-assisted thoracoscopic surgery (VATS).
Eleven patients with 11 tumors underwent CT-guided transfissural placement of a hook wire before VATS. This route was selected for all patients, because the distance between the tumor and interlobar fissure was much shorter than the required distance traversed using the conventional approach. Complications were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.
The hook wire was successfully placed using the transfissural route in all but one case. Of these ten successful placements, two tumors needed a second puncture for optimal placement, because the CT scan showed that the first hook wire was not properly placed in the lung. In one patient, we did not attempt replacement after the first placement was incorrect. In ten successful procedures, the mean distance traversed in the parenchyma of the unaffected lung lobe was 27.9 mm. The distance between the pleura and placed hook wire was significantly shorter than the estimated distance between the pleura and hook wire using the conventional route (mean 16.3 vs. 40.9 mm; P = 0.0002). Grade 1 adverse events occurred (11 pneumothoraxes and 4 pulmonary hemorrhages). No grade 2 or higher adverse event was observed.
The transfissural route used for preoperative localization before VATS is useful for selected patients because this route may allow for more limited lung parenchyma resection.

DOI： 10.1007/s00270-014-0862-9

呼吸器外科領域における周術期管理について

宗淳一, 豊岡伸一, 足羽孝子, 小林求, 福田智美, 村田尚道, 井上真一郎, 牧佑歩, 三好新一郎

臨床呼吸生理 47 21 - 25 2015.2

Language：Japanese Publisher：臨床呼吸生理研究会

呼吸器外科領域における周術期管理について検討した。術前評価不足や抗凝固薬中止忘れなど、術前評価や準備不足により中止となった症例はPERIO導入により減少した。PERIO群は従来群に比較して有意に術後歩行開始日数が早かった。63歳以上呼吸器外科手術症例において、嚥下チーム介入群では術後肺炎の発症が減少した。せん妄発症率はD-mac群で有意に低下し、せん妄発症リスク因子数が多い症例でせん妄発症予防効果が顕著であった。特に75歳以上の患者で有意な低下を認めた。82歳以上の原発性肺癌手術症例における包括評価方式(DPC)と出来高方式による入院費差額の年次推移を比較し、PERIO、嚥下チーム、せん妄対策チームの導入により、経時的にDPC差額が増額した。

Validity of using lobe-specific regional lymph node stations to assist navigation during lymph node dissection in early stage non-small cell lung cancer patients Reviewed

Shinichiro Miyoshi, Kazuhiko Shien, Shinichi Toyooka, Kentaroh Miyoshi, Hiromasa Yamamoto, Seiichiro Sugimoto, Junichi Soh, Makio Hayama, Masaomi Yamane, Takahiro Oto

SURGERY TODAY 44 ( 11 ) 2028 - 2036 2014.11

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Purpose The validity of our proposed lobe-specific regional lymph node stations (LSRLNS) was evaluated as a method for navigation during lymphadenectomy in patients with early stage non-small cell lung cancer (NSCLC).
Methods A total of 725 NSCLC patients with c-T2N1M0 or less extensive disease who had undergone a curative operation with complete mediastinal lymph node dissection (MLND) were studied. The LSRLNS were #2, #3, #4 and #10 for the right upper lobe, #11i, #11s, #7 and #8 for the right lower lobe, #4, #5 and #6 for the left superior division, #11, #5 and #7 for the left lingular division and #11, #7 and #8 for the left lower lobe.
Results If the LSRLNS were used for pathological examinations during surgery, 599 p-N0 and 39 p-N1 patients diagnosed with no metastasis would have been subjected to a selective MLND, while 20 p-N1 and 65 p-N2 patients who had a diagnosis of metastasis would have been navigated to a complete MLND. Two p-N2 patients with a diagnosis of no metastasis would have inappropriately undergone a selective MLND, resulting in the false negative rate at 0.3 %.
Conclusion Intra-operative pathological examination using our LSRLNS may accurately reveal the status of metastasis, and appropriately lead to a selective or complete MLND in patients with c-T2N1M0 or less extensive disease.

DOI： 10.1007/s00595-013-0772-5

【肺癌:最新の分子標的療法】肺癌のマイクロRNA異常

牧佑歩, 山本寛斉, 宗淳一, 三好新一郎, 豊岡伸一

Pharma Medica 32 ( 11 ) 49 - 52 2014.11

A New Human Lung Adenocarcinoma Cell Line Harboring the EML4-ALK Fusion Gene Reviewed

Hideko Isozaki, Masayuki Yasugi, Nagio Takigawa, Katsuyuki Hotta, Eiki Ichihara, Akihiko Taniguchi, Shinichi Toyooka, Shinsuke Hashida, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 44 ( 10 ) 963 - 968 2014.10

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Objective: The echinoderm microtubule associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was identified in patients with non-small cell lung cancer. To the best of our knowledge, there are only three cell lines harboring the EML4-ALK fusion gene, which have contributed to the development of therapeutic strategies. Therefore, we tried to establish a new lung cancer cell line harboring EML4-ALK.
Methods: A 61-year-old Japanese female presented with chest discomfort. She was diagnosed with left lung adenocarcinoma with T4N3M1 Stage IV. Although she was treated with chemotherapy, her disease progressed with massive pleural effusion. Because the EML4-ALK rearrangement was found in a biopsied specimen using fluorescence in situ hybridization, she was treated with crizotinib. She did well for 3 months.
Results: Tumor cells were obtained from the malignant pleural effusion before treatment with crizotinib. Cells continued to proliferate substantially for several weeks. The cell line was designated ABC-11. The EML4-ALK fusion protein and genes were identified in ABC-11 cells using fluorescence in situ hybridization and immunohistochemistry, respectively. ABC-11 cells were sensitive to crizotinib and next-generation ALK inhibitors (ceritinib and AP26113), as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Phosphorylated ALK protein and its downstream signaling were suppressed by treatment with crizotinib in western blotting. Furthermore, we could transplant ABC-11 cells subcutaneously into BALB/c nu/nu mice.
Conclusions: We successfully established a new lung adenocarcinoma cell line harboring the EML4-ALK fusion gene. This cell line could contribute to future research of EML4-ALK-positive lung cancer both in vivo and in vitro.

DOI： 10.1093/jjco/hyu110

Percutaneous Radiofrequency Ablation for Pulmonary Metastases from Esophageal Cancer: Retrospective Evaluation of 21 Patients Reviewed

Yusuke Matsui, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Toshihiro Iguchi, Yasuhiro Shirakawa, Toshiyoshi Fujiwara, Shinichi Toyooka, Susumu Kanazawa

JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 25 ( 10 ) 1566 - 1572 2014.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Purpose: To evaluate retrospectively Outcomes after radiofrequency (RF) ablation for pulmonary Metastases from esophageal cancer.
Materials and Methods: This study included 21 consecutive patients who met inclusion. criteria (all men; mean age, 66.0 y) and had pulmonary metastases from esophageal cancer. There were 31 tumors (mean size, 1.7 cm) that Were treated with 27 planned ablation sessions. At the initial RF ablation sessions, 3 patients had viable extrapulmonary recurrences, and 18 patients had Viable recurrences confined to the lung. Primary study endpoints included patient survival and the determination of prognostic factors. Secondary endpoints included local efficacy and safety of the treatment. The log-rank test was used to identify prognostic factors. Adverse events Were evaluated according to,the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.
Results: Median follow-up duration after the initial RF ablation was 22.4 months (range, 6.2-76.1 mo). Estimated overall survival rates were 85.7% at 1 year, 54.8% at 2 years, and 38.4% at 3 years after the initial RF ablation session. The presence of viable extrapulmonary recurrences at the initial RF ablation session was an unfavorable prognostic factor (P < .001). Local tumor progression was observed in 25.8% (8 of 31) of tumors and occurred 2.6-10.0 months (median, 4.8 mo) after RP ablation. Grade 3 adverse events occurred in 7.4% (2 of 27) of sessions, including pleural effusion requiring chest tube placement and pneumoderma requiring surgical intervention. No grade 4 or greater adverse events occurred.
Conclusions: RF ablation is a promising treatment option for patients with pulmonary metastases from esophageal cancer.

DOI： 10.1016/j.jvir.2014.06.030

Novel germline G660D mutation in HER2 gene detected by whole-exome sequencing can predispose a patient to developing familial lung adenocarcinoma Reviewed

Hiromasa Yamamoto, Koichiro Higasa, Masakiyo Sakaguchi, Kazuhiko Shien, Junichi Soh, Koichi Ichimura, Masashi Furukawa, Shinsuke Hashida, Kazunori Tsukuda, Nagio Takigawa, Keitaro Matsuo, Katsuyuki Kiura, Sinichiro Miyoshi, Fumihiko Matsuda, Shinichi Toyooka

CANCER RESEARCH 74 ( 19 ) 2014.10

アファチニブ耐性を獲得した非小細胞肺癌細胞株の分子生物学的特徴(The molecular characters of acquired resistant non-small cell lung cancer cells to afatinib)

橋田真輔, 枝園和彦, 渡邉元嗣, 大塚智昭, 諏澤憲, 牧佑歩, 山本寛斉, 宗淳一, 浅野博昭, 佃和憲, 三好新一郎, 豊岡伸一

日本癌学会総会記事 73回 J - 1044 2014.9

Field Cancerizationによる非小細胞肺癌発現遺伝子の探索(Analysis of molecular alterations in non-small cell lung cancers based on Field cancerization effect)

牧佑歩, 渡辺元嗣, 大塚智昭, 諏澤憲, 橋田真輔, 山本寛斉, 宗淳一, 浅野博昭, 佃和憲, 豊岡伸一, 三好新一郎

日本癌学会総会記事 73回 J - 1068 2014.9

がんマーカー、サイトケラチン19(CK19)機能の新展開 HER2活性化におけるCK19の役割(Critical role of Cytokeratin-19 in an oncogenic activation of HER2)

大塚智昭, 阪口政清, 渡邉元嗣, 諏澤憲, 橋田真輔, 牧佑歩, 山本寛斉, 宗淳一, 浅野博昭, 佃和憲, 三好新一郎, 豊岡伸一

日本癌学会総会記事 73回 E - 2071 2014.9

新規HER2膜貫通部領域遺伝子変異の機能解析(Novel HER2 mutations in transmembrane dmain result in constitutive autophosphorylation of HER2)

諏澤憲, 阪口政清, 山本寛斉, 宗淳一, 牧佑歩, 橋田真輔, 大塚智昭, 渡邉元嗣, 浅野博昭, 佃和憲, 三好新一郎, 豊岡伸一

日本癌学会総会記事 73回 P - 1328 2014.9

家族性・孤発性肺腺癌におけるHER2膜貫通領域の新規遺伝子変異(Novel functional mutations in the transmembrane domain of HER2 gene in familial and sporadic lung adenocarcinomas)

山本寛斉, 日笠幸一郎, 阪口政清, 枝園和彦, 宗淳一, 市村浩一, 佃和憲, 瀧川奈義夫, 松尾恵太郎, 木浦勝行, 三好新一郎, 松田文彦, 豊岡伸一

日本癌学会総会記事 73回 E - 2012 2014.9

Drug Resistance to EGFR Tyrosine Kinase Inhibitors for Non-small Cell Lung Cancer Reviewed

Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Shinichiro Miyoshi, Shinichi Toyooka

ACTA MEDICA OKAYAMA 68 ( 4 ) 191 - 200 2014.8

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

Non-small cell lung cancer (NSCLC) harboring an activating mutation within the epidermal growth factor receptor (EGFR) was defined as a clinically distinct molecular group. These lesions show oncogene addiction to EGFR and dramatic responses to the EGFR tyrosine kinase inhibitors (TKIs). Several large Phase III trials have shown that EGFR-TKIs improved the progression-free survival of patients with EGFR mutant NSCLC compared to conventional chemotherapy. However, the long-term effectiveness of EGFR-TKIs is usually limited because of acquired drug resistance. To overcome this resistance to EGFR-TKIs, it will be essential to identify the specific mechanisms underlying the resistance. Many investigators have attempted to identify the mechanisms using preclinical models and drug-resistant clinical samples. As a result, several mechanisms have been showed to be responsible for the resistance, but not all of the relevant mechanisms have been uncovered. In this review, we provide an overview of mechanisms underlying drug-resistance to EGFR-TKIs, focusing on results obtained with preclinical models, and we present some possible strategies to overcome the EGFR-TKI resistance.

DOI： 10.18926/AMO/52785

Presence of the minor EGFR T790M mutation is associated with drug-sensitive EGFR mutations in lung adenocarcinoma patients Reviewed

Shinsuke Hashida, Junichi Soh, Shinichi Toyooka, Tomoaki Tanaka, Masashi Furukawa, Kazuhiko Shien, Hiromasa Yamamoto, Hiroaki Asano, Kazunori Tsukuda, Koichi Hagiwara, Shinichiro Miyoshi

ONCOLOGY REPORTS 32 ( 1 ) 145 - 152 2014.7

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

The T790M mutation in the epidermal growth factor receptor (EGFR) gene is known to be associated with the acquired resistance of lung adenocarcinoma patients to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). The minor T790M mutant allele is occasionally detected in EGFR-TKI-naive tumor samples, yet findings concerning the clinical impact of the minor T790M mutation vary among previous studies. In the present study, we assessed the clinical impact of the minor T790M mutation using a novel, highly sensitive assay combining high-resolution melting (HRM), mutant-enriched PCR and co-amplification at a lower denaturation temperature (COLD)-PCR. We determined the T790M mutational status in 146 surgically resected lung adenocarcinomas without a history of EGFR-TKI treatment using mutant-enriched COLD-HRM (MEC-HRM) and standard HRM assays. The sensitivities of the MEC-HRM and standard HRM assays for the detection of T790M-mutant alleles among wild-type alleles were 0.01 and 10%, respectively. Although the T790M mutation was not detected using a standard HRM assay, we identified 19 (13%) T790M mutations using the MEC-HRM assay and defined these 19 mutations as minor T790M mutations. The proportion of T790M alleles was <0.1% in 17 (84%) of the 19 samples. Multivariate analyses revealed that a minor T790M mutation was significantly associated with the presence of EGFR exon 19 deletions or the L858R mutation (both of which are drug-sensitive EGFR mutations) (P=0.04). In conclusion, the minor EGFR T790M mutations were present in 13% of EGFR-TKI-naive surgically resected lung adenocarcinomas and were associated with drug-sensitive EGFR mutations.

DOI： 10.3892/or.2014.3197

小児がん治療のUp to Date AYA世代のがんをどう治療するか? 稀少がん肉腫の新治療戦略水平分業型治療連携とパゾパニブ血管新生阻害剤による分子標的治療

高橋克仁, 山村倫子, 冨田裕彦, 矢嶋淳, 寺岡慧, 波多江亮, 大野烈士, 宗淳一, 山本寛斉, 豊岡伸一, 小池幸宏, 烏野隆博, 小山隆文, 楢原啓之, 大山優

日本癌治療学会誌 49 ( 3 ) 764 - 764 2014.6

アスベスト問題予防・診断・治療を科学する悪性胸膜中皮腫におけるマイクロRNA異常

豊岡伸一, 宗淳一, 橋田真輔, 山本寛斉, 牧祐歩, 三好新一郎

日本衛生学雑誌 69 ( Suppl. ) S115 - S115 2014.5

A case of carcinoma showing thymus-like differentiation with a rapidly lethal course Reviewed

Tomohiro Nogami, Naruto Taira, Shinichi Toyooka, Takehiro Tanaka, Taeko Mizoo, Takayuki Iwamoto, Tadahiko Shien, Junichi Soh, Shinichiro Miyoshi, Hiroyoshi Doihara

Case Reports in Oncology 7 ( 3 ) 840 - 844 2014.4

Language：English Publishing type：Research paper (scientific journal) Publisher：S. Karger AG

A 55-year-old woman underwent a total thyroidectomy for carcinoma showing thymus-like differentiation (CASTLE). The patient was referred to our hospital after the tumor was found to have directly invaded the cervical esophagus and the entire circumference of the trachea. A total thyroidectomy was performed, followed by end-to-end anastomosis of the trachea, suprahyoid release and dissection of bilateral pulmonary ligaments. No major complications, including anastomotic dehiscence or stenosis, were observed. The patient experienced some swallowing disturbances and hoarseness during the perioperative period but fully recovered. Radiotherapy to the neck was performed as an adjuvant therapy. Eleven months after surgery, lower back pain and right leg numbness developed and led to gait inability. Multiple lung and bone recurrences were observed, but no local recurrence. Palliative radiotherapy to the bone metastasis was performed. The patient died of pleural metastasis 14 months after the initial diagnosis of CASTLE.

DOI： 10.1159/000370306

Massive Subcutaneous and Mediastinal Emphysema with Little Pneumothorax Treated by Surgery after Pulmonary Radiofrequency Ablation Reviewed

Yusuke Konishi, Hiromasa Yamamoto, Takao Hiraki, Junichi Soh, Shinichi Toyooka, Susumu Kanazawa, Shinichiro Miyoshi

CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY 37 ( 2 ) 548 - 551 2014.4

Hereditary Lung Cancer Syndrome Targets Never Smokers with Germline EGFR Gene T790M Mutations Reviewed

Adi Gazdar, Linda Robinson, Dwight Oliver, Chao Xing, William D. Travis, Junichi Soh, Shinichi Toyooka, Lori Watumull, Yang Xie, Kemp Kernstine, Joan H. Schiller

JOURNAL OF THORACIC ONCOLOGY 9 ( 4 ) 456 - 463 2014.4

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Introduction: Hereditary lung cancer syndromes are rare, and T790M germline mutations of the epidermal growth factor receptor (EGFR) gene predispose to the development of lung cancer. The goal of this study was to determine the clinical features and smoking status of lung cancer cases and unaffected family members with this germline mutation and to estimate its incidence and penetrance.
Methods: We studied a family with germline T790M mutations over five generations (14 individuals) and combined our observations with data obtained from a literature search (15 individuals).
Results: T790M germline mutations occurred in approximately 1% of non-small-cell lung cancer cases and in less than one in 7500 subjects without lung cancer. Both sporadic and germline T790M mutations were predominantly adenocarcinomas, favored female gender, and were occasionally multifocal. Of lung cancer tumors arising in T790M germline mutation carriers, 73% contained a second activating EGFR gene mutation. Inheritance was dominant. The odds ratio that T790M germline carriers who are smokers will develop lung cancer compared with never smoker carriers was 0.31 (p = 6.0E-05). There was an overrepresentation of never smokers with lung cancer with this mutation compared with the general lung cancer population (p = 7.4E-06).
Conclusion: Germline T790M mutations result in a unique hereditary lung cancer syndrome that targets never smokers, with a preliminary estimate of 31% risk for lung cancer in never smoker carriers, and this risk may be lower for heavy smokers. The resultant cancers share several features and differences with lung cancers containing sporadic EGFR mutations.

DOI： 10.1097/JTO.0000000000000130

Wedge Resection of the Bronchial Corner at the Bifurcation of the Lobar Bronchi for a Low-Grade Bronchial Tumor Reviewed

Hiromasa Yamamoto, Shinichi Toyooka, Shinichiro Miyoshi

THORACIC AND CARDIOVASCULAR SURGEON 62 ( 2 ) 181 - 183 2014.3

Language：English Publishing type：Research paper (scientific journal) Publisher：GEORG THIEME VERLAG KG

We experienced a case of wedge resection of the bronchus for a bronchial carcinoid of the left upper bronchus located near the bifurcation of the upper and lower lobar bronchi. Bronchial resection was performed longitudinally including the bronchial corner of the upper and lower lobar bronchi, and the length of resected bronchus from the bronchial corner to distant sites was made nearly equal. The presented procedure is useful as a parenchyma-preserving bronchial resection.

DOI： 10.1055/s-0032-1330924

Asymptomatic but Functional Paraganglioma of the Posterior Mediastinum Reviewed

Ken Suzawa, Hiromasa Yamamoto, Koichi Ichimura, Shinichi Toyooka, Shinichiro Miyoshi

ANNALS OF THORACIC SURGERY 97 ( 3 ) 1077 - 1080 2014.3

Language：English Publisher：ELSEVIER SCIENCE INC

A 72-year-old woman was referred to our hospital because of a posterior mediastinal tumor. On the basis of detailed imaging tests, including I-123-metaiodobenzylguanidine single photon emission computed tomography-computed tomography, and elevated values of catecholamines in the plasma and urine, the tumor was diagnosed as a functional mediastinal paraganglioma even in the absence of symptoms. After preoperative blood pressure control, surgical resection was performed. During the operation, the systemic blood pressure increased transiently as a result of surgical manipulation of the tumor. Soon after the tumor was removed, the patient conversely experienced hypotension. The postoperative course was uneventful, and pathologic diagnosis revealed a paraganglioma. (C) 2014 by The Society of Thoracic Surgeons

DOI： 10.1016/j.athoracsur.2013.06.100

Use of a vessel sealing system versus conventional electrocautery for lung parenchymal resection: a comparison of the clinicopathological outcomes in porcine lungs Reviewed

Seiichiro Sugimoto, Shinichi Toyooka, Norichika Iga, Masashi Furukawa, Ryujiro Sugimoto, Kazuhiko Shien, Hitoshi Nishikawa, Junichi Soh, Masaomi Yamane, Takahiro Oto, Shinichiro Miyoshi

SURGERY TODAY 44 ( 3 ) 540 - 545 2014.3

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

LigaSure, a vessel sealing system, has been shown to have excellent hemostatic properties; however, its use for lung parenchymal resection has been limited. We herein examined the hemostatic properties and potential for inducing histological lung injury of the LigaSure system in non-anatomic pulmonary resection to estimate the feasibility of its clinical application.
Non-anatomic pulmonary wedge resections of the right cranial, middle, and caudal lobes were performed in four pigs using the LigaSure system (Group A) or electrocautery (Group B). In each resection, the resection time, blood loss, and weight of the resected lung were measured. The thermal effect on the lung tissue was examined by means of intraoperative thermography and histology.
A total of 12 lung wedge resections were performed in each group. For an equivalent length of operation and weight of the resected lung parenchyma, Group A showed significantly lower blood loss and lower maximum and minimum temperatures of the lung tissue, as assessed by thermography, than Group B. The degree of thermal injury as estimated by a histological examination was lower in Group A than in Group B.
Our study suggests that the LigaSure system may be superior to conventional electrocautery, indicating its clinical usefulness for non-anatomic pulmonary resection.

DOI： 10.1007/s00595-013-0545-1

Detection of airway ischaemic damage after lung transplantation by using autofluorescence imaging bronchoscopy Reviewed

Norichika Iga, Takahiro Oto, Masanori Okada, Masaaki Harada, Hitoshi Nishikawa, Kentaroh Miyoshi, Shinji Otani, Seiichiro Sugimoto, Masaomi Yamane, Shinichi Toyooka, Shinichiro Miyoshi

EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY 45 ( 3 ) 509 - 513 2014.3

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS INC

OBJECTIVES: Airway complications related to ischaemia are a major cause of morbidity after lung transplantation. Early detection of airway ischaemia and optimal management of the anastomotic site could reduce the risk of airway complications. Autofluorescence imaging (AFI) bronchoscopy has been increasingly recognized as an effective technique for detecting abnormal mucosal thickening. The aim of this study was to investigate whether AFI bronchoscopy can facilitate the detection of airway ischaemic damage in lung transplant patients.
METHODS: Twenty Landrace pigs were used to create a tracheal autotransplantation model. A four-ring length of trachea was excised and implanted orthotopically. The tracheal autograft was observed on postoperative days 0, 2, 4 and 7 with AFI bronchoscopy. The extent and origin of graft autofluorescence were examined using histology and measured according to fluorescence intensity.
RESULTS: The lesions on the tracheal autografts appeared as bright green fluorescence on AFI bronchoscopy. On confocal fluorescence microscopy, high-intensity green fluorescence was observed in the elastin fibre layer of the submucosa. The fluorescence intensity of elastin was significantly higher in the graft showing fluorescence than the graft that did not show fluorescence and that at the control site.
CONCLUSIONS: Bright green fluorescence was seen in an elastin fibre layer in the submucosa, which was likely a result of epithelial sloughing. There is a close relationship between the bright green fluorescence pattern observed using AFI bronchoscopy and airway ischaemic damage. We conclude that AFI bronchoscopy may detect airway ischaemic damage after lung transplantation.

DOI： 10.1093/ejcts/ezt437

気管支鏡検査で診断し外科的切除を行った肺原発悪性黒色腫の1例

萱谷紘枝, 南大輔, 渡邉元嗣, 山本寛斉, 宗淳一, 久保寿夫, 堀田勝幸, 田端雅弘, 豊岡伸一, 三好新一郎, 谷本光音, 木浦勝行

気管支学 36 ( 2 ) 208 - 208 2014.3

Preclinical Evaluation of MicroRNA-34b/c Delivery for Malignant Pleural Mesothelioma Reviewed

Tsuyoshi Ueno, Shinichi Toyooka, Takuya Fukazawa, Takafumi Kubo, Junichi Soh, Hiroaki Asano, Takayuki Muraoka, Norimitsu Tanaka, Yuho Maki, Kazuhiko Shien, Masashi Furukawa, Masakiyo Sakaguchi, Hiromasa Yamamoto, Kazunori Tsukuda, Shinichiro Miyoshi

ACTA MEDICA OKAYAMA 68 ( 1 ) 23 - 26 2014.2

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

The microRNA-34s (miR-34s) have p53 response elements in their 5'-flanking regions and demonstrate tumor-suppressive functions. In malignant pleural mesothelioma (MPM), we previously reported that expression of miR-34b and miR-34c (miR-34b/c) was frequently downregulated by methylation in MPM cell lines and primary tumors. The forced overexpression of miR-34b/c showed significant antitumor effects with the induction of apoptosis in MPM cells. In this study, we examined the in vivo antitumor effects of miR-34b/c using adenovirus vector on MPM. We subcutaneously transplanted NCI-H290, a human MPM cell line, into BALB/C mice and injected adenovirus vector expressing miR-34b/c, luciferase driven by the cytomegalovirus promoter (Ad-miR-34b/c or Ad-Luc), or PBS control into tumors over 5mm in diameter. A statistically significant growth inhibition of the tumor volume was observed in the Ad-miR-34b/c group from day 6 onward compared to the Ad-Luc group. The inhibition rate of Ad-miR-34b/c, compared to the tumor volume treated with Ad-Luc, was 58.6% on day 10 and 54.7% on day13. Our results indicate that adenovirus-mediated miR-34b/c gene therapy could be useful for the clinical treatment of MPM.

DOI： 10.18926/AMO/52140

Anti-Cancer Effects of REIC/Dkk-3-encoding Adenoviral Vector for the Treatment of Non-small Cell Lung Cancer Reviewed

Kazuhiko Shien, Norimitsu Tanaka, Masami Watanabe, Junichi Soh, Masakiyo Sakaguchi, Keitaro Matsuo, Hiromasa Yamamoto, Masashi Furukawa, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Nam-Ho Huh, Shinichiro Miyoshi, Hiromi Kumon, Shinichi Toyooka

PLOS ONE 9 ( 2 ) e87900 2014.2

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Objectives: REIC/Dkk-3 is down-regulated in a broad range of human cancer cells and is considered to function as a tumor suppressor. We previously reported that REIC/Dkk-3-expressing adenovirus vector (Ad-REIC) induced endoplasmic reticulum (ER) stress and cancer-specific apoptosis in human prostate cancer. In this study, we examined the therapeutic impact of Ad-REIC on non-small cell lung cancer (NSCLC).
Materials and Methods: We examined the anti-tumor effect of Ad-REIC on 25 NSCLC cell lines in vitro and A549 cells in vivo. Two of these cell lines were artificially established as EGFR-tyrosine kinase inhibitor (TKI) resistant sublines.
Results: Ad-REIC-treatment inhibited the cell viability by 40% or more in 13 (52%) of the 25 cell lines at multiplicity of infection (MOI) of 20 (20 MOI). These cell lines were regarded as being highly sensitive cells. The cell viability of a nonmalignant immortalized cell line, OUMS-24, was not inhibited at 200 MOI of Ad-REIC. The effects of Ad-REIC on EGFR-TKI resistant sublines were equivalent to those in the parental cell lines. Here, we demonstrated that Ad-REIC treatment activated c-Jun N-terminal kinase (JNK) in NSCLC cell lines, indicating the induction of ER stress with GRP78/BiP (GRP78) up-regulation and resulting in apoptosis. A single intratumoral injection of Ad-REIC significantly inhibited the tumorigenic growth of A549 cells in vivo. As predictive factors of sensitivity for Ad-REIC treatment in NSCLC, we examined the expression status of GRP78 and coxsackievirus and adenovirus receptor (CAR). We found that the combination of the GRP78 and CAR expressional statuses may be used as a predictive factor for Ad-REIC sensitivity in NSCLC cells.
Conclusion: Ad-REIC induced JNK activation and subsequent apoptosis in NSCLC cells. Our study indicated that Ad-REIC has therapeutic potential against NSCLC and that the expression statuses of GRP78 and CAR may predict a potential therapeutic benefit of Ad-REIC.

DOI： 10.1371/journal.pone.0087900

非小細胞肺癌におけるF-18 FDG PET/CTの有用性転移性リンパ節と胸膜浸潤の診断に関して

新家崇義, 田中高志, アラファト・アルキン, 小河七子, 佐野由佳, 井田健太郎, 加藤勝也, 佐藤修平, 金澤右, 宗淳一, 豊岡伸一, 三好新一郎, 田中健大, 市村浩一, 吉野正, 加地充昌

Japanese Journal of Radiology 32 ( Suppl. ) 61 - 61 2014.2

Novel Germline Mutation in the Transmembrane Domain of HER2 in Familial Lung Adenocarcinomas Reviewed

Hiromasa Yamamoto, Koichiro Higasa, Masakiyo Sakaguchi, Kazuhiko Shien, Junichi Soh, Koichi Ichimura, Masashi Furukawa, Shinsuke Hashida, Kazunori Tsukuda, Nagio Takigawa, Keitaro Matsuo, Katsuyuki Kiura, Shinichiro Miyoshi, Fumihiko Matsuda, Shinichi Toyooka

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE 106 ( 1 ) djt338 2014.1

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS INC

We encountered a family of Japanese descent in which multiple members developed lung cancer. Using whole-exome sequencing, we identified a novel germline mutation in the transmembrane domain of the human epidermal growth factor receptor 2 (HER2) gene (G660D). A novel somatic mutation (V659E) was also detected in the transmembrane domain of HER2 in one of 253 sporadic lung adenocarcinomas. Because the transmembrane domain of HER2 is considered to be responsible for the dimerization and subsequent activation of the HER family and downstream signaling pathways, we performed functional analyses of these HER2 mutants. Mutant HER2 G660D and V659E proteins were more stable than wild-type protein. Both the G660D and V659E mutants activated Akt. In addition, they activated p38, which is thought to promote cell proliferation in lung adenocarcinoma. Our findings strongly suggest that mutations in the transmembrane domain of HER2 may be oncogenic, causing hereditary and sporadic lung adenocarcinomas.

DOI： 10.1093/jnci/djt338

【胸壁・横隔膜の手術-その1】診断胸壁原発脂肪肉腫におけるFDG PET/CTの有用性

山本治慎, 杉本誠一郎, 三好健太郎, 山本寛斉, 宗淳一, 山根正修, 豊岡伸一, 大藤剛宏, 三好新一郎

胸部外科 67 ( 1 ) 4 - 8 2014.1

Language：Japanese Publisher：(株)南江堂

76歳男性。増大する右胸壁腫瘤と右上肢のしびれ、脱力感を主訴に近医を受診、精査にて右大小胸筋や鎖骨下動静脈を背側から圧排する10cm大の腫瘤を指摘された。今回、穿刺吸引細胞診にて多形性細胞肉腫の診断にて精査加療目的で著者らの施設へ紹介となった。胸部造影CTでは右胸壁の胸郭出口に10cm大の腫瘍が存在しており、内部は不均一で脂肪成分を含み、右鎖骨下動静脈を背側から圧排するも、右腕神経叢や骨性胸郭への明らかな浸潤は認められなかった。PET/CTでは腫瘍内部にはFDGの高集積がみられたが辺縁部は低集積であり、遠隔臓器転移は認められなかった。以上、これらの所見より、本症例は右胸壁原発脂肪肉腫が疑われ、治療は腫瘍辺縁部が低悪性度のため浸潤や癒着は軽度と予測して腫瘍摘出術が施行された。その結果、摘出標本は11.4×6.3×8.8cm大で、被膜に覆われ黄白色調であり、内部は充実性で一部に出血が認められた。また、病理組織学的所見では腫瘍の辺縁部には高分化型脂肪肉腫の増殖がみられ、腫瘍内部では多形性を示す異型性の強い細胞が出血・壊死を伴って増殖し、脱分化型脂肪肉腫と診断された。尚、術後1年でPETにて右腕神経叢腹側にFDGの高集積を認め腫瘍の局所再発と診断され、広範囲切除術が計画されたが、患者の意思により目下は近医にて放射線治療の施行中である。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J00349&link_issn=&doc_id=20131225140001&doc_link_id=40019920853&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F40019920853&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

[The role of 18F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) in liposarcoma of the chest wall]. Reviewed

Yamamoto H, Sugimoto S, Miyoshi K, Yamamoto H, Soh J, Yamane M, Toyooka S, Oto T, Miyoshi S

Kyobu geka. The Japanese journal of thoracic surgery 67 ( 1 ) 4 - 8 2014.1

Surgical Resection of a Massive Primary Mediastinal Liposarcoma Using Clamshell Incision Combined with Lower Median Sternotomy: Report of a Case Reviewed

Yutaka Hirano, Hiromasa Yamamoto, Koichi Ichimura, Shinichi Toyooka, Shinichiro Miyoshi

ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY 20 606 - 608 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：MEDICAL TRIBUNE INC

We experienced a case of massive mediastinal liposarcoma expanding to the bilateral pleural cavities. Preoperative positron emission tomography-computed tomography scan showed that the uptake of F-18-fluorodeoxyglucose (FDG) into the tumor was slight for its size. Clamshell incision together with lower median sternotomy provided the excellent visualization and the complete resection of the tumor. The surgical resection should be performed even for a massive liposarcoma, especially if the uptake of F-FDG into the tumor is low, as complete surgical resection is the only definitive treatment for liposarcoma.

DOI： 10.5761/atcs.cr.13.02263

Density of Tumor-Infiltrating FOXP3+T Cells as a Response Marker for Induction Chemoradiotherapy and a Potential Prognostic Factor in Patients Treated with Trimodality Therapy for Locally Advanced Non-Small Cell Lung Cancer Reviewed

Hiroyuki Tao, Kazuhiko Shien, Junichi Soh, Eisuke Matsuda, Shinichi Toyooka, Kazunori Okabe, Shinichiro Miyoshi

ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY 20 ( 6 ) 980 - 986 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：MEDICAL TRIBUNE INC

Purpose: To examine the relationship between the density of tumor-infiltrating T cell sub-populations and the pathological response to induction chemoradiotherapy (CRT) in patients with locally advanced NSCLC, and to assess the impact of T cell density on patient prognosis.
Methods: A total of 64 patients with c-stages IIA-IIIB NSCLC who underwent induction CRT followed by R0 surgery were enrolled. Tumor-infiltrating T cells expressing either FOXP3 or CD8 were detected by immunohistochemical staining.
Results: Mean numbers of tumor-infiltrating FOXP3+ T cells were 39.9 for patients with minor pathological responses (n = 9), 18.4 for those with major pathological responses (n = 25), and 12.9 for those with complete pathological responses (n = 30; P < 0.001). The number of CD8+ T cells was not associated with pathological responses. Patients with lower FOXP3+ T cell densities showed better survival, although the difference was not statistically significant.
Conclusion: Our study demonstrated that the density of tumor-infiltrating FOXP3+ T cells indicated the degree of response for induction CRT and prognosis in patients treated with trimodality therapy for locally advanced NSCLC, suggesting that FOXP3+ T cells may be target for adjunct immunotherapy.

DOI： 10.5761/atcs.oa.13-00237

Thoracoscopic Lobectomy as Salvage Surgery for Local Recurrence of Non-Small Cell Lung Cancer after Carbon Ion Radiotherapy in an Initially Operable Patient Reviewed

Seiichiro Sugimoto, Shinichi Toyooka, Ken Suzawa, Kouichi Ichimura, Osamu Fujii, Shinichiro Miyoshi

ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY 20 501 - 504 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：MEDICAL TRIBUNE INC

Carbon ion radiotherapy (CIRT) for patients with early-stage non-small cell lung cancer (NSCLC) has recently provided favorable local control with very few toxic reactions. Because CIRT for NSCLC has been mostly performed for elderly or inoperable patients, salvage surgery for NSCLC after CIRT has rarely been reported. We describe a case of complete thoracoscopic right upper lobectomy with mediastinal lymphadenectomy performed as salvage surgery for local recurrence of stage IA NSCLC after CIRT in an initially operable patient who had refused surgery 27 months previously. Pleural adhesions caused by CIRT were localized to the pulmonary apex and the central pulmonary structures were intact at the time of the salvage surgery, which allowed us to successfully perform thoracoscopic lobectomy without any complications. Thus, salvage surgery for NSCLC after CIRT may be feasible in an initially operable patient, as CIRT appears to be unlikely to cause any difficulties in the salvage surgery.

DOI： 10.5761/atcs.cr.13-00223

Adult Mesenchymal Hamartoma of the Chest Wall: Report of a Case Reviewed

Hiromasa Yamamoto, Junichi Soh, Koichi Ichimura, Yusuke Konishi, Shinichi Toyooka, Takayuki Nojima, Shinichiro Miyoshi

ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY 20 663 - 665 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：MEDICAL TRIBUNE INC

We present an adult case of the chest wall tumor, which was accidentally pointed out by a medical checkup. Surgical resection was performed for the tumor, as preoperative biopsy of the tumor suggested the possibility of malignancy. Postoperative pathological examination revealed the diagnosis of mesenchymal hamartoma of the chest wall, which usually occurs in early infancy and childhood. Immunohistochemical staining for Sox9 was positive for chondrocytes and partially positive for spindle tumor cells. It is considered that the present case was not pointed out until the patient became an adult, because the tumor was relatively small and thus asymptomatic.

DOI： 10.5761/atcs.cr.13-00225

The degree of microRNA-34b/c methylation in serum-circulating DNA is associated with malignant pleural mesothelioma Reviewed

Takayuki Muraoka, Junichi Soh, Shinichi Toyooka, Keisuke Aoe, Nobukazu Fujimoto, Shinsuke Hashida, Yuho Maki, Norimitsu Tanaka, Kazuhiko Shien, Masashi Furukawa, Hiromasa Yamamoto, Hiroaki Asano, Kazunori Tsukuda, Takumi Kishimoto, Takemi Otsuki, Shinichiro Miyoshi

LUNG CANCER 82 ( 3 ) 485 - 490 2013.12

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Objectives: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. microRNA-34b/c (miR-34b/c), which plays an important role in the pathogenesis of MPM, is frequently downregulated by DNA methylation in approximately 90% of MPM cases. In this study, we estimated the degree of miR-34b/c methylation in serum-circulating DNA using a digital methylation specific PCR assay (MSP).
Materials and methods: A real-time MSP assay was performed using the SYBR Green method. The melting temperature (Tm) of each PCR product was examined using a melting curve analysis. For a digital MSP assay, 40 wells were analyzed per sample. A total of 110 serum samples from 48 MPM cases, 21 benign asbestos pleurisy (BAP) cases, and 41 healthy volunteers (HVs) were examined.
Results: Positive range of Tm value for miR-34b/c methylation was defined as 77.71-78.79 degrees C which was the mean 3 standard deviations of 40 wells of a positive control. The number of miR-34b/c methylated wells was counted per sample according to this criterion. The number of miR-34b/c methylated wells in MPM cases was significantly higher than that in BAP cases (P = 0.03) or HVs (P < 0.001). Advanced MPM cases tended to have higher number of miR-34b/c methylated wells than early MPM cases. Receiver-operating characteristic (ROC) curve analysis revealed that three number of miR-34b/c methylated wells per sample was the best cut-off of positivity of MPM with a 67% of sensitivity and a 77% specificity for prediction. The area under the ROC curve was 0.77.
Conclusions: Our digital MSP assay can quantify miR-34b/c methylation in serum-circulating DNA. The degree of miR-34b/c methylation in serum-circulating DNA is associated with MPM, suggesting that this approach might be useful for the establishment of a new detection system for MPM. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2013.09.017

【最新肺癌学-基礎と臨床の最新研究動向-】肺癌の分子生物学と発癌機序分子生物学マイクロRNA変化

山本寛斉, 宗淳一, 三好新一郎, 豊岡伸一

日本臨床 71 ( 増刊6 最新肺癌学 ) 109 - 113 2013.11

キュアサルコーマボード共同治療連携病院間"水平"連携による肉腫、GISTの集学的治療

高橋克仁, 山村倫子, 冨田裕彦, 上浦祥司, 矢嶋淳, 寺岡慧, 波多江亮, 大野烈士, 宗淳一, 豊岡伸一, 小池幸宏, 烏野隆博, 楢原啓之, 小山隆文, 大山優

日本癌治療学会誌 48 ( 3 ) 1214 - 1214 2013.9

新規高感度検出法によるEGFR T790M変異陽性肺腺癌の臨床的特徴の同定

橋田真輔, 宋淳一, 豊岡伸一, 大塚智昭, 諏澤健, 古川公之, 枝園和彦, 山本寛斉, 浅野博昭, 佃和憲, 三好新一郎

日本癌治療学会誌 48 ( 3 ) 1153 - 1153 2013.9

Bleeding into a pulmonary cyst caused by pulmonary radiofrequency ablation Reviewed

Ryotaro Kishi, Hidefumi Mimura, Takao Hiraki, Hideo Gobara, Mayu Uka, Shinichi Toyooka, Susumu Kanazawa

Journal of Vascular and Interventional Radiology 24 ( 7 ) 1069 - 1071 2013.7

Different sizes of centrilobular ground-glass opacities in chest high-resolution computed tomography of patients with pulmonary veno-occlusive disease and patients with pulmonary capillary hemangiomatosis Reviewed

Aya Miura, Satoshi Akagi, Kazufumi Nakamura, Keiko Ohta-Ogo, Katsushi Hashimoto, Satoshi Nagase, Kunihisa Kohno, Kengo Kusano, Aiko Ogawa, Hiromi Matsubara, Shinichi Toyooka, Takahiro Oto, Aiji Ohtsuka, Tohru Ohe, Hiroshi Ito

CARDIOVASCULAR PATHOLOGY 22 ( 4 ) 287 - 293 2013.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background: Centrilobular ground-glass opacity (GGO) is one of the characteristic findings in chest high-resolution computed tomography (HRCT) of patients with pulmonary veno-occlusive disease (PVOD) and patients with pulmonary capillary hemangiomatosis (PCH). However, clinical differential diagnosis of these two diseases is difficult and has not been established. In order to clarify their differences, we compared the sizes of GGOs in chest HRCT and the sizes of capillary assemblies in pulmonary vascular casts between patients diagnosed pathologically with PVOD and PCH.
Methods: We evaluated chest HRCT images for four patients with idiopathic pulmonary arterial hypertension (IPAH), three patients with PVOD and three patients with PCH, and we evaluated pulmonary vascular casts of lung tissues obtained from those patients at lung transplantation or autopsy.
Results: Centrilobular GGOs in chest HRCT were observed in patients with PVOD and patients with PCH but not in patients with IPAH. We measured the longest diameter of the GGOs. The size of centrilobular GGOs was significantly larger in patients with PCH than in patients with PVOD (5.60 +/- 1.43 mm versus 2.51 +/- 0.79 mm, P<.01). We succeeded in visualization of the 3-dimensional structures of pulmonary capillary vessels obtained from the same patients with PVOD and PCH undergoing lung transplantation or autopsy and measured the diameters of capillary assemblies. The longest diameter of capillary assemblies was also significantly larger in patients with PCH than in patients with PVOD (5.44 +/- 1.71 mm versus 3.07 +/- 1.07 mm, P<.01).
Conclusion: Measurement of the sizes of centrilobular GGOs in HRCT is a simple and useful method for clinical differential diagnosis of PVOD and PCH. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.carpath.2012.12.002

多数の具体的達成・評価項目票使用による診療参加型臨床実習の導入

山根正修, 杉本誠一郎, 宗淳一, 万代康弘, 三好健太郎, 山本寛斉, 豊岡伸一, 大藤剛宏, 三好新一郎

医学教育 44 ( Suppl. ) 110 - 110 2013.7

Downregulation of microRNA-34 induces cell proliferation and invasion of human mesothelial cells Reviewed

Norimitsu Tanaka, Shinichi Toyooka, Junichi Soh, Kazunori Tsukuda, Kazuhiko Shien, Masashi Furukawa, Takayuki Muraoica, Yuho Maki, Tsuyoshi Ueno, Hiromasa Yamamoto, Hiroaki Asano, Takemi Otsuki, Shinichiro Miyoshi

ONCOLOGY REPORTS 29 ( 6 ) 2169 - 2174 2013.6

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Malignant mesothelioma (MM) is an aggressive tumor with a dismal prognosis, and the molecular alterations involved in this disease remain unknown. We previously reported that microRNA-34s (miR-34s) are methylated and downregulated in MM and may play an important role in the carcinogenesis of MM. In this study, we downregulated miR-34s in human mesothelial cells to investigate the cellular effect of miR-34 knockdown. For the cell study, we used LP-9, a human mesothelial cell line, and three human primary-cultured mesothelial cell lines. RNA-based miR-34a, -34b and -34c inhibitors were transfected into these cells, and their effects on proliferation and invasion were evaluated. A scramble RNA oligonucleotide was used as a control. The protein expression status was estimated using western blotting. After miR-34 inhibitor transfection, miR-34a, -34b and -34c were downregulated in all the examined mesothelial cell lines. miR-34 inhibitor transfection significantly increased cell proliferation in all of the mesothelial cell lines, compared with the scramble control. The invasive ability also increased in the miR-34 inhibitor transfectants, compared with the scramble control, in the LP-9 cell line. Western blotting confirmed the upregulation of c-MET, phospho-c-MET, and Bcl-2 proteins in LP-9 cells after miR-34 inhibitor transfection. In conclusion, our study showed that the downregulation of miR-34s induced an oncogenic phenotype in non-malignant mesothelial cells. The present study, together with the results of our previous report, strongly suggest that miR-34s play an important role in the early carcinogenic process involved in the transformation of human mesothelial cells to MM.

DOI： 10.3892/or.2013.2351

Acquired Resistance to EGFR Inhibitors Is Associated with a Manifestation of Stem Cell-like Properties in Cancer Cells Reviewed

Kazuhiko Shien, Shinichi Toyooka, Hiromasa Yamamoto, Junichi Soh, Masaru Jida, Kelsie L. Thu, Shinsuke Hashida, Yuho Maki, Eiki Ichihara, Hiroaki Asano, Kazunori Tsukuda, Nagio Takigawa, Katsuyuki Kiura, Adi F. Gazdar, Wan L. Lam, Shinichiro Miyoshi

CANCER RESEARCH 73 ( 10 ) 3051 - 3061 2013.5

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) is a critical problem in the treatment of lung cancer. Although several mechanisms have been shown to be responsible for acquired resistance, all mechanisms have not been uncovered. In this study, we investigated the molecular and cellular profiles of the acquired resistant cells to EGFR-TKI in EGFR-mutant lung cancers. Four EGFR-mutant cell lines were exposed to gefitinib by stepwise escalation and high-concentration exposure methods, and resistant sublines to gefitinib were established. The molecular profiles and cellular phenotypes of these resistant sublines were characterized. Although previously reported, alterations including secondary EGFR T790M mutation, MET amplification, and appearance of epithelial-to-mesenchymal transition (EMT) features were observed, these 2 drug-exposure methods revealed different resistance mechanisms. The resistant cells with EMT features exhibited downregulation of miRNA-200c by DNA methylation. Furthermore, the HCC827-derived subline characterized by the high-concentration exposure method exhibited not only EMT features but also stem cell-like properties, including aldehyde dehydrogenase isoform 1 (ALDH1A1) overexpression, increase of side-population, and self-renewal capability. Resistant sublines with stem cell-like properties were resistant to conventional chemotherapeutic agents but equally sensitive to histone deacetylase and proteasome inhibitors, compared with their parental cells. ALDH1A1 was upregulated in clinical samples with acquired resistance to gefitinib. In conclusion, our study indicates that the manner of EGFR-TKI exposure influences the mechanism of acquired resistance and the appearance of stem cell-like property with EGFR-TKI treatment. Cancer Res; 73(10); 3051-61. (C) 2013 AACR.

DOI： 10.1158/0008-5472.CAN-12-4136

非小細胞肺癌術後補助化学療法としてのS-1+CBDCA併用療法とS-1単剤継続維持療法の多施設共同認容性試験(SLCG1001)

松本博文, 福田実, 豊岡伸一, 佐野功, 長島聖二, 橋口浩二, 谷口英樹, 中村洋一, 永安武, 河野茂, 奥村典仁, 岡部和倫, 中村廣繁, 片岡正文, 山下素弘, 中田昌男, 片岡和彦, 吉岡弘鎮, 坂本純一, 伊達洋至

気管支学 35 ( 3 ) 330 - 330 2013.5

Sacrificing the pulmonary arterial branch to the spared lobe is a risk factor of bronchopleural fistula in sleeve lobectomy after chemoradiotherapy Reviewed

Shinichi Toyooka, Junichi Soh, Kazuhiko Shien, Seiichiro Sugimoto, Masaomi Yamane, Takahiro Oto, Hiroshi Date, Shinichiro Miyoshi

EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY 43 ( 3 ) 568 - 572 2013.3

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS INC

A sleeve lobectomy is a widely accepted procedure for enabling the pulmonary parenchyma to be spared. Induction chemoradiotherapy (CRT) followed by surgery is one treatment option for locally advanced non-small cell lung cancer (NSCLC), but CRT is considered to have a negative effect on subsequent surgery, especially for anastomotic healing. In this study, we describe our experience performing sleeve lobectomies and the associated anastomotic complications after induction CRT.
The medical records of NSCLC patients who underwent surgery after receiving CRT were reviewed. The relationships between anastomotic complications and clinicopathological factors were examined.
Between December 1998 and October 2011, a total of 104 patients received CRT followed by surgery. Among them, 14 NSCLC patients underwent a bronchial sleeve resection: nine patients underwent a right upper lobe resection, two patients underwent a left lingular division and lower lobe resection and one patient each underwent a right lower lobe, a right upper and middle lobe and a right middle and lower lobe resection. A bronchopleural fistula at the anastomosis occurred in two patients. A pulmonary arterial (PA) branch to the spared lobe had been sacrificed in both of these patients because of tumour involvement. In contrast, the PA branches to the spared lobes were preserved in 11 of the 12 patients who did not exhibit anastomotic complications (P = 0.033).
Our experience strongly suggests that the sacrifice of the PA branch to the spared lobe is a possible risk factor for anastomotic complications for a sleeve lobectomy after induction CRT.

DOI： 10.1093/ejcts/ezs323

Micropapillary componentを有する肺腺癌の遺伝子異常

古川公之, 豊岡伸一, 市村浩一, 宗淳一, 橋田真輔, 多田龍平, 枝園和彦, 山本寛斎, 浅野博昭, 佃和憲, 三好新一郎

日本外科学会雑誌 114 ( 臨増2 ) 552 - 552 2013.3

極細径気管支内視鏡検査にて右肺末梢性動静脈奇形(AVM)を観察しえた1例

久本晃子, 後藤田裕子, 宋淳一, 豊岡伸一, 市原英基, 谷本安, 宮原伸明, 金廣有彦, 谷本光音, 木浦勝行

気管支学 35 ( 2 ) 222 - 222 2013.3

Silenced Expression of NFKBIA in Lung Adenocarcinoma Patients with a Never-smoking History Reviewed

Masashi Furukawa, Junichi Soh, Hiromasa Yamamoto, Kouichi Ichimura, Kazuhiko Shien, Yuho Maki, Takayuki Muraoka, Norimitsu Tanaka, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Shinichi Toyooka, Shinichiro Miyoshi

ACTA MEDICA OKAYAMA 67 ( 1 ) 19 - 24 2013.2

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Nuclear factor of kappa-light polypeptide gene enhancer in B cells inhibitor alpha (NFKBIA), which is a tumor suppressor gene, was found to be silenced in lung adenocarcinomas. We examined NFKBIA expression, mutations in the EGFR and K-ras genes, and EML4-ALK fusion in 101 resected lung adenocarcinoma samples from never-smokers. NFKBIA expression was evaluated using immunohistochemistry. NFKBIA expression was negative in 16 of the 101 samples (15.8%). EGFR and K-ras mutations and EML4-ALK fusion were detected in 61 (60.5%), 1 (1.0%), and 2 (2.0%) of the 101 samples, respectively, in a completely mutually exclusive manner. Negative NFKBIA expression was observed significantly more frequently among the tumors with none of the three genetic alterations compared to those with such alterations (p = 0.009). In addition, negative NFKBIA expression was significantly more frequent among the EGFR-wild type samples compared to the EGFR-mutant samples (p = 0.013). In conclusion, NFKBIA expression was silenced in adenocarcinomas without EGFR/K-ras mutations or EML4-ALK fusion, suggesting that the silencing of NFKBIA may play an important role in the carcinogenesis of adenocarcinomas independent of EGFR/K-ras mutations or EML4-ALK fusion.

DOI： 10.18926/AMO/49253

Impact of GLUT1 and Ki-67 expression on early-stage lung adenocarcinoma diagnosed according to a new international multidisciplinary classification Reviewed

Yuho Maki, Junichi Soh, Kouichi Ichimura, Kazuhiko Shien, Masashi Furukawa, Takayuki Muraoka, Norimitsu Tanaka, Tsuyoshi Ueno, Hiromasa Yamamoto, Hiroaki Asano, Kazunori Tsukuda, Shinichi Toyooka, Shinichiro Miyoshi

ONCOLOGY REPORTS 29 ( 1 ) 133 - 140 2013.1

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

High expression levels of glucose transporter isoform 1 (GLUT1) and Ki-67 are reportedly associated with malignancy-related clinicopathological factors in malignant tumors. Recently, a new histological IASLC/ATS/ERS classification for lung adenocarcinoma was proposed. In this study, we investigated the clinicopathological impact of GLUT1 and Ki-67 expression on early-stage lung adenocarcinoma classified according to the IASLC/ATS/ERS classification. One hundred and five patients with completely resected stage IA lung adenocarcinoma were retrospectively classified into two groups, a 'non-invasive type' (n=31) or an 'invasive type' (n=74), based on the IASLC/ATS/ERS classification. GLUT1 and Ki-67 expression status was evaluated using immunohistochemistry. The epidermal growth factor receptor (EGFR) and KRAS mutation status was determined using PCR-based assays. Positive GLUT1 and Ki-67 expression and EGFR and KRAS mutations were detected in 28 (27%), 33 (31%), 51 (49%) and 5 (8%) cases, respectively. Positive GLUT1 expression was significantly associated with a wild-type EGFR and mutant KRAS status. A multivariate analysis revealed that positive GLUT1 expression was independently associated with the 'invasive type'. In multivariate analyses for overall survival (OS) and disease-free survival (DFS), positive Ki-67 and GLUT1 expression was the only independent factor for a poor OS (P=0.012) and DFS (P=0.040), respectively. In addition, when stratified according to the GLUT1 and Ki-67 status, double-positive cases had the poorest DFS and OS times, compared with the other categories. Positive GLUT1 expression is associated with the invasive character of early-stage lung adenocarcinoma and with early disease relapse. Our results strongly suggest that GLUT1 and Ki-67 play important roles in acquiring biological malignant potential in early-stage lung adenocarcinoma.

DOI： 10.3892/or.2012.2087

Impact of aberrant methylation of microRNA-9 family members on non-small cell lung cancers. Reviewed International journal

Takayuki Muraoka, Junichi Soh, Shinichi Toyooka, Yuho Maki, Kazuhiko Shien, Masashi Furukawa, Tsuyoshi Ueno, Norimitsu Tanaka, Hiromasa Yamamoto, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

Molecular and clinical oncology 1 ( 1 ) 185 - 189 2013.1

Language：English Publishing type：Research paper (scientific journal)

MicroRNAs (miRs) contribute to cancer development and progression by acting as oncogenes and tumor suppressor genes. miR-9 family members (miR-9s), including miR-9-1, 9-2 and 9-3, have been shown to be oncogenically involved through the downregulation of E-cadherin expression, which promotes the epithelial-mesenchymal transition. Tumor suppressive roles of miR-9s have also been reported to silence miR-9 through methylation, which is associated with an shortened overall survival (OS) period in several types of cancer. In this study, the impact of miR-9s methylation on non-small cell lung cancers (NSCLC) was investigated. In total, 293 resected NSCLC samples were examined and the miR-9s methylation status was determined using a combined bisulfite restriction analysis. miR-9 expression was analyzed by in situ hybridization. Methylation of miR-9-1, 9-2 and 9-3 was present in 20 (7%), 33 (11%) and 34 (12%) of the cases, respectively. Methylation of any miR-9s (miR-9s methylation) was observed in 76 of the cases (26%), and miR-9 expression was silenced in cases with miR-9s methylation. Logistic regression analysis demonstrated that male gender [odds ratio (OR), 2.0; 95% confidence interval (95% CI), 1.1-3.6; P=0.01] and pathologically negative lymph node metastasis (OR, 4.8; 95% CI, 1.4-17.2; P=0.002) were independent relative factors for miR-9s methylation. Additionally, miR-9s methylation [hazard ratio (HR), 4.2; 95% CI, 1.2-27.0; P=0.026] and early pathological stage (HR, 8.3; 95% CI, 2.1-28.6; P=0.004) were found to be independent predictive factors for prolonged OS time by the Cox proportional hazard test. miR-9s methylation which induces expression silencing is common in NSCLC cases without lymph nodal metastasis, suggesting that miR-9s are oncogenically involved in NSCLC carcinogenesis through the promotion of tumor metastasis.

DOI： 10.3892/mco.2012.18

Contralateral pneumothorax in bullous lung after pneumonectomy: report of two cases. Reviewed

Masashi Furukawa, Takahiro Oto, Shinichi Toyooka, Junichi Soh, Masaomi Yamane, Shinichiro Miyoshi

General thoracic and cardiovascular surgery 61 ( 1 ) 35 - 7 2013.1

Language：English Publishing type：Research paper (scientific journal)

Contralateral pneumothorax after pneumonectomy is potentially fatal. We experienced two cases of right pneumothorax after left pneumonectomy in which the patients had multiple bullae in the right lung. Case 1 involved a 49-year-old man with non-small-cell lung cancer (NSCLC) who underwent left pneumonectomy after induction chemoradiotherapy. Eleven months after surgery, he had pneumothorax and was treated with chest tube drainage and pleurodesis. He was discharged but died of recurrent pneumothorax 1 month later. Case 2 involved a 57-year-old man with NSCLC who had left pneumonectomy. Five months after surgery, he had pneumothorax and was treated with chest tube drainage. Because of prolonged air leak, ligation of the ruptured bulla was performed with a percutaneous cardiopulmonary support system on standby. No pneumothorax recurrence occurred for 2 years. Although management of pneumothorax after pneumonectomy is challenging, surgical intervention may be useful and necessary especially when there is high risk of recurrent pneumothorax.

DOI： 10.1007/s11748-012-0112-5

The impact of prolonged cold preservation on the graft function and gene expression levels in an experimental lung transplantation model Reviewed

Osamu Yoshida, Masaomi Yamane, Sumiharu Yamamoto, Mikio Okazaki, Shinichi Toyooka, Takahiro Oto, Yoshifumi Sano, Shinichiro Miyoshi

SURGERY TODAY 43 ( 1 ) 81 - 87 2013.1

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Ischemia reperfusion injury (IRI) remains a significant cause of morbidity and mortality after lung transplantation. Early growth response-1 (EGR1) drives the expression of inflammatory mediators and has an important role in IRI. We hypothesized that the severe IRI caused by a long preservation induces a specific expression pattern of EGR1 and its target genes which would correlate with the lung graft function.
SD rat lungs were preserved at 4 A degrees C for 3 or 18 h, then transplanted and reperfused. Pulmonary grafts were evaluated for the blood gas oxygenation and pathological findings. The intra-graft mRNA levels of EGR1 and its downstream target genes were measured by real-time PCR. A Western blotting analysis of the EGR1 expression was used to validate the changes in the protein level.
There was upregulation of EGR1, MIP-2 and PAI-1 when there was prolonged hypothermic preservation. The expression levels of MIP-2 and PAI-1 were observed to increase for up to 4 h in the 18 h preserved lungs. There were no differences in the expression levels of IL-1 beta and ICAM-1 between the lungs subjected to short and long periods of ischemia.
Our data showed that prolonged hypothermic graft preservation deteriorates the pulmonary graft function, which was associated with the induction of EGR1 and its downstream target genes, which may aggravate IRI following lung transplantation.

DOI： 10.1007/s00595-012-0234-5

DNA Methylation Profiles of Lymphoid and Hematopoietic Malignancies (Retraction of vol 10, pg 2928, 2004) Reviewed

Takao Takahashi, Narayan Shivapurkar, Jyotsna Reddy, Hisayuki Shigematsu, Kuniharu Miyajima, Makoto Suzuki, Shinichi Toyooka, Sabine Zoechbauer-Mueller, Johannes Drach, Gunjan Parikh, Yingye Zheng, Ziding Feng, Steven H. Kroft, Charles Timmons, Robert W. McKenna, Adi F. Gazdar

CLINICAL CANCER RESEARCH 19 ( 1 ) 307 - 307 2013.1

Bronchoplasty to adjust mismatches in the proximal and distal bronchial stumps during bronchial sleeve resection of the left lower lobe and lingular division. Reviewed International journal

Toyooka S, Soh J, Oto T, Miyoshi S

European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 43 ( 1 ) 182 - 183 2013.1

Language：English Publishing type：Research paper (scientific journal)

We treated two lung cancer patients with metastatic hilar lymph node at the left lower lobe, involving the bifurcation of the left upper- and lower lobar bronchi and the lingular pulmonary artery. After induction chemoradiotherapy, we performed a bronchial sleeve resection of the left lower lobe and lingular division. In these cases, anastomosis of the left superior divisional and main bronchial stumps was necessary, which required correction of an orifice size mismatch. For this purpose, we performed different procedures on each patient. In Procedure 1, we edged the larger superior divisional bronchial stump with the partially excised walls of the upper lobar and the lingular divisional bronchi. In Procedure 2, we reefed the membranous portion of the main bronchus with adjusting stitches. Our procedure is useful for adjusting mismatch of the bronchial stump in anastomosis in a bronchial sleeve resection of the left lower lobe and lingular division.

DOI： 10.1093/ejcts/ezs379

Induction chemoradiotherapy is superior to induction chemotherapy for the survival of non-small-cell lung cancer patients with pathological mediastinal lymph node metastasis Reviewed

Shinichi Toyooka, Katsuyuki Kiura, Kazuhiko Shien, Kuniaki Katsui, Katsuyuki Hotta, Susumu Kanazawa, Hiroshi Date, Shinichiro Miyoshi

INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY 15 ( 6 ) 954 - 960 2012.12

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

OBJECTIVES: The purpose of this study was to compare the clinical outcomes of induction chemoradiotherapy and chemotherapy and to identify the prognostic factors for non-small-cell lung cancer patients with mediastinal lymph node metastasis who were treated with induction therapy.
METHODS: Between August 1995 and December 2010, 50 non-small-cell lung cancer patients with pathological mediastinal lymph node metastasis were scheduled to receive induction therapy followed by surgery. Irinotecan plus cisplatin was used for induction chemotherapy from June 1995 to April 1999, and docetaxel plus cisplatin with concurrent radiation at a dose of 40-46 Gy has been used for induction chemoradiotherapy since May 1999.
RESULTS: Thirty-five patients were treated with induction chemoradiotherapy and 15 were treated with induction chemotherapy. For the entire population, the 3-year and 5-year overall survival rates were 64.1 and 53.9%, respectively, and the 1-year and 2-year disease-free survival rates were 70.0 and 53.1%, respectively. Among the clinicopathological factors, the chemoradiotherapy group exhibited longer overall survival and disease-free survival than the chemotherapy group (overall survival, P = 0.0020; disease-free survival, P = 0.015). Pathological downstaging was also significantly associated with favorable overall survival (P = 0.0042) and disease-free survival (P = 0.021). A multivariate analysis showed that chemoradiotherapy (P = 0.0099) and pathological downstaging (P = 0.039) were independent prognostic factors.
CONCLUSIONS: Our results indicated that induction chemoradiotherapy was superior to induction chemotherapy with regard to the outcome of non-small-cell lung cancer patients with mediastinal lymph node metastasis.

DOI： 10.1093/icvts/ivs412

Impact of age on epidermal growth factor receptor mutation in lung cancer Reviewed

Tsuyoshi Ueno, Shinichi Toyooka, Kenichi Suda, Junichi Soh, Yasushi Yatabe, Shinichiro Miyoshi, Keitaro Matsuo, Tetsuya Mitsudomi

LUNG CANCER 78 ( 3 ) 207 - 211 2012.12

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Aging is one of the best, but rarely referred, risk factors for various types of cancer including lung cancer, because age could be a surrogate for accumulation of genetic events in cancers. Smoking inversely associates with the presence of epidermal growth factor receptor (EGFR) mutation in lung cancer, but its strong confounding with age and sex makes it difficult to evaluate sole impact of age. To clarify an impact of age on EGFR mutation, we conducted a cross-sectional study based on data of 1262 lung cancer patients. The associations between EGFR mutation and age, considering sex, smoking and histology, were evaluated using logistic regression models. In multivariate analysis, we found a significant increase of EGFR mutation prevalence by increase of age (p-trend = 0.0004). Consistent trend was observed among never-smoking females (p-trend = 0.011) and never-smoking males also showed similar trend although not significant. These were consistently observed when we limit the subject to those with adenocarcinoma. In conclusion, age independently associates with EGFR mutation among lung cancer. Positive association between EGFR mutation and age among never-smokers regardless of sex might indicate that EGFR mutation occurs cumulatively by unidentified internal/external factors other than smoking. (c) 2012 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2012.09.006

MicroRNA miR-34b/c Enhances Cellular Radiosensitivity of Malignant Pleural Mesothelioma Cells Reviewed

Yuho Maki, Hiroaki Asano, Shinichi Toyooka, Junichi Soh, Takafumi Kubo, Kuniaki Katsui, Tsuyoshi Ueno, Kazuhiko Shien, Takayuk Muraoka, Norimitsu Tanaka, Hiromasa Yamamoto, Kazunori Tsukuda, Takumi Kishimoto, Susumu Kanazawa, Shinichiro Miyoshi

ANTICANCER RESEARCH 32 ( 11 ) 4871 - 4875 2012.11

Language：English Publishing type：Research paper (scientific journal) Publisher：INT INST ANTICANCER RESEARCH

Background: We previously reported that epigenetic silencing of microRNA-34b1c (miR-34b/c) plays an important role in the pathogenesis of malignant pleural mesothelioma (MPM). We examined the impact of miR-34b/c restoration on the radiosensitivity of MPM cells. Materials and Methods: We established stable miR-34b/c and scramble transfectants of two MPM cell lines, H2052 and H28. We examined these transfectants by clonogenic survival assay, phosphorylated his-tone H2AX (gamma H2AX) foci assay, cell-cycle analysis, and western blotting. Results: The clonogenic survival assay revealed that miR-34b/c radiosensitized MPM cells. gamma H2AX foci assay showed that DNA double-strand break repair was delayed in miR-34b/c transfectants. The proportion of sub-G(1) phase cells was increased in miR-34b/c transfectants after irradiation. miR-34b/c inhibited expression of cyclin-D1, cyclin-dependent kinase 416, B-cell lymphoma-2 (BCL-2) and increased cleaved poly (ADP-ribose) polymerase (cPARP) and cleaved caspase-3 after irradiation. Conclusion: Our results indicate that miR-34b/c enhances radiosensitivity by promoting radiation-induced apoptosis and suggested that miR-34b/c might be a useful therapeutic molecule to enhance radiotherapy in MPM.

Knockdown of the Epidermal Growth Factor Receptor Gene to Investigate Its Therapeutic Potential for the Treatment of Non-Small-Cell Lung Cancers Reviewed

Kazuhiko Shien, Tsuyoshi Ueno, Kazunori Tsukuda, Junichi Soh, Kenichi Suda, Takafumi Kubo, Masashi Furukawa, Takayuki Muraoka, Yuho Maki, Norimitsu Tanaka, Hiromasa Yamamoto, Katsuyuki Kiura, Tetsuya Mitsudomi, Shinichi Toyooka, Shinichiro Miyoshi

CLINICAL LUNG CANCER 13 ( 6 ) 488 - 493 2012.11

Language：English Publishing type：Research paper (scientific journal) Publisher：CIG MEDIA GROUP, LP

Epidermal growth factor receptor (EGFR) can be a therapeutic target in non-small-cell lung cancer with EGFR activation, even if EGFR mutation is not present. By contrast, EGFR cannot be a target when EGFR is not activated, even if EGFR protein is expressed. For acquired resistant cells to EGFR-tyrosine kinase inhibitors, EGFR can be a target if those cells depend on EGFR and are not driven by other oncogenes.
Background: Epidermal growth factor receptor (EGFR) is often overexpressed in non small-cell lung cancer (NSCLC). Anti-EGFR agents, including EGFR-tyrosine kinase inhibitors are considered to be effective when a drug-sensitive EGFR mutation is present. However, inherent and acquired resistances are major problems of EGFR-targeting therapies. In this study, we performed EGFR knockdown by using small interfering RNAs in NSCLC cell lines to examine the significance of targeting EGFR for NSCLC therapy. Methods: We treated 13 NSCLC cell lines, including 8 EGFR mutant and 5 EGFR wild type by using gefitinib or small interfering RNAs against EGFR (siEGFR). Three cell lines (PC-9-GR1, RPC-9, and HCC827-ER) were experimentally established with acquired resistance to EGFR-tyrosine kinase inhibitors. The antitumor effect was determined by using an 3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium, inner salt (MTS) or colony formation assay. The protein expression was evaluated by using Western blotting. Results: All 13 cell lines expressed EGFR protein, and siEGFR downregulated EGFR protein expression in all. The cell viability was suppressed by siEGFR in 6 of 8 EGFR-mutant cell lines (suppressed 57%-92% of control cells), including PC-9-GR1 and RPC-9. The NCI-H1650 and HCC827-ER harbored EGFR mutations but were not suppressed. Of note, PTEN (phosphatase and tensin homolog) was deleted in NCI-H1650, and c-MET was amplified in HCC827-ER. It was not suppressed in any of the EGFR wild-type cells except in the NCI-H411, in which EGFR is phosphorylated, which indicates its activation. Conclusions: Analysis of the results indicated that EGFR can be a therapeutic target in NSCLCs with EGFR activation. In contrast, targeting EGFR is not appropriate for tumors in which EGFR is not activated, even if EGFR is expressed.

DOI： 10.1016/j.cllc.2012.02.003

DIRECT THERAPEUTIC EFFECT OF REIC/DKK-3-ENCODING ADENOVIRAL VECTOR FOR NON-SMALL CELL LUNG CANCER Reviewed

Yamamoto Hiromasa, Tanaka Norimitsu, Toyooka Shinichi, Watanabe Masami, Sakaguchi Masakiyo, Soh Junichi, Shien Kazuhiko, Furukawa Masashi, Asano Hiroaki, Tsukuda Kazunori, Nasu Yasutomo, Huh Nam-ho, Kumon Hiromi, Miyoshi Shinichirou

JOURNAL OF THORACIC ONCOLOGY 7 ( 11 ) S463 2012.11

微小乳頭状肺腺癌におけるEGFR、K-ras、EML4-ALKの変異の様式(EGFR, K-ras and EML4-ALK mutational profile of lung adenocarcinomas with micropapillary component)

古川公之, 宗淳一, 豊岡伸一, 枝園和彦, 三好健太郎, 山本寛斉, 杉本誠一郎, 山根正修, 大藤剛宏, 三好新一郎

肺癌 52 ( 5 ) 671 - 671 2012.10

正常中皮細胞におけるmicroRNA34の抑制効果 Tiny RNA drives mesothelial cell mad

田中則光, 豊岡伸一, 宗淳一, 佃和憲, 枝園和彦, 古川公之, 村岡孝幸, 牧佑歩, 上野剛, 久保孝文, 山本寛斎, 浅野博昭, 大槻剛巳, 三好新一郎

日本癌治療学会誌 47 ( 3 ) 1275 - 1275 2012.10

まれなEGFR変異を有する肺腺癌の1例

木村紘爾, 山根正修, 豊岡伸一, 古川公之, 難波圭, 三好健太郎, 山本寛斉, 宗淳一, 大藤剛宏, 三好新一郎

肺癌 52 ( 5 ) 650 - 650 2012.10

新規に樹立した悪性胸膜中皮腫細胞株の分子生物学的解析

山本寛斉, 多田龍平, 枝園和彦, 古川公之, 宗淳一, 三村雄輔, 片山英樹, 青江啓介, 岡部和倫, 松本常男, 豊岡伸一, 三好新一郎

肺癌 52 ( 5 ) 550 - 550 2012.10

Basal segmental auto-transplantation after pneumonectomy for advanced central lung cancer Reviewed

Takahiro Oto, Katsuyuki Kiura, Shinichi Toyooka, Shinichiro Miyoshi

EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY 42 ( 3 ) 579 - 581 2012.9

Language：English Publisher：OXFORD UNIV PRESS INC

In patients with central lung cancer that extensively involves the bronchus/pulmonary artery, a double-sleeve lobectomy is often difficult to perform. We describe a case of post-pneumonectomy basal segmental auto-transplantation using a lung preservation technique that uses cold low-potassium dextran glucose solution to protect the lung graft from ischaemia-reperfusion injury during the ex situ division of the segmental graft and the pathological investigations for the clearance of the surgical margins. A right basal segmental auto-transplantation procedure was performed in a patient with stage-IIIA squamous cell lung cancer. This technique could allow extensive pulmonary resection while minimizing the loss of pulmonary reserve.

DOI： 10.1093/ejcts/ezs224

Intrathoracic irrigation with arbekacin for methicillin-resistant Staphylococcus aureus empyema following lung resection Reviewed

Tsuyoshi Ueno, Shinichi Toyooka, Junichi Soh, Kentaroh Miyoshi, Seiichiro Sugimoto, Masaomi Yamane, Takahiro Oto, Shinichiro Miyoshi

INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY 15 ( 3 ) 437 - 441 2012.9

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

OBJECTIVES: Empyema is a well-known complication following lung resection. In particular, empyema caused by methicillin-resistant Staphylococcus aureus (MRSA) is difficult to treat. Here, we present our experience of MRSA empyema treated with local irrigation using arbekacin.
METHODS: Six patients consisted of 4 males and 2 females with an average age of 65.7 years. They developed MRSA empyema following lung resection and were treated at our institution between 2007 and 2011. Cases comprised four primary and one metastatic lung cancer, and 1 patient was a living lung transplantation donor. The surgical procedure consisted of four lobectomies, one segmentectomy and one wedge resection. After diagnosis of MRSA empyema, anti-MRSA drugs were administered intravenously in all cases. In addition, arbekacin irrigation at a dose of 100 mg dissolved in saline was performed after irrigation with saline only.
RESULTS: The average number of postoperative days for the diagnosis of MRSA empyema was 13 (range 4-19). The period of irrigation ranged from 6 to 46 days. Arbekacin irrigation did not induce nephrotoxicity or other complications, and no bacteria resistant to arbekacin was detected in the thoracic cavity. We re-operated on 1 case because he had pulmonary fistula and severe wound infection. At the time of removing the thoracic catheter, MRSA in the pleural effusion disappeared completely in 3 patients. The period until MRSA concentration in the pleural effusion became negative after starting arbekacin irrigation ranged from 4 to 9 days. In the remaining cases, in which MRSA did not disappear, the catheter was removed because of no inflammatory reaction after stopping irrigation and clamping the catheters. All patients were discharged from our institution without thoracic catheterization and no patients had relapsed during the follow-up period ranging from 6 to 44 months.
CONCLUSIONS: Irrigation of the thoracic cavity with arbekacin proved to be an effective, safe and readily available method for treating MRSA empyema following lung resection.

DOI： 10.1093/icvts/ivs285

Takotsubo cardiomyopathy associated with pulmonary resections after induction chemoradiotherapy for non-small cell lung cancer. Reviewed

Shinichi Toyooka, Satoshi Akagi, Masashi Furukawa, Kazufumi Nakamura, Junichi Soh, Masaomi Yamane, Takahiro Oto, Shinichiro Miyoshi

General thoracic and cardiovascular surgery 60 ( 9 ) 599 - 602 2012.9

Language：English Publishing type：Research paper (scientific journal)

Takotsubo cardiomyopathy (TTC), also known as transient left ventricular (LV) apical ballooning syndrome, is characterized by transient LV dysfunction. We present the case of a 72-year-old man who was diagnosed as having TTC after surgery for two lung tumors. The patient was treated with induction chemoradiotherapy (CRT) followed by pulmonary resections for double primary non-small cell lung cancers (NSCLC): cT4N1M0 disease in the right lung and cT2N0M0 in the left lung. Induction CRT was performed. A right upper lobectomy was initially performed, and a left upper divisionectomy was subsequently performed. At 3 days after the second surgery, he developed dyspnea and general fatigue accompanied by a T-wave inversion on electrocardiography (ECG). An echocardiogram revealed akinesis at the apex with a 30 % ejection fraction. He was diagnosed as having TTC and recovered with supportive care. This case is the first report of TTC occurring after tri-modality therapy for NSCLC.

DOI： 10.1007/s11748-012-0058-7

Resection of the entire first rib for fibrous dysplasia using a combined posterior-transmanubrial approach Reviewed

Masashi Furukawa, Junichi Soh, Shinichi Toyooka, Toshifumi Ozaki, Shinichiro Miyoshi

General Thoracic and Cardiovascular Surgery 60 ( 9 ) 584 - 586 2012.9

Language：English Publishing type：Research paper (scientific journal)

A 27-year-old woman presented with pain of the left anterior chest of 2-year duration. Chest X-ray revealed a mass in the upper-left lung field and chest computed tomography (CT) a 6-cm first-rib tumor. CT-guided biopsy was performed and the tumor diagnosed as fibrous dysplasia. Because of continued pain, surgery was deemed necessary. Surgery began with the use of the posterior approach in the prone position to expose the first thoracic vertebra and detach the first rib at the costotransverse joint. After transitioning to the spine position, the transmanubrial approach was used to resect the tumor en bloc with the left first rib. Histological examination revealed the tumor to be fibrous dysplasia. Postoperative recovery was uneventful. The outcomes of this case suggest that the combined posterior-transmanubrial approach described here is a safe, successful approach for first-rib resection of a space-occupying tumor that yields good cosmetic results. © The Japanese Association for Thoracic Surgery 2012.

DOI： 10.1007/s11748-012-0044-0

Influence of Radiofrequency Ablation of Lung Cancer on Pulmonary Function Reviewed

Akihiro Tada, Takao Hiraki, Toshihiro Iguchi, Hideo Gobara, Hidefumi Mimura, Shinichi Toyooka, Katsuyuki Kiura, Toshihide Tsuda, Toshiharu Mitsuhashi, Susumu Kanazawa

CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY 35 ( 4 ) 860 - 867 2012.8

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

The purpose of this study was to evaluate altered pulmonary function retrospectively after RFA.
This retrospective study comprised 41 ablation sessions for 39 patients (22 men and 17 women; mean age, 64.8 years). Vital capacity (VC) and forced expiratory volume in 1 s (FEV1) at 1 and 3 months after RFA were compared with the baseline (i.e., values before RFA). To evaluate the factors that influenced impaired pulmonary function, univariate analysis was performed by using multiple variables. If two or more variables were indicated as statistically significant by univariate analysis, these variables were subjected to multivariate analysis to identify independent factors.
The mean VC and FEV1 before RFA and 1 and 3 months after RFA were 3.04 and 2.24 l, 2.79 and 2.11 l, and 2.85 and 2.13 l, respectively. The values at 1 and 3 months were significantly lower than the baseline. Severe pleuritis after RFA was identified as the independent factor influencing impaired VC at 1 month (P = 0.003). For impaired FEV1 at 1 month, only severe pleuritis (P = 0.01) was statistically significant by univariate analysis. At 3 months, severe pleuritis (VC, P = 0.019; FEV1, P = 0.003) and an ablated parenchymal volume a parts per thousand yen20 cm(3) (VC, P = 0.047; FEV1, P = 0.038) were independent factors for impaired VC and FEV1.
Pulmonary function decreased after RFA. RFA-induced severe pleuritis and ablation of a large volume of marginal parenchyma were associated with impaired pulmonary function.

DOI： 10.1007/s00270-011-0221-z

Induction Chemoradiotherapy Followed by Surgical Resection for Clinical T3 or T4 Locally Advanced Non-Small Cell Lung Cancer Reviewed

Kazuhiko Shien, Shinichi Toyooka, Katsuyuki Kiura, Keitaro Matsuo, Junichi Soh, Masaomi Yamane, Takahiro Oto, Mitsuhiro Takemoto, Hiroshi Date, Shinichiro Miyoshi

ANNALS OF SURGICAL ONCOLOGY 19 ( 8 ) 2685 - 2692 2012.8

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

To examine the usefulness of trimodality therapy in patients with clinical T3 or T4 (cT3-4) locally advanced non-small cell lung cancer (LA-NSCLC).
Between 1997 and 2009, a total of 76 LA-NSCLC patients with cT3-4 underwent surgery. Among them, 36 patients underwent induction chemoradiotherapy with docetaxel and cisplatin plus concurrent radiation followed by surgery (IC group). The other 40 patients initially underwent surgery (IS group). The outcomes of the IC and IS groups were then investigated. To minimize possible biases caused by confounding treatment indications, we performed a retrospective cohort analysis by applying a propensity score (PS). Patients were divided into three groups according to PS tertiles, and comparisons between the IC and IS groups were made by PS tertile-stratified Cox proportional hazard models.
For the entire cohort, which had a median follow-up duration of 48 months, the 3- and 5-year overall survival rates were 83.8 and 78.9%, respectively, in the IC group, versus 66.8 and 56.5%, respectively, in the IS group (P = 0.0092). After adjustments for potentially confounding variables, the IC group continued to have a significantly longer overall survival than the IS group (P = 0.0045). In addition, when the analysis was limited to 52 patients with cT3-4N0 or N1 disease, the IC group had a significantly longer overall survival than the IS group after adjustments for confounding variables (P = 0.019).
Our study indicates that trimodality therapy is highly effective in patients with cT3-4 LA-NSCLC.

DOI： 10.1245/s10434-012-2302-x

肺切除後気胸の治療(Treatment for pneumothorax after pneumonectomy)

古川公之, 宗淳一, 山根正修, 豊岡伸一, 大藤剛宏, 三好新一郎

日本気胸・嚢胞性肺疾患学会雑誌 12 ( 1 ) 87 - 87 2012.8

Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1 Reviewed

Kadoaki Ohashi, Lecia V. Sequist, Maria E. Arcila, Teresa Moran, Juliann Chmielecki, Ya-Lun Lin, Yumei Pan, Lu Wang, Elisa de Stanchina, Kazuhiko Shien, Keisuke Aoe, Shinichi Toyooka, Katsuyuki Kiura, Lynnette Fernandez-Cuesta, Panos Fidias, James Chih-Hsin Yang, Vincent A. Miller, Gregory J. Riely, Mark G. Kris, Jeffrey A. Engelman, Cindy L. Vnencak-Jones, Dora Dias-Santagata, Marc Ladanyi, William Pao

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 109 ( 31 ) E2127 - E2133 2012.7

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL ACAD SCIENCES

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/ BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.

DOI： 10.1073/pnas.1203530109

Prognostic impact of cancer stem cell-related markers in non-small cell lung cancer patients treated with induction chemoradiotherapy Reviewed

Kazuhiko Shien, Shinichi Toyooka, Kouichi Ichimura, Junichi Soh, Masashi Furukawa, Yuho Maki, Takayuki Muraoka, Norimitsu Tanaka, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Masaomi Yamane, Takahiro Oto, Katsuyuki Kiura, Shinichiro Miyoshi

LUNG CANCER 77 ( 1 ) 162 - 167 2012.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

The expression of several cancer stem cell (CSC)-related markers has been confirmed in non-small cell lung cancer (NSCLC). The aim of this study was to clarify the clinical role of CSC-related markers in patients with NSCLC undergoing induction chemoradiotherapy (CRT). Fifty patients with clinically diagnosed N2 or N3 NSCLC who underwent induction CRT with docetaxel and cisplatin concurrently with thoracic radiation followed by surgery were examined in this study. The expressions of CSC related markers (CD133, ALDH1, ABCG2, and Bmi-1) were examined using immunohistochemical staining in surgically resected specimens. Among the 50 patients, 20 patients had no residual tumor cells in the resected specimen when examined pathologically; CSC-related marker expressions and their correlation to survival were evaluated in the other 30 patients. After a median follow-up period of 72 months, the 5-year overall survival rate of the patients with CD133-positive or ALDH1-positive specimens was significantly worse than that of the patients with both CD133-negative and ALDH1-negative expressions (449% vs. 90.0%, respectively; P=0.042). In a multivariate analysis. CD133 and ALDH1 negativity (P=0.047) and cN2-3 single station metastasis (P=0.03) were significant independent prognostic factors for prolonged survival. The expressions of CSC-related markers after CRT were significantly correlated with a poor prognosis in patients with NSCLC. The development of therapeutic strategies including adjuvant therapy that take CSC-related marker positivity into consideration is likely to be a key factor in further improvements of the prognosis of patients undergoing trimodality therapy. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2012.02.006

A Case of Delayed Massive Hemothorax Caused by the Rupture of a Pulmonary Artery Pseudoaneurysm after Radiofrequency Ablation of Lung Tumors Reviewed

Junichi Soh, Shinichi Toyooka, Hideo Gobara, Takao Hiraki, Seiichiro Sugimoto, Masaomi Yamane, Takahiro Oto, Susumu Kanazawa, Shinichiro Miyoshi

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 42 ( 7 ) 646 - 649 2012.7

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Radiofrequency ablation has been applied as a minimally invasive therapy for the local control of lung tumors, including primary and metastatic neoplasms. Hemorrhagic complications after radiofrequency ablation can usually be treated conservatively, but such complications can be massive and fatal in some cases. In this paper, we report the rare case of delayed massive hemothrax caused by the rupture of a pulmonary artery pseudoaneurysm after lung radiofrequency ablation that was treated using transcatheter coil embolization followed by a left lower lobectomy. A 75-year-old woman underwent radiofrequency ablation for the treatment of a metastatic lung tumor in the left lower lobe arising from a colorectal carcinoma located close to a branch of the pulmonary artery. Thirty-six hours later, hemothorax and hemorrhagic shock occurred as a result of a ruptured pulmonary artery pseudoaneurysm and radiofrequency ablation-induced damage to the interlobular pleura. After transcatheter coil embolization of the pulmonary artery pseudoaneurysm, she recovered from a state of shock and a left lower lobectomy was performed. Histological findings revealed the presence of residual tumor cells in the ablated lung tumor. The postoperative course was uneventful, and no evidence of recurrence of the primary disease was seen at 1 year after the surgery. Although hemothorax secondary to the rupture of a pulmonary artery pseudoaneurysm after lung radiofrequency ablation is a rare complication, it should be recognized as a serious potential complication of lung radiofrequency ablation for a tumor located close to the pulmonary artery branch.

DOI： 10.1093/jjco/hys068

[Primary mediastinal lymphoma; a clinicopathologic case series]. Reviewed

Sugimoto S, Soh J, Maki Y, Kurosaki T, Yamane M, Toyooka S, Oto T, Miyoshi S

Kyobu geka. The Japanese journal of thoracic surgery 65 ( 7 ) 527 - 531 2012.7

縦隔悪性リンパ腫の臨床病理学的検討

杉本誠一郎, 宗淳一, 牧佑歩, 黒崎毅史, 山根正修, 豊岡伸一, 大藤剛宏, 三好新一郎

胸部外科 65 ( 7 ) 527 - 531 2012.7

Language：Japanese Publisher：(株)南江堂

縦隔悪性リンパ腫8例を対象に、診断、治療、臨床病理学的因子を検討した。その結果、発見動機は検診5例、有症状3例であった。白血球数高値は2例、CRP高値は4例、可溶性インターロイキン2受容体高値5例、LDH高値3例であった。最大腫瘍径中央値は8.5(1.5〜4)cmで、7例が7cm以上の巨大な腫瘍であった。PET-CTを5例に施行し、いずれも中等度以上のFDG集積を認め、うち2例は非常に高度の集積であった。診断方法はCTガイド下針生検5例、胸腔鏡補助下生検および切除術1例、小開胸生検1例、胸腺摘出術1例であった。組織型は結節硬化型Hodgkinリンパ腫3例、びまん性大細胞型B細胞性リンパ腫3例、前駆Tリンパ芽球性リンパ腫/白血病1例、胸腺MALTリンパ腫1例であった。治療は手術2例、化学療法もしくは化学療法+放射線療法6例であった。生存期間中央値は34.5(10〜71)ヵ月で、全例が生存中である。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J00349&link_issn=&doc_id=20120621060002&doc_link_id=40019360672&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F40019360672&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer Reviewed

Norimitsu Tanaka, Shinichi Toyooka, Junichi Soh, Takafumi Kubo, Hiromasa Yamamoto, Yuho Maki, Takayuki Muraoka, Kazuhiko Shien, Masashi Furukawa, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Keisuke Aoe, Shinichiro Miyoshi

Lung Cancer 108 254 - 255 2012.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Ireland Ltd

The publisher regrets errors were introduced in Fig. 3 A of the article described above. The images for both p-Scramble and p-miR-34b/c in SBC5 were incorrect. An amended version of Fig. 3 is shown below. Note that the analyses for both migration and invasion assays were appropriate and thus it is not necessary to correct the bar graphs in Fig. 3 as well as the legends for Fig. 3. The authors also consider that there is no need to correct any other parts of this article. The publisher would like to apologise for any inconvenience caused.

DOI： 10.1016/j.lungcan.2016.04.016

Phrenic Nerve Injury after Radiofrequency Ablation of Lung Tumors: Retrospective Evaluation of the Incidence and Risk Factors Reviewed

Yusuke Matsui, Takao Hiraki, Hideo Gobara, Mayu Uka, Yoshihisa Masaoka, Akihiro Tada, Shinichi Toyooka, Toshiharu Mitsuhashi, Hidefumi Mimura, Susumu Kanazawa

JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 23 ( 6 ) 780 - 785 2012.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Purpose: To retrospectively investigate the incidence of and risk factors for phrenic nerve injury after radiofrequency (RF) ablation of lung tumors.
Materials and Methods: The study included 814 RF ablation procedures of lung tumors. To evaluate the development of phrenic nerve injury, chest radiographs obtained before and after the procedure were examined. Phrenic nerve injury was assumed to have developed if the diaphragmatic level was elevated after the procedure. To identify risk factors for phrenic nerve injury, multiple variables were compared between cases of phrenic nerve injury and randomly selected controls by using univariate analyses. Multivariate analysis was then performed to identify independent risk factors.
Results: Evaluation of phrenic nerve injury from chest radiographs was possible after 786 procedures. Evidence of phrenic nerve injury developed after 10 cases (1.3%). Univariate analysis revealed that larger tumor size >= 20 mm; P = .014), proximity of the phrenic nerve to the tumor (< 10 mm; P < .001), the use of larger electrodes (array diameter or noninsulated tip length >= 3 cm; P = .001), and higher maximum power applied during ablation (>= 100 W; P < .001) were significantly associated with the development of phrenic nerve injury. Multivariate analysis demonstrated that the proximity of the phrenic nerve to the tumor (< 10 mm; P < .001) was a significant independent risk factor.
Conclusions: The incidence of phrenic nerve injury after RF ablation was 1.3%. The proximity of the phrenic nerve to the tumor was an independent risk factor for phrenic nerve injury.

DOI： 10.1016/j.jvir.2012.02.014

【抗がん剤治療の最前線:分子標的薬剤の使用による進歩(前篇)】新たな標的となる遺伝子とその変異、新薬 HSP90阻害薬の幕開け非小細胞肺がんを中心に

上野剛, 豊岡伸一, 宗淳一, 猶本良夫, 三好新一郎

最新医学 67 ( 6月増刊 ) 1534 - 1542 2012.6

Language：Japanese Publisher：(株)最新医学社

熱ショックタンパク(HSP)90阻害薬は,発がん性タンパクの発現を抑制し,強い抗腫瘍効果を示す薬剤である.現在,我々が用いたAUY-922を始め,非常にHSP90に親和性の高い新規薬剤の開発がなされている.これらは,より低濃度で抗腫瘍効果を発揮し,初期の阻害薬で起った重度の副作用の発生を抑えた.また,肺がんでは,ALK遺伝子変異肺がんに対し,感受性が高いことが分かった.現在,多数の臨床試験が施行中であり,今後,期待される分子標的薬の1つである.(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J00516&link_issn=&doc_id=20120625220019&doc_link_id=%2Fap7saisa%2F2012%2F0067s2%2F020%2F1534-1542%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fap7saisa%2F2012%2F0067s2%2F020%2F1534-1542%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Long-term outcome of induction chemoradiotherapy with docetaxel and cisplatin followed by surgery for non-small-cell lung cancer with mediastinal lymph node metastasis Reviewed

Shinichi Toyooka, Katsuyuki Kiura, Mitsuhiro Takemoto, Takahiro Oto, Nagio Takigawa, Toshiyoshi Fujiwara, Shinichiro Miyoshi, Hiroshi Date

INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY 14 ( 5 ) 565 - 569 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

The purpose of this study was to show the long-term outcome of induction chemoradiotherapy, using docetaxel and cisplatin with concurrent radiotherapy followed by surgery for non-small-cell lung cancer (NSCLC) with mediastinal nodal metastasis. Between January 2000 and July 2006, 22 consecutive NSCLC patients with pathologically proven mediastinal nodal metastasis were treated with tri-modality therapy. The regimen consisted of docetaxel and cisplatin plus concurrent radiation at a dose of 40-46 Gy. The induction therapy was followed by surgery 4-6 weeks later. The pulmonary resections were composed of a lobectomy in 19 patients, including 3 with a sleeve lobectomy, a bilobectomy in 2 patients and a left pneumonectomy in 1 patient. With a median follow-up duration of 8.7 years, the 3-year and 7-year overall survival (OS) rates for the entire population were 72.7 and 63.6%, respectively. Our results suggest that tri-modality therapy is promising for NSCLC patients with mediastinal nodal metastasis.

DOI： 10.1093/icvts/ivs028

DNA methylation status of REIC/Dkk-3 gene in human malignancies Reviewed

Tatsuro Hayashi, Hiroaki Asano, Shinichi Toyooka, Kazunori Tsukuda, Junichi Soh, Tadahiko Shien, Naruto Taira, Yuho Maki, Norimitsu Tanaka, Hiroyoshi Doihara, Yasutomo Nasu, Nam-ho Huh, Shinichiro Miyoshi

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY 138 ( 5 ) 799 - 809 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

The REIC (reduced expression in immortalized cells)/Dkk-3 is down-regulated in various cancers and considered to be a tumor suppressor gene. REIC/Dkk-3 mRNA has two isoforms (type-a,b). REIC type-a mRNA has shown to be a major transcript in various cancer cells, and its promoter activity was much stronger than that of type-b. In this study, we examined the methylation status of REIC/Dkk-3 type-a in a broad range of human malignancies.
We examined REIC/Dkk-3 type-a methylation in breast cancers, non-small-cell lung cancers, gastric cancers, colorectal cancers, and malignant pleural mesotheliomas using a quantitative combined bisulfite restriction analysis assay and bisulfate sequencing. REIC/Dkk-3 type-a and type-b expression was examined using reverse transcriptional PCR. The relationships between the methylation and clinicopathological factors were analyzed.
The rate of REIC/Dkk-3 type-a methylation ranged from 26.2 to 50.0% in the various primary tumors that were examined. REIC/Dkk-3 type-a methylation in breast cancer cells was significantly heavier than that in the other cell lines that we tested. REIC/Dkk-3 type-a methylation was inversely correlated with REIC/Dkk-3 type-a expression. There was a correlation between REIC/Dkk-3 type-a and type-b mRNA expression. REIC/Dkk-3 type-a expression was restored in MDA-MB-231 cells using 5-aza-2'-deoxycytidine treatment. We found that estrogen receptor-positive breast cancers were significantly more common among the methylated group than among the non-methylated group.
REIC/Dkk-3 type-a methylation was frequently detected in a broad range of cancers and appeared to play a key role in silencing REIC/Dkk-3 type-a expression in these malignancies.

DOI： 10.1007/s00432-012-1158-6

Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer Reviewed

Norimitsu Tanaka, Shinichi Toyooka, Junichi Soh, Takafumi Kubo, Hiromasa Yamamoto, Yuho Maki, Takayuki Muraoka, Kazuhiko Shien, Masashi Furukawa, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Keisuke Aoe, Shinichiro Miyoshi

LUNG CANCER 76 ( 1 ) 32 - 38 2012.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Small-cell lung cancer (SCLC) is an aggressive tumor with a dismal prognosis among primary lung cancers. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family is comprised of tumor-suppressive miRNAs, and its reduced expression by methylation has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the alteration and tumor-suppressive impact of miR-34s in SCLC. The methylation of miR-34a and miR-34b/c was observed in 4 (36%) and 7 (64%) of 11 SCLC cell lines, respectively. Among the 27 SCLC clinical specimens, miR-34a and miR-34b/c were methylated in 4(15%) and 18 (67%), respectively. In contrast, 13 (28%) miR-34a methylated cases and 12 (26%) miR-34b/c methylated cases were found in 47 NSCLC primary tumors. The frequency of miR-34b/c methylation was significantly higher in SCLC than in NSCLC (p < 0.001). The expressions of miR-34s were reduced in methylated cell lines and tumors and restored after 5-aza-2'-deoxycytidine treatment, indicating that methylation was responsible for the reduced expression of miR-34s. Because the frequency of methylation was higher in miR-34b/c, we focused on miR-34b/c for a functional analysis. We examined the effect of miR-34b/c introduction on cell proliferation, migration and invasion. The transfection of miR-34b/c to two SCLC cell lines (H1048 and SBC5) resulted in the significant inhibition of cell growth, migration, and invasion, compared with control transfectants. Our results indicate that the aberrant methylation of miR-34b/c plays an important role in the pathogenesis of SCLC, implying that miR-34b/c may be a useful therapeutic target for SCLC. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2011.10.002

Strong anti-tumor effect of NVP-AUY922, a novel Hsp90 inhibitor, on non-small cell lung cancer Reviewed

Tsuyoshi Ueno, Kazunori Tsukuda, Shinichi Toyooka, Midori Ando, Munenori Takaoka, Junichi Soh, Hiroaki Asano, Yuho Maki, Takayuki Muraoka, Norimitsu Tanaka, Kazuhiko Shien, Masashi Furukawa, Tomoki Yamatsuji, Katsuyuki Kiura, Yoshio Naomoto, Shinichiro Miyoshi

LUNG CANCER 76 ( 1 ) 26 - 31 2012.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

The anti-tumor activity of a newly developed Hsp90 inhibitor, NVP-AUY922 (AUY922), against non-small cell lung cancer (NSCLC) was examined. Twenty-one NSCLC cell lines were used, the somatic alterations of which were characterized. Cell proliferation was analyzed using a modified MTS assay. Expression of the client proteins was assessed using Western blotting. The cell cycle was analyzed using flow cytometry. The IC50 value of AUY922 for the NSCLC cell lines ranged from 5.2 to 860 nM (median, 20.4 nM). Based on previous data, cells with an IC50 of less than 50 nM were classified as sensitive cells and 19 of the 21 NSCLC cell lines were judged to be sensitive. The IC50 of five malignant pleural mesothelioma (MPM) cell lines revealed that the MPM cells had a significantly higher IC50 value (median, 89.2 nM; range, 22.2-24, 100 nM) than the NSCLC cells (p = 0.015). There was significant depletion of both the total and phosphorylated client proteins - EGFR, MET, HERZ and ART - at low drug concentrations (50-100 nM) in drug-sensitive cell lines. Cell-cycle analysis was performed for two sensitive cell lines, H1975 and H838. Following AUY922 treatment, an increase in the sub-G(0)-G(1) cell population, as well as appearance of cleaved PARP expression, indicated the induction of apoptosis. In conclusion, AUY922 was effective against most NSCLC cell lines, independent of the type of known molecular alteration, and appears to be a promising new drug for the treatment of NSCLC. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2011.09.011

肺切除術後の肺嚢胞における対側性気胸二症例報告(Contralateral pneumothorax in bullous lung after pneumonectomy: Report of two cases)

古川公之, 宗淳一, 豊岡伸一, 大藤剛宏, 三好新一郎

日本呼吸器外科学会雑誌 26 ( 3 ) P30 - 10 2012.4

非小細胞肺癌に対する新たな個別化治療戦略 REIC/Dkk-3遺伝子治療の可能性

宗淳一, 豊岡伸一, 田中則光, 渡部昌実, 山本寛斉, 阪口政清, 許南浩, 那須保友, 公文裕巳, 三好新一郎

日本呼吸器外科学会雑誌 26 ( 3 ) P17 - 01 2012.4

EGFRチロシンキナーゼ阻害剤に対する耐性機構と克服

宗淳一, 豊岡伸一, 上野剛, 三好新一郎

肺癌 52 ( 2 ) 131 - 135 2012.4

Language：Japanese Publisher：(NPO)日本肺癌学会

本邦の肺腺癌の約40%に認められるepidermal growth factor receptor(EGFR)変異肺癌に対する有効な治療法の開発は、肺癌治療成績の向上において重要である。EGFR変異肺癌にはEGFRチロシンキナーゼ阻害剤(EGFR-TKI)が高い感受性を示すが、遺伝子変異がもたらすEGFR変異蛋白に対するEGFR-TKIとアデノシン3リン酸(ATP)の親和性の関係を知ることは感受性・耐性の原因を理解する上で大切である。また、薬剤に対する獲得耐性の機構としては、T790M変異に代表されるEGFR遺伝子の2次変異とMET遺伝子増幅などのキナーゼ乗り換え耐性の2つに大別される。EGFR-TKI耐性肺癌の克服には、これら耐性化機構の理解に基づいた新規薬剤および治療法の開発が不可欠である。多くの薬剤が開発されているが、heat shock protein 90(Hsp90)阻害剤は、変異型EGFR・MET・AKTなどの複数のクライアント蛋白の安定化を阻害することで抗腫瘍効果を示すため、様々な機構を持つEGFR-TKI耐性肺癌への治療効果が期待され、現在臨床試験が行われている。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J01244&link_issn=&doc_id=20120614240001&doc_link_id=%2Fec7jaluc%2F2012%2F005202%2F001%2F0131-0135%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2012%2F005202%2F001%2F0131-0135%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

線維性骨異形成症に対するposterior approachとtransmanubrial approachによる第一肋骨の切除術(Resection of the First Rib for Fibrous Dysplasia Using Posterior and Transmanubrial Approach)

古川公之, 宗淳一, 豊岡伸一, 三好新一郎

日本呼吸器外科学会雑誌 26 ( 3 ) O29 - 04 2012.4

中葉肺癌のリンパ節転移様式に関する検討

枝園和彦, 豊岡伸一, 沢田茂樹, 山下素弘, 森山重治, 林達朗, 岡部和倫, 西英行, 重松久行, 安藤陽夫, 岡崎幹生, 佐野由文, 井野川英利, 前田宏也, 片岡正文, 水谷尚雄, 三好新一郎

日本呼吸器外科学会雑誌 26 ( 3 ) O08 - 05 2012.4

Peculiar mechanisms of graft recovery through anti-inflammatory responses after rat lung transplantation from donation after cardiac death Reviewed

Sumiharu Yamamoto, Mikio Okazaki, Masaomi Yamane, Kentaro Miyoshi, Shinji Otani, Tomokazu Kakishita, Osamu Yoshida, Naohisa Waki, Shinichi Toyooka, Takahiro Oto, Yoshifumi Sano, Shinichiro Miyoshi

TRANSPLANT IMMUNOLOGY 26 ( 2-3 ) 133 - 139 2012.3

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Background: Although lung transplantation from donation after cardiac death (DCD), especially uncontrolled DCD, is limited by warm ischemic periods, the molecular mechanism of warm ischemia-reperfusion-injury (IRI) has not been well elucidated. The purpose of this study was to clarify the particular longitudinal mechanisms of molecular factors involved in warm IRI.
Methods: Cold ischemic-time (CIT)-group lungs were retrieved and subjected to 3-h of cold preservation, whereas warm ischemic-time (WIT)-group lungs were retrieved after 3-h of warm ischemia. Orthotopic rat lung transplantation was performed and the grafts were reperfused for 1 or 4-h. The graft functions, gene expression, and activation of inflammatory molecules in the grafts were analyzed. Exhaled-carbon-monoxide-concentration (ExCO-C) was measured during reperfusion.
Results: Only the WIT-group showed obvious primary graft dysfunction at 1-h reperfusion, but the graft function was recovered during 4-h reperfusion. Most of pro-inflammatory cytokines and stress-induced molecules showed different expression and activation patterns between CIT and WIT groups. In the WIT-group, the expressions of anti-inflammatory molecules, IL-10 and HO-1, were significantly increased at 1-h reperfusion compared to the CIT-group, and these high levels were maintained through 4-h reperfusion. Furthermore, ExCO-C levels in the WIT-group increased immediately after reperfusion compared to the CIT-group.
Conclusions: This study indicates that warm IRI may involve a different mechanism than cold IRI and anti-inflammatory pathways may play important roles in the graft recovery after lung transplantation from uncontrolled DCD. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.trim.2011.11.002

Presence of EGFR mutation in pathologically non-malignant specimens from computed tomography-guided lung needle biopsies Reviewed

Tsuyoshi Ueno, Junichi Soh, Takao Hiraki, Hiroaki Asano, Koichi Ichimura, Kentaro Shibamoto, Hideo Gobara, Susumu Kanazawa, Shinichi Toyooka, Shinichiro Miyoshi

ONCOLOGY LETTERS 3 ( 2 ) 401 - 404 2012.2

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Activating mutations of the epidermal growth factor receptor (EGFR) gene are characteristic of non-small cell lung cancer (NSCLC). EGFR mutations were previously detected in histologically normal lung tissue around NSCLC tumors. Computed tomography-guided lung needle biopsy (CTNB) is an accurate and useful technique for the diagnosis of lung tumors. However, pathologically non-malignant cases occasionally become apparent following lung tumor resection. In this study, we determined the EGFR mutational status of lung tumors diagnosed as non-malignant in CTNB specimens, but diagnosed as NSCLC following surgical resection. Between 2000 and 2008, 1,109 CTNBs were performed at Okayama University Hospital. Among them, 15 cases were initially diagnosed as non-malignant by CTNB, but diagnosed as NSCLC following surgical resection as a result of a high likelihood of malignancy by clinical findings. Twelve paired DNAs of CTNB and corresponding resected specimens were available to examine the EGFR mutational status using a mutant-enriched PCR assay. EGFR mutations were detected in one out of 12 CTNB specimens and three of the corresponding resected tumors. This case harbored the same EGFR mutation in the CTNB specimen and resected tumor, but not in the distant corresponding nonmalignant lung tissue. Our results indicated that the detection of EGFR mutations may therefore aid the diagnosis of NSCLC in pathologically non-malignant CTNB specimens.

DOI： 10.3892/ol.2011.471

The anti-proliferative effect of heat shock protein 90 inhibitor, 17-DMAG, on non-small-cell lung cancers being resistant to EGFR tyrosine kinase inhibitor Reviewed

Naruyuki Kobayashi, Shinichi Toyooka, Junichi Soh, Hiromasa Yamamoto, Hideaki Dote, Kensuke Kawasaki, Hiroki Otani, Takafumi Kubo, Masaru Jida, Tsuyoshi Ueno, Midori Ando, Atsuko Ogino, Katsuyuki Kiura, Shinichiro Miyoshi

LUNG CANCER 75 ( 2 ) 161 - 166 2012.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, is frequently observed after initiation of TKIs therapy. Non-small-cell lung cancers (NSCLC) with activating EGFR mutations were reported to be sensitive to heat shock protein 90 (Hsp90) inhibitors regardless of the secondary TKI-resistant T790M mutation. We established EGFR-TKI resistant clones for PC-9 cell lines, harboring EGFR exon 19 deletions, with or without the secondary T790M mutation. We examined the anti-proliferative effect of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), an orally active Hsp90 inhibitor, on the growth of NSCLC cell lines in vitro and in vivo. In MTS assay, the IC50 values of 17-DMAG for 13 EGFR-mutant cell lines including eight EGFR-TKI resistant cell lines ranged from 0.04 to 0.16 mu M while those for seven EGFR-wild type cell lines ranged from 1.6 to 27.4 mu M. Western blot analysis revealed that phospho-EGFR, phospho-Akt, phospho-MAPK, cdk4, and cyclin D1 were more readily depleted by 17-DMAG treatment in EGFR-mutant cell lines than in EGFR-wild type cell lines. Cleaved PARP expression confirmed apoptosis in response to 17-DMAG treatment in EGER-mutant cell lines but not in EGFR-wild type cell lines. In mice xenograft models, 17-DMAG significantly reduced the growth of EGFR-mutant lines irrespective of T790M mutation. These results suggested that 17-DMAG is a potential novel therapeutic agent for NSCLC patients with EGFR mutations with or without EGFR-TKI resistance. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2011.04.022

Current status of postoperative follow-up for lung cancer in Japan: Questionnaire survey by the Setouchi Lung Cancer Study Group-A0901 Reviewed

Shigeki Sawada, Hiroshi Suehisa, Motohiro Yamashita, Masao Nakata, Norihito Okumura, Kazunori Okabe, Hiroshige Nakamura, Hirohito Tada, Shinichi Toyooka, Hiroshi Date

General Thoracic and Cardiovascular Surgery 60 ( 2 ) 104 - 111 2012.2

Language：English

Purpose: There is no recommended standard follow-up program after resection for lung cancer. Under these circumstances, each doctor establishes his or her own follow-up protocol. This questionnaire survey was conducted to grasp the current status of postoperative follow-up in Japan. Methods: The questionnaire survey was aimed at determining what examinations were performed and at what frequencies in the setting of postoperative follow-up. Based on these results, examinations performed at a frequency of &gt
50% and the time points after resection at which they were performed were selected and presented as components of an average follow-up program. Results: Questionnaires were sent to 44 institutions, and 26 doctors responded to the questionnaire. All 26 of the doctors performed physical examinations, blood examinations, chest radiography, and computed tomography (CT) routinely, but their frequencies varied widely among the doctors. The average frequencies of the follow-up examinations as judged from this survey are as follows: Physical and blood examinations are performed three to four times a year for the first 3 years and twice a year during the next 2 years. CT is scheduled at 6 and 12 months after resection and is repeated annually thereafter. Chest radiography is performed three to four times a year for the first 3 years and once a year thereafter, between the CT examinations. Conclusion: The follow-up programs used in clinical practice vary widely among institutions and doctors in terms of the types of examination performed and the frequencies at which they are performed. © 2012 The Japanese Association for Thoracic Surgery.

DOI： 10.1007/s11748-011-0850-9

CT fluoroscopy-guided cutting needle biopsy of focal pure ground-glass opacity lung lesions: Diagnostic yield in 83 lesions Reviewed

Daisaku Inoue, Hideo Gobara, Takao Hiraki, Hidefumi Mimura, Katsuya Kato, Kentaro Shibamoto, Tatsuhiko Iishi, Yusuke Matsui, Shinichi Toyooka, Susumu Kanazawa

EUROPEAN JOURNAL OF RADIOLOGY 81 ( 2 ) 354 - 359 2012.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Objective: The objective of our study was to retrospectively determine the diagnostic yield of CT fluoroscopy-guided cutting needle biopsy of focal pure ground-glass opacity lung lesions.
Materials and methods: Biopsies were performed using 20-G coaxial cutting needles for 83 focal pure ground-glass opacity lung lesions (mean lesion size, 12.1 mm). After excluding the lesions for which biopsy specimens were unobtainable and final diagnoses were undetermined, the diagnostic yield, including sensitivity and specificity for a diagnosis of malignancy and accuracy, was calculated. The lesions were then divided into 2 groups: the diagnostic failure group, comprising lesions with false-negative results and for which a biopsy specimen was unobtainable; and the diagnostic success group, comprising lesions with true-negative results and true-positive results. Various variables were compared between the 2 groups by univariate analysis.
Results: Biopsy specimens were obtained from 82 lesions, while specimens could not be obtained from 1 lesion. Final diagnosis was undetermined in 16 lesions. The sensitivity and specificity for a diagnosis of malignancy were 95% (58/61) and 100% (5/5), respectively. Diagnostic accuracy was 95% (63/66). The 4 lesions in diagnostic failure group were smaller, deeper, and more likely to be located in the lower lobe and further, for those lesions, number of specimens obtained was smaller, compared with 63 lesions in diagnostic success group. However, none of the differences were statistically significant.
Conclusion: CT fluoroscopy-guided cutting needle biopsy provided high diagnostic yield for focal pure ground-glass opacity lung lesions. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.ejrad.2010.11.025

肺癌切除後に発症し治療に難渋した肺アスペルギルス症の1例

三好雄一郎, 山根正修, 牧佑歩, 宗淳一, 豊岡伸一, 大藤剛宏, 三好新一郎

肺癌 52 ( 1 ) 109 - 109 2012.2

STAT3 expression in activating EGFR-driven adenocarcinoma of the lung Reviewed

Saburo Takata, Nagio Takigawa, Yoshihiko Segawa, Toshio Kubo, Kadoaki Ohashi, Toshiyuki Kozuki, Norihiro Teramoto, Motohiro Yamashita, Shinichi Toyooka, Mitsune Tanimoto, Katsuyuki Kiura

LUNG CANCER 75 ( 1 ) 24 - 29 2012.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Bronchioloalveolar carcinoma (BAC) pattern is often seen at the margin of invasive adenocarcinomas. We investigated EGFR signaling abnormalities involved in the progression of adenocarcinoma. Fifty tumors were obtained from patients who underwent surgery for lung adenocarcinoma seen as dense areas in ground glass opacity on computed tomography. Six, 18, and 26 tumors <1 cm, 1-2 cm, and >= 2 cm in diameter, respectively, were analyzed. Of the 24 tumors <= 2 cm in diameter, nine were preinvasive and 15 were invasive. EGFR, pAKT, and pMAPK were overexpressed in the center of the adenocarcinoma compared to the BAC component (p < 0.01) by immunohistochemistry, while pSTAT3 expression was reversed (p = 0.017). In the tumors <= 2 cm in diameter, pSTAT3 expression in the central area was higher in preinvasive tumors than in invasive tumors (p = 0.005). pSTAT3 was identified in the BAC component of 88% of the EGFR mutant (n = 17) and 82% of the wild-type tumors (n = 33). Transgenic mice expressing delE748-A752 EGFR and two lung cancer cell lines (PC-9 mutant and A549 wild-type EGFR) were also investigated. In transgenic mice, pSTAT3 was overexpressed in the BAC component around the adenocarcinoma center. Two lung cancer cell lines that overexpressed pSTAT3 were equally sensitive to a JAK2/STAT3 inhibitor (JSI-124). The role of STAT3 in the progression of adenocarcinoma should be further pursued. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2011.05.015

Bronchiolitis Obliterans Organizing Pneumonia after Radiofrequency Ablation of Lung Cancer: Report of Three Cases Reviewed

Takao Hiraki, Hideo Gobara, Katsuya Kato, Shinichi Toyooka, Hidefumi Mimura, Susumu Kanazawa

JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 23 ( 1 ) 126 - 130 2012.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

The present report describes three cases of a bronchiolitis obliterans organizing pneumonia (BOOP)-like reactive pneumonitis following radiofrequency (RF) ablation for lung cancer. The incidence of BOOP-like reactive pneumonitis after RF ablation at the authors' institution was estimated to be approximately 0.4% (three of 840 sessions). The patients presented with nonspecific symptoms. Computed tomography images showed consolidation or ground-glass opacity in a peripheral-dominant distribution and/or patchy air-space opacities. The disease was nonresponsive to antibiotic therapy but responded favorably to pulse therapy of steroids. BOOP-like reactive pneumonitis should be recognized as a complication following lung RF ablation.

DOI： 10.1016/j.jvir.2011.09.011

Spontaneous Regression of Primary Lung Cancer Arising from an Emphysematous Bulla Reviewed

Masashi Furukawa, Takahiro Oto, Masaomi Yamane, Shinichi Toyooka, Katsuyuki Kiura, Shinichiro Miyoshi

ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY 17 ( 6 ) 577 - 579 2011.12

Language：English Publishing type：Research paper (scientific journal) Publisher：MEDICAL TRIBUNE INC

Bullous emphysema is an important risk factor for lung cancer. Here, we report the case of a 56-year-old man who underwent surgical treatment for primary lung cancer arising from the wall of a bulla. Chest computed tomography (CT) had revealed a nodule arising from the bulla wall. This nodule showed positive uptake of (18)fluorodeoxyglucose (FDG) during positron emission tomography (PET)-CT. However, repeat CT performed after 2 months showed a spontaneous decrease in the tumor size. Exploratory resection revealed non-small cell lung cancer, which was confirmed by the findings of intraoperative frozen-section analysis; therefore, right upper lobectomy and mediastinal lymph node dissection were performed. The postoperative, pathological diagnosis was squamous cell carcinoma arising from the wall of a bulla. From this case, we infer that lung cancer arising from the wall of a bulla may spontaneously regress, and FDG/PET is a useful tool to diagnose lung tumor in patients with pulmonary bullous disease.

DOI： 10.5761/atcs.cr.10.01638

Diaphragmatic Hernia after Percutaneous Radiofrequency Ablation of Lung Tumor Reviewed

Takao Hiraki, Hideo Gobara, Yoshihisa Masaoka, Shinichi Toyooka, Susumu Kanazawa

JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 22 ( 12 ) 1777 - 1778 2011.12

Ileal perforation induced by acute radiation injury under gefitinib treatment Reviewed

Takayuki Muraoka, Kazunori Tsukuda, Shinichi Toyooka, Shunsuke Kagawa, Yoshio Naomoto, Mitsuhiro Takemoto, Kuniaki Katsui, Susumu Kanazawa, Yuho Maki, Hiroko Masuda, Masaaki Harada, Hiroaki Asano, Minoru Naito, Shinichiro Miyoshi

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 16 ( 6 ) 774 - 777 2011.12

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER TOKYO

Enteritis is one of the side effects of radiotherapy to the abdominal cavity. Radiation enteritis involves damage to mucous membranes in the acute phase and to stromal tissues in the late phase. Perforation of the intestine tends to occur in the late phase, and rarely in the acute phase. However, we describe here a case of intestinal perforation occurring in the acute phase after irradiation in a patient who received gefitinib treatment. Gefitinib, one of the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), is widely used to treat non-small cell lung cancer (NSCLC) patients, but is simultaneously known to inhibit wound healing. We suspect that gefitinib may affect regeneration of the small intestinal mucosa injured by irradiation. A 76-year-old woman had NSCLC with metastases to the 5th lumbar, sacral, and right iliac bones. To control the pain from bone metastasis, anterior-posterior opposing portal irradiation (total 35 Gy) was started, and was completed over 22 days. On day 25 after starting radiotherapy, the patient began to take gefitinib. On day 35, she presented with acute peritonitis, and an emergency laparotomy was performed. The terminal ileum was affected by radiation enteritis and there were two pin-hole perforations. In the surgical specimen, no cancerous lesions were detected, and immunohistochemical staining of phosphorylated EGFR (pEGFR) was negative. pEGFR has an important role in mucous membrane repair after irradiation. Intestinal perforation in the acute phase of radiation enteritis may be associated with impaired mucosal repair mechanisms due to the use of an EGFR-TKI such as gefitinib, as evidenced by the absence of pEGFR.

DOI： 10.1007/s10147-011-0249-8

Activations of mitogen-activated protein kinases and regulation of their downstream molecules after rat lung transplantation from donors after cardiac death Reviewed

S. Yamamoto, M. Yamane, O. Yoshida, M. Okazaki, N. Waki, S. Toyooka, T. Oto, S. Miyoshi

Transplantation Proceedings 43 ( 10 ) 3628 - 3633 2011.12

Language：English Publishing type：Research paper (international conference proceedings)

Accepting organs donated after cardiac death (DCD) is an effective approach to the donor shortage. However, lung transplantations from DCD donors show severe rapid pulmonary graft dysfunction (PGD) followed by warm ischemiareperfusion injury (IRI). This study sought to clarify the molecular mediators in warm IRI, including activation of mitogen-activated protein kinase (MAPK) and the downstream cascades. We performed single left lung transplantation using organs from male Sprague-Dawley rats after 0 (CIT group), 30 (30WIT group), or 180 (180WIT group) minutes of warm ischemia time. Pulmonary graft functions were estimated by blood gas analysis. At 1 hour after reperfusion, the phosphorylation status of MAPKs (ERK, p38, and JNK) and the gene expression levels of transcription factors (Egr-1 and ATF-3) and immune mediators (MCP-1, MIP-2, PAI-1, ICAM-1, TNF-α, IL-1β, IL-6, and COX-2) in the grafts were examined using Western blotting and real-time polymerase chain reaction assays. Severe PGD was observed in the 180WIT group compared with transplanted lungs in the other groups, which exhibited good pulmonary graft function. ERK and JNK activations, as well as mRNA levels of transcription factors (Egr-1 and ATF3) significantly increased with greater warm ischemic times. The pattern of JNK activation correlated with the severity of PGD. MCP-1, ICAM-1, IL-1β, IL-6, and COX-2 were also up-regulated among the 180WIT group, although MIP-2 and PAI-1 showed no significant differences among the groups. We suggest that the ERK and JNK pathways may play important roles to induce the injury caused by prolonged warm ischemia followed by reperfusion in the setting of lung transplantation from DCD donors. © 2011 Published by Elsevier Inc.

DOI： 10.1016/j.transproceed.2011.09.075

Methylation Profiling of Lung Cancer: A Decade of Progress Reviewed

Shinichi Toyooka, Adi F. Gazdar

MOLECULAR CANCER THERAPEUTICS 10 ( 11 ) 2020 - 2020 2011.11

Elevation of Antidonor Immunoglobulin M Levels Precedes Acute Lung Transplant Rejection Reviewed

Kentaroh Miyoshi, Yoshifumi Sano, Masaomi Yamane, Shinichi Toyooka, Takahiro Oto, Shinichiro Miyoshi

ANNALS OF THORACIC SURGERY 92 ( 4 ) 1233 - 1238 2011.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background. No useful noninvasive biomarker exists for diagnosing acute rejection after lung transplantation (LTx). In this study, antidonor T-cell antibodies were monitored daily in living-donor lobar LTx recipients to determine whether they are correlated with the onset of steroid-responsive typical acute rejection.
Methods. Ten nonsensitized patients who underwent bilateral living-donor lobar LTxs donated from 2 persons were analyzed. In 5 patients, unilateral acute rejection developed during the first 14 days after LTx and responded to subsequent pulse steroid therapies. The other patients experienced no rejection episodes during the period. Immunoreactivity against T cells from each lobe of the donors was monitored daily by detecting antidonor immunoglobulin (Ig) M and IgG using flow cytometry crossmatching for 14 days after LTx.
Results. There was a remarkable increase in IgM levels against rejected grafts around the onset of acute rejection, but this increase was not observed against nonrejected grafts. The mean IgM levels against rejected grafts 14 days after transplantation was significantly higher than that against nonrejected grafts in the acute rejection group (p = 0.009) and the no rejection group (p = 0.010). In the acute rejection group, the IgM level against rejected grafts became significantly higher than those against nonrejected grafts 2 days before the clinical onset of acute rejection. These trends were statistically marginal or not detected for IgG levels.
Conclusions. Significant immunoreactivity of IgM, but not IgG, preceded the clinical onset of acute rejection. Antidonor IgM monitoring can contribute to the early detection of steroid-responsive acute rejection. (Ann Thorac Surg 2011;92:1233-8) (C) 2011 by The Society of Thoracic Surgeons

DOI： 10.1016/j.athoracsur.2011.04.090

Radiofrequency Ablation of Lung Cancer at Okayama University Hospital: A Review of 10 Years of Experience Reviewed

Takao Hiraki, Hideo Gobara, Hidefumi Mimura, Shinichi Toyooka, Hiroyasu Fujiwara, Kotaro Yasui, Yoshifumi Sano, Toshihiro Iguchi, Jun Sakurai, Nobuhisa Tajiri, Takashi Mukai, Yusuke Matsui, Susumu Kanazawa

ACTA MEDICA OKAYAMA 65 ( 5 ) 287 - 297 2011.10

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

The application of radiofrequency ablation for the treatment of lung cancer by our group at Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences began in June 2001, and in the present report, we review our 10-year experience with this treatment modality at Okayama University Hospital. The local efficacy of radiofrequency ablation for the treatment of lung cancer depends on tumor size and the type of electrode used, but not on tumor type. An important factor for the prevention of local failure may be the acquisition of an adequate ablative margin. The combination of embolization and radiation therapy enhances the local efficacy. Local failure may be salvaged by repeating the radiofrequency ablation, particularly in small tumors. Survival rates after radiofrequency ablation are quite promising for patients with clinical stage I non-small cell lung cancer and pulmonary metastasis from colorectal cancer, hepatocellular carcinoma, and renal cell carcinoma. The complications caused by radiofrequency ablation can be treated conservatively in the majority of cases. However, attention should be paid to rare but serious complications. This review shows that radiofrequency ablation is a promising treatment for patients with lung cancer.

DOI： 10.18926/AMO/47010

Early effects of the ex vivo evaluation system on graft function after swine lung transplantation Reviewed

Shinji Otani, Takahiro Oto, Tomokazu Kakishita, Kentaroh Miyoshi, Shiro Hori, Masaomi Yamane, Shinichi Toyooka, Shinichiro Miyoshi

EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY 40 ( 4 ) 956 - 961 2011.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Objectives: Ex vivo lung evaluation (ex vivo) has been developed as a useful method by which to assess lungs from donation-after-cardiac death (DCD) donors prior to transplant. However, the safety of the ex vivo circulation itself with respect to grafts has not been fully investigated. The aim of this study is to evaluate the effects of the ex vivo circuit using a swine lung transplant model. Methods: Lungs with or without 2-h warm ischemia were used. To assess post-transplant graft function, the left lung was transplanted after 2-h ex vivo or cold preservation; blood gas analysis of the left pulmonary vein (partial pressure of oxygen, PO(2)) was performed during the 6-h post-transplant follow-up period. Data were compared between the ex vivo (+) and ex vivo (-) groups. Results: Partial pressure of oxygen/inspired oxygen fraction (PO(2)/FiO(2)) in the ex vivo (-) group was significantly greater than that in the ex vivo (+) group until 3 h after transplant. The PO(2)/FiO(2) levels in both groups then increased and became similar at 6 h after transplant, regardless of whether ischemic or non-ischemic lungs (p < 0.001 and p = 0.004, respectively) were used. Conclusions: Negative effects of the ex vivo system were limited and seen only in the immediate post-transplant period. Therefore, in DCD swine lung transplantation, the ex vivo system appears to be safe. (C) 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ejcts.2010.12.071

神経内分泌癌の診断と治療 I期肺大細胞神経内分泌癌切除症例に対する診断および治療成績岡山大学呼吸器外科研究会共同研究

岡崎幹生, 佐野由文, 山本寛斉, 岡部和倫, 末久弘, 山下素弘, 上野剛, 豊岡伸一, 中田昌男, 重松久之, 安藤陽夫, 井野川英利, 前田宏也, 永廣格, 片岡正文, 森山重治, 水谷尚雄, 杉本龍士郎, 小谷一敏, 三好新一郎

肺癌 51 ( 5 ) 354 - 354 2011.10

21世紀の肺癌治療戦略標準治療と個別化治療肺癌治療の進歩臨床につながった分子腫瘍学

豊岡伸一, 宗淳一, 三好新一郎

日本医学会総会会誌 28回 ( I ) 209 - 209 2011.10

悪性胸膜中皮腫に対するマイクロRNA34b/cを用いたアデノウイルス遺伝子治療の可能性(Anti-proliferative effect of microRNA-34b/c adenoviral gene transfer on malignant pleural mesotheliomas)

宗淳一, 豊岡伸一, 久保孝文, 上野剛, 深澤拓也, 阪口政清, 佃和憲, 浅野博昭, 山本寛斉, 許南浩, 三好新一郎

日本癌学会総会記事 70回 267 - 267 2011.9

肺がんの亜分類と標的治療分子標的薬の今後の展望(Beyond EGFR/ALK/HER2)

豊岡伸一, 宗淳一, 上野剛, 山根正修, 大藤剛宏, 三好新一郎

日本癌学会総会記事 70回 287 - 287 2011.9

胸部悪性腫瘍疾患に対する新規Hsp90阻害薬NVP-AUY922の抗腫瘍効果の検討(Antitumor evaluation of NVP-AUY922, a novel Hsp90 inhibitor, on thoracic malignant cell lines)

上野剛, 豊岡伸一, 佃和憲, 高岡宗徳, 宗淳一, 牧佑歩, 村岡孝幸, 田中則光, 浅野博昭, 山根正修, 大藤剛宏, 猶本良夫, 三好新一郎

日本癌学会総会記事 70回 404 - 404 2011.9

小細胞肺癌におけるmicroRNA-34b/cのメチル化とその役割

田中則光, 豊岡伸一, 宗淳一, 牧祐歩, 村岡孝幸, 上野剛, 浅野博昭, 佃和憲, 三好新一郎

日本癌治療学会誌 46 ( 2 ) 769 - 769 2011.9

Molecular oncology of lung cancer. Reviewed

Shinichi Toyooka, Tetsuya Mitsudomi, Junichi Soh, Keiju Aokage, Masaomi Yamane, Takahiro Oto, Katsuyuki Kiura, Shinichiro Miyoshi

General thoracic and cardiovascular surgery 59 ( 8 ) 527 - 37 2011.8

Language：English Publishing type：Research paper (scientific journal)

Progress in genetic engineering has made it possible to elucidate the molecular biological abnormalities in lung cancer. Mutations in KRAS and P53 genes, loss of specific alleles, and DNA methylation of the tumor suppressor genes were the major abnormalities investigated between 1980 and the 2000s. In 2004, mutations in the epidermal growth factor receptor (EGFR) gene that cause oncogene addiction were discovered in non-small-cell lung cancers (NSCLCs), especially in adenocarcinomas. Because they are strongly associated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), a great deal of knowledge has been acquired in regard to both EGFR and other genes in the EGFR family and their downstream genes. Moreover, in 2007 the existence of the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was discovered in NSCLC; and the same as EGFR-TKIs, ALK inhibitors are being found to be highly effective in lung cancers that have this translocation. These discoveries graphically illustrate that molecular biological findings are directly linked to the development of clinical oncology and to improving the survival rates of lung cancer patients. Here, we review the remarkable progress in molecular biological knowledge acquired thus far in regard to lung cancer, especially NSCLC, and the future possibilities.

DOI： 10.1007/s11748-010-0743-3

Epigenetic Silencing of MicroRNA-34b/c Plays an Important Role in the Pathogenesis of Malignant Pleural Mesothelioma Reviewed

Takafumi Kubo, Shinichi Toyooka, Kazunori Tsukuda, Masakiyo Sakaguchi, Takuya Fukazawa, Junichi Soh, Hiroaki Asano, Tsuyoshi Ueno, Takayuki Muraoka, Hiromasa Yamamoto, Yasutomo Nasu, Takumi Kishimoto, Harvey I. Pass, Hideki Matsui, Nam-ho Huh, Shinichiro Miyoshi

CLINICAL CANCER RESEARCH 17 ( 15 ) 4965 - 4974 2011.8

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Unlike other malignancies, TP53 mutations are rare in MPM. Recent studies have showed that altered expression of microRNA (miRNA) is observed in human malignant tumors. In this study, we investigated the alterations of miR-34s, a direct transcriptional target of TP53, and the role of miR-34s on the pathogenesis of MPM.
Experimental Design: Aberrant methylation and expression of miR-34s were examined in MPM cell lines and tumors. miR-34b/c was transfected to MPM cells to estimate the protein expression, cell proliferation, invasion, and cell cycle.
Results: Aberrant methylation was present in 2 (33.3%) of 6 MPM cell lines and 13 (27.7%) of 47 tumors in miR-34a and in all 6 MPM cell lines (100%) and 40 (85.1%) of 47 tumors in miR-34b/c. Expression of miR-34a and 34b/c in all methylated cell lines was reduced and restored with 5-aza-2'-deoxycytidine treatment. Because epigenetic silencing was the major event in miR-34b/c, we investigated the functional role of miR-34b/c in MPM. miR-34b/c-transfected MPM cells with physiologic miR-34b/c expression exhibited antiproliferation with G(1) cell cycle arrest and suppression of migration, invasion, and motility. The forced overexpression of miR-34b/c, but not p53, showed a significant antitumor effect with the induction of apoptosis in MPM cells.
Conclusions: We show that the epigenetic silencing of miR-34b/c by methylation is a crucial alteration and plays an important role in the tumorigenesis of MPM, suggesting potential therapeutic options for MPM. Clin Cancer Res; 17(15); 4965-74. (C)2011 AACR.

DOI： 10.1158/1078-0432.CCR-10-3040

頸部及び剣状突起下アプローチで同時切除した縦隔内甲状腺腫合併胸腺癌の1例

三浦章博, 宗淳一, 木村紘爾, 山根正修, 豊岡伸一, 大藤剛宏, 土井原博義, 三好新一郎

肺癌 51 ( 4 ) 314 - 314 2011.8

ラジオ波焼灼術後に生じた仮性肺動脈瘤へのコイル塞栓が気管支に穿通した1例

木村紘爾, 宗淳一, 古川公之, 林達朗, 山根正修, 豊岡伸一, 大藤剛宏, 三好新一郎, 金澤右

肺癌 51 ( 4 ) 317 - 317 2011.8

両側肺腺癌に対する術前放射線化学療法後両側の肺切除を行い、その後"たこつぼ心筋症"を発症した1例

林達朗, 豊岡伸一, 宗淳一, 古川公之, 山根正修, 大藤剛宏, 三好新一郎, 木浦勝行

肺癌 51 ( 4 ) 312 - 312 2011.8

Percutaneous radiofrequency ablation of clinical stage I non-small cell lung cancer Reviewed

Takao Hiraki, Hideo Gobara, Hidefumi Mimura, Yusuke Matsui, Shinichi Toyooka, Susumu Kanazawa

JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 142 ( 1 ) 24 - 30 2011.7

Language：English Publishing type：Research paper (scientific journal) Publisher：MOSBY-ELSEVIER

Objective: This study aimed at retrospectively evaluating the outcomes of radiofrequency ablation of clinical stage I non-small cell lung cancer.
Methods: This study was carried out on 50 nonsurgical candidates (29 men and 21 women; mean age, 74.7 years) with clinical stage I (IA, n = 38; IB, n = 12) histologically proven non-small cell lung cancer. A total of 52 tumors were treated with 52 ablation sessions. Radiofrequency ablation was performed percutaneously under computed tomography fluoroscopic guidance. The outcomes of radiofrequency ablation were evaluated, including toxicity, local efficacy, and patient survival. Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. Local efficacy was evaluated by using computed tomography scan with a contrast medium. The overall, cancer-specific, and disease-free survivals were estimated with Kaplan-Meier analysis.
Results: Grade 2 and 3 adverse events occurred after 6 (12%) and 3 (6%) of the 52 sessions, respectively. The median follow-up period was 37 months. Local progression was observed in 16 (31%) of the 52 tumors. The median survival time was 67 months. The overall, cancer-specific, and disease-free survivals were 94%, 100%, and 82% at 1 year, 86%, 93%, and 64% at 2 years, and 74%, 80%, and 53% at 3 years, respectively.
Conclusions: Radiofrequency ablation of clinical stage I non-small cell lung cancer was minimally invasive and provided promising patient survival, although the local efficacy needs to be improved. (J Thorac Cardiovasc Surg 2011;142:24-30)

DOI： 10.1016/j.jtcvs.2011.02.036

Inhibition of mTOR by temsirolimus contributes to prolonged survival of mice with pleural dissemination of non-small-cell lung cancer cells Reviewed

Toshiaki Ohara, Munenori Takaoka, Shinichi Toyooka, Yasuko Tomono, Toshio Nishikawa, Yasuhiro Shirakawa, Tomoki Yamatsuji, Noriaki Tanaka, Toshiyoshi Fujiwara, Yoshio Naomoto

CANCER SCIENCE 102 ( 7 ) 1344 - 1349 2011.7

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Temsirolimus (CCI-779), a recently synthesized analogue of rapamycin, specifically inhibits mTOR and has been approved for clinical use in renal cell carcinoma. Recent reports have indicated the growth inhibitory effect of temsirolimus in some cancers including non-small-cell lung carcinoma (NSCLC). In this study, we aimed to explore the potential therapeutic use of temsirolimus as a treatment for NSCLC. Using cultured NSCLC cells (A549, H1299, and H358), we determined the effect of temsirolimus on cell proliferation and its antitumor effects on subcutaneous tumors, as well as its contribution to the survival of mice having pleural dissemination of cancer cells, mimicking advanced NSCLC. Temsirolimus suppressed proliferation of NSCLC cells in a dose-dependent manner, with an IC(50) of < 1 nM. Western blot analysis revealed that temsirolimus treatment specifically inhibited the phosphorylation of mTOR and its downstream effectors in 1 h, accompanied by an increased cell population in the G(0)/G(1) phase, but according to flow cytometry, the cell population did not increase in the sub-G(0) phase. When NSCLC subcutaneous tumor-bearing mice were treated with temsirolimus, tumor volume was significantly reduced (tumor volume on day 35: vehicle vs temsirolimus = 1239 vs 698 cm(3); P < 0.05). Furthermore, prolonged survival was observed in pleural disseminated tumor-bearing mice with temsirolimus treatment (median survival: vehicle vs temsirolimus = 53.5 vs 72.5 days; P < 0.05). These results suggest that temsirolimus could be useful for NSCLC treatment, due to its antiproliferative effect, and could be a potential treatment for advanced NSCLC, giving prolonged survival. (Cancer Sci 2011; 102: 1344-1349)

DOI： 10.1111/j.1349-7006.2011.01967.x

Less maintenance immunosuppression in lung transplantation following hematopoietic stem cell transplantation from the same living donor Reviewed

Chen F, Yamane M, Inoue M, Shiraishi T, Oto T, Minami M, Yanagisawa J, Fujinaga T, Shoji T, Toyooka S, Okumura M, Miyoshi S, Bando T, Date H

Am J Transplant 2011 Jul;11(7):1509-16. doi: 10.1111/j.1600-6143.2011.03591.x. Epub 2011 Jun 14 2011.7

Aberrant Methylation of p21 Gene in Lung Cancer and Malignant Pleural Mesothelioma Reviewed

Hirotake Teramen, Kazunori Tsukuda, Norimitsu Tanaka, Tsuyoshi Ueno, Takafumi Kubo, Midori Ando, Junichi Soh, Hiroaki Asano, Harvery I. Pass, Shinichi Toyooka, Shinichiro Miyoshi

ACTA MEDICA OKAYAMA 65 ( 3 ) 179 - 184 2011.6

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Suppression of p21 has been implicated in the genesis and progression of many human malignancies. DNA methylation is an important mechanism of gene silencing in human malignancies. In this study, we examined the expression status and aberrant methylaion of p21 in lung cancers and malignant pleural mesotheliomas (MPM). We used 12 small cell lung cancer (SCLC) cell lines, 13 non-small cell lung cancer (NSCLC) cell lines, 50 primary NSCLCs, 6 MPM cell lines and 10 primary MPMs. The expression and methylation of p21 was examined by reverse transcription-PCR (RT-PCR), Western blotting and methylation-specific PCR (MSP) assay. Loss of p21 protein expression was observed in 7 SCLC cell lines (58.3%), 5 NSCLC cell lines (38.5%) and 3 MPM cell lines (50%) while mRNA expression was lost in 2 SCLC cell lines (16.7%), 2 NSCLC cell lines (15.4%) and none of the MPM cell lines. Aberrant methylation of p21 was found in 8.3% of SCLC cell lines, 30.2% of NSCLCs and 6.3% of MPMs. Among primary NSCLCs, methylation in adenocarcinomas was significantly more frequent than in squamous cell carcinomas. Loss of p21 expression was frequently observed in lung cancers and MPMs and aberrant methylation was one of the mechanisms of suppression of p21, especially in NSCLCs.

DOI： 10.18926/AMO/46629

Pediatric transplantation:International consensus and future in Japan 小児肺移植における生体肺葉移植の位置づけ(Pediatric transplantation: International consensus and future in Japan Living-donor-lobar lung transplantation: A practical option for pediatric lung transplant candidates in Japan)

大藤剛宏, 山根正修, 伊達洋至, 南正人, 白石武史, 杉本誠一郎, 青景圭樹, 原田昌明, 伊賀徳周, 西川仁士, 岡田真典, 大谷真二, 三好健太郎, 脇直久, 宗淳一, 豊岡伸一, 三好新一郎

日本外科学会雑誌 112 ( 臨増1-2 ) 197 - 197 2011.5

The impact of adenoviral gene transfer of microRNA-34b/c on malignant pleural mesotheliomas Reviewed

Soh Junichi, Toyooka Shinichi, Kubo Takafumi, Fukazawa Takuya, Sakaguchi Masakiyo, Ueno Tsuyoshi, Tsukuda Kazunori, Asano Hiroaki, Yamamoto Hiromasa, Huh Nam-ho, Miyoshi Shinichiro

CANCER RESEARCH 71 2011.4

Technique for Creation of Artificial Pneumothorax for Pain Relief during Radiofrequency Ablation of Peripheral Lung Tumors: Report of Seven Cases Reviewed

Takao Hiraki, Hideo Gobara, Kentaro Shibamoto, Hidefumi Mimura, Yuko Soda, Mayu Uka, Yoshihisa Masaoka, Shinichi Toyooka, Susumu Kanazawa

JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 22 ( 4 ) 503 - 506 2011.4

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

This report describes seven cases in which a pneumothorax was artificially created for relief from severe pain that occurred during radiofrequency (RF) ablation of peripheral lung tumors. In this procedure the multitined probe surrounding the legion was advanced into the chest, displaoing the tines and the peripheral tumor away from the parietal pleura and the chest wall and resulting in pain relief in one patient; in the remaining patients, an intravenous catheter was also introduced, followed by the administration of carbon dioxide (CO2) into the space between the tumor and the parietal pleura. The pain decreased-considerably-immediately after this procedure. No complication related to the creation of the artificial pneumothorax was observed. Creation of an artificial pneumothorax is a safe and effective method for pain relief.

DOI： 10.1016/j.jvir.2010.12.018

NSCLCの外科的切除におけるCTNBの病理学的陰性試料のEGFR変異の検出(Detection of EGFR mutation in pathological negative specimens of CTNB in surgically resected NSCLCs)

上野剛, 豊岡伸一, 宗淳一, 浅野博昭, 佃和憲, 田中則光, 村岡孝幸, 山根正修, 大藤剛宏, 三好新一郎

日本呼吸器外科学会雑誌 25 ( 3 ) O23 - 04 2011.4

神経性食思不振症に合併した小児両側自然気胸の1例

岡田真典, 山根正修, 宗淳一, 豊岡伸一, 大藤剛宏, 三好新一郎

日本呼吸器外科学会雑誌 25 ( 3 ) P22 - 06 2011.4

肺癌におけるmicroRNA-9sの異常メチル化と臨床病理学的特徴の相関

村岡孝幸, 豊岡伸一, 宗淳一, 牧佑歩, 上野剛, 青景圭樹, 山根正修, 大藤剛宏, 三好新一郎

日本呼吸器外科学会雑誌 25 ( 3 ) O04 - 05 2011.4

Role of Computed Tomography Fluoroscopy-Guided Cutting Needle Biopsy of Lung Lesions After Transbronchial Examination Resulting in Negative Diagnosis Reviewed

Yusuke Matsui, Takao Hiraki, Hidefumi Mimura, Hideo Gobara, Daisaku Inoue, Tatsuhiko Iishi, Shinichi Toyooka, Susumu Kanazawa

CLINICAL LUNG CANCER 12 ( 1 ) 51 - 55 2011.1

Language：English Publishing type：Research paper (scientific journal) Publisher：CIG MEDIA GROUP, LP

Introduction: Computed tomography (CT)-guided lung biopsy is occasionally used for the lesions that were diagnosed as nonmalignant by transbronchial examination despite the fact that other clinical data suggested those as malignant. The purpose of this study is to evaluate the outcomes of CT fluoroscopy-guided cutting needle biopsy of lung lesions after transbronchial examination resulting in negative diagnosis. Patients and Methods: We retrospectively evaluated the outcomes of CT fluoroscopy-guided lung biopsy for 351 lesions (mean size, 2.8 cm) that were found to be nonmalignant by transbronchial examination. Diagnostic yield, including sensitivity and specificity for the diagnosis of malignancy, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. Various variables were analyzed to determine the factors for diagnostic failure. Results: The biopsy result was nondiagnostic, true-positive, true-negative, false-positive, or false-negative for 2, 262, 70, 0, or 17 lesions, respectively. Thus, the sensitivity, specificity, PPV, NPV, and accuracy of CT fluoroscopy-guided cutting needle biopsy was found to be 93% (262/281), 100% (70/70), 100% (262/262), 80% (70/87), and 94% (332/351), respectively. There was no significant risk factor for diagnostic failure. Conclusion: Computed tomography fluoroscopy-guided cutting needle lung biopsy is a useful technique to correct or confirm negative diagnosis by transbronchial examination.

DOI： 10.3816/CLC.2011.n.007

Surgery after induction chemoradiotherapy

Toyooka, S., Soh, J., Sugimoto, S., Yamane, M., Oro, T., Miyoshi, S.

Japanese Journal of Chest Diseases 70 ( 9 ) 2011

肺癌切除後に発症し治療に難渋した肺アスペルギルス症の一例

三好雄一郎, 山根正修, 牧佑歩, 宗淳一, 豊岡伸一, 大藤剛宏, 三好新一郎

岡山医学会雑誌 122 ( 3 ) 280 - 280 2010.12

非典型部位に発生した胸腺腫の1切除例

田中真, 宗淳一, 大谷真二, 山根正修, 豊岡伸一, 大藤剛宏, 三好新一郎

岡山医学会雑誌 122 ( 3 ) 280 - 280 2010.12

術前補助療法進行非小細胞肺癌に対する導入化学放射線療法

枝園和彦, 豊岡伸一, 武本充広, 宗淳一, 山根正修, 大藤剛宏, 堀田勝幸, 頼冠名, 瀧川奈義夫, 田端雅弘, 木浦勝行, 三好新一郎

肺癌 50 ( 5 ) 472 - 472 2010.10

肺癌の分子標的治療基礎から臨床へ EGFR-TKIの耐性機構とその克服

豊岡伸一, 宗淳一, 大谷弘樹, 小林成行, 久保孝文, 上野剛, 青景圭樹, 山根正修, 大藤剛宏, 木浦勝行, 三好新一郎

肺癌 50 ( 5 ) 450 - 450 2010.10

肺移植後に発症した空腸悪性リンパ腫の一例

村岡孝幸, 浅野博昭, 大藤剛宏, 佃和憲, 伊賀徳周, 原田昌明, 古川公之, 増田紘子, 澤田芳行, 田中則光, 内藤稔, 宗淳一, 山根正修, 豊岡伸一, 三好新一郎

日本癌治療学会誌 45 ( 2 ) 880 - 880 2010.9

マイクロRNA34b/cのメチル化による発現低下は悪性胸膜中皮腫の重要な分子病態である(Epigenetic silencing of microRNA-34b/c plays a pivotal role in pathogenesis of malignant mesothelioma pathogenesis)

久保孝文, 豊岡伸一, 佃和憲, 阪口政清, 深澤拓也, 宗淳一, 浅野博昭, 那須保友, 岸本卓巳, 松井秀樹, 許南浩, 三好新一郎

日本癌学会総会記事 69回 44 - 44 2010.8

肺癌における癌抑制遺伝子LKB1遺伝子不活化に関する検討(The profile of LKB1 altered non-small-cell lung cancers)

宗淳一, 豊岡伸一, 上野剛, 久保孝文, 浅野博昭, 佃和憲, 三好新一郎

日本癌学会総会記事 69回 455 - 455 2010.8

シグナル伝達 EGFR変異肺小細胞癌におけるOncogenic Addictionの機構について(Signal transduction The mechanism of oncogenic addiction of EGFR mutated non small cell lung cancer)

佃和憲, 久保孝文, 豊岡伸一, 宗淳一, 三好新一郎

日本癌学会総会記事 69回 105 - 105 2010.8

Brachial Nerve Injury Caused by Percutaneous Radiofrequency Ablation of Apical Lung Cancer: A Report of Four Cases Reviewed

Takao Hiraki, Hideo Gobara, Hidefumi Mimura, Yoshifumi Sano, Shinichi Toyooka, Kentaro Shibamoto, Ryotaro Kishi, Mayu Uka, Susumu Kanazawa

JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 21 ( 7 ) 1129 - 1133 2010.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

The present report describes four cases of brachial nerve injury caused by percutaneous radiofrequency (RF) ablation of lung cancer. All the tumors were located in the lung apex. The patients developed symptoms indicative of a low brachial plexus injury during RF ablation or as long as 7 days afterward. These symptoms partially receded over time. The indications of RF ablation in patients with apical lung cancer should be carefully determined because of the risk of brachial nerve injury associated with the procedure.

DOI： 10.1016/j.jvir.2010.03.007

Suppression of Inflammatory Cytokines During Ex Vivo Lung Perfusion With an Adsorbent Membrane Reviewed

Tomokazu Kakishita, Takahiro Oto, Shiro Hori, Kentaroh Miyoshi, Shinji Otani, Sumiharu Yamamoto, Naohisa Waki, Osamu Yoshida, Mikio Okazaki, Masaomi Yamane, Shinichi Toyooka, Yoshifumi Sano, Shinichiro Miyoshi

ANNALS OF THORACIC SURGERY 89 ( 6 ) 1773 - 1781 2010.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background. Lung grafts can be perfused ex vivo for 2 hours without edema formation; however, prolonged ex vivo lung perfusion (EVLP) eventually induces lung injury. This study evaluated the change in proinflammatory cytokines of the perfusate during EVLP and investigated the effect of cytokine removal using an adsorbent membrane.
Methods. Porcine heart-lung blocks were harvested after electrically induced cardiac arrest and underwent 12-hour EVLP with an adsorbent membrane (membrane group: n = 5) and without an adsorbent membrane (control group: n = 6).
Results. In the control group, both tumor necrosis factor-alpha and interleukin 8 levels were elevated in the perfusate 2 hours after perfusion. Although tumor necrosis factor-alpha and interleukin 8 levels were significantly lower in the membrane group than in the control group during the EVLP period, there was no significant difference in oxygenation, pulmonary vascular resistance, edema formation, or myeloperoxidase activity between the two groups.
Conclusions. Tumor necrosis factor-alpha and interleukin 8 levels of the perfusate were elevated during EVLP. Although adverse effects of these inflammatory cytokines were anticipated, removal of inflammatory cytokines by the adsorbent membrane did not improve lung function during prolonged EVLP. Factors other than the cytokines may play a major role in causing lung injury during EVLP. Further research is needed to investigate the real mechanism of lung graft injury during prolonged EVLP and to establish longer EVLP duration for graft treatment. This strategy could contribute to the salvage of potentially damaged lungs, especially from cardiac death donors, and to expansion of the donor pool. (Ann Thorac Surg 2010; 89: 1773-81) (C) 2010 by The Society of Thoracic Surgeons

DOI： 10.1016/j.athoracsur.2010.02.077

Calcineurin Inhibitor-Related Cholestasis Complicating Lung Transplantation Reviewed

Takahiro Oto, Mikio Okazaki, Ken Takata, Moritoki Egi, Masaomi Yamane, Shinichi Toyooka, Yoshifumi Sano, Gregory I. Snell, Keiji Goto, Shinichiro Miyoshi

ANNALS OF THORACIC SURGERY 89 ( 5 ) 1664 - 1665 2010.5

Language：English Publisher：ELSEVIER SCIENCE INC

Hepatotoxicity, including cholestasis, is a rare but significant complication of treatment with calcineurin inhibitors. Timely life-saving therapy with revision of immunosuppression is mandatory. A 43-year-old woman with pulmonary hypertension was found to have severe cholestasis (serum bilirubin up to 35 mg/dL) after a living-donor lobar lung transplantation. Calcineurin-inhibitor cholestasis markedly improved after withdrawal of the calcineurin inhibitor, initiation of sirolimus, and interleukin-2 receptor blockade. Awareness of the diagnostic criteria of this rare posttransplant complication is important to initiate timely therapy. (Ann Thorac Surg 2010;89:1664-5) (C) 2010 by The Society of Thoracic Surgeons

DOI： 10.1016/j.athoracsur.2009.09.081

Frequent silencing of tumor suppressive MicroRNA-34b/c by aberrant methylation in malignant mesothelioma Reviewed

Kubo Takafumi, Toyooka Shinichi, Tsukuda Kazunori, Asano Hiroaki, Sakaguchi Masakiyo, Soh Junichi, Ueno Tsuyoshi, Yamamoto Hiromasa, Yamane Masaomi, Oto Takahiro, Nasu Yasutomo, Matsui Hideki, Huh Nam Ho, Miyoshi Shinichro

CANCER RESEARCH 70 2010.4

肺癌診療の分子生物学的展開肺腺癌の遺伝子異常はどこまで解明されたか? EGFR、KRAS遺伝子変異・増幅を中心に肺腺癌に迫る

宗淳一, 豊岡伸一, 山本寛斉, 重松久之, 上野剛, 久保孝文, 浅野博昭, 山根正修, 佃和憲, 大藤剛宏, 三好新一郎

日本呼吸器外科学会雑誌 24 ( 3 ) 372 - 372 2010.4

肺移植後急性拒絶反応と抗ドナー特異的抗体価の推移急性拒絶発症を予見できるか

三好健太郎, 佐野由文, 岡崎幹生, 山根正修, 豊岡伸一, 大藤剛宏, 三好新一郎

日本呼吸器外科学会雑誌 24 ( 3 ) 416 - 416 2010.4

肺癌特異的癌抑制遺伝子であるLKB1遺伝子不活化メカニズムに関する検討

宗淳一, 豊岡伸一, 山本寛斉, 重松久之, 上野剛, 久保孝文, 浅野博昭, 山根正修, 佃和憲, 大藤剛宏, 三好新一郎

日本呼吸器外科学会雑誌 24 ( 3 ) 501 - 501 2010.4

肺癌診療の分子生物学的展開 EGFR変異肺癌に対する治療戦略現在と今後

豊岡伸一, 宗淳一, 大谷弘樹, 小林成行, 久保孝文, 上野剛, 山本寛斉, 山根正修, 大藤剛宏, 三好新一郎

日本呼吸器外科学会雑誌 24 ( 3 ) 373 - 373 2010.4

EGFRチロシンキナーゼ阻害剤に対する耐性株の樹立と分子生物学的特徴の検討

上野剛, 豊岡伸一, 宗淳一, 治田賢, 久保孝文, 浅野博昭, 佃和憲, 山根正修, 大藤剛宏, 三好新一郎

日本呼吸器外科学会雑誌 24 ( 3 ) 500 - 500 2010.4

EGFR阻害剤耐性を示すEGFR変異陽性肺癌細胞株に対するHeat shock protein 90阻害剤の抗腫瘍効果の検討

宗淳一, 豊岡伸一, 小林成行, 山本寛斉, 土手秀樹, 大谷弘樹, 久保孝文, 治田賢, 上野剛, 安藤翠, 荻野敦子, 木浦勝行, 三好新一郎

組織培養研究 29 ( 1 ) 122 - 123 2010.3

EGFRチロシンキナーゼ阻害剤に対する耐性株の樹立と分子生物学的特徴の検討

上野剛, 豊岡伸一, 治田賢, 佃和憲, 宗淳一, 浅野博昭, 久保孝文, 村岡孝幸, 牧佑歩, 山根正修, 大藤剛宏, 三好新一郎

組織培養研究 29 ( 1 ) 59 - 59 2010.3

肺癌細胞株におけるTAE226の変異型EGFRチロシンキナーゼ特異的な不活化作用とその抗腫瘍効果の検討

宗淳一, 豊岡伸一, 大谷弘樹, 高岡宗徳, 阪口正清, 治田賢, 久保孝文, 山本寛斉, 浅野博昭, 佃和憲, 木浦勝行, 許南浩, 猶本良夫, 三好新一郎

組織培養研究 29 ( 1 ) 121 - 121 2010.3

Triplet Chemotherapy with Cisplatin, Docetaxel, and Irinotecan for Patients with Recurrent or Refractory Non-small Cell Lung Cancer Reviewed

Nobukazu Fujimoto, Katsuyuki Kiura, Nagio Takigawa, Yoshiro Fujiwara, Shinichi Toyooka, Shigeki Umemura, Masahiro Tabata, Hiroshi Ueoka, Mitsune Tanimoto

ACTA MEDICA OKAYAMA 64 ( 1 ) 33 - 37 2010.2

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

We examined the feasibility of triplet chemotherapy using cisplatin, docetaxel, and irinotecan for patients with recurrent or refractory non-small cell lung cancer (NSCLC), retrospectively. Twenty five patients (21 men and 4 women) with NSCLC and good performance status who were :E 70 years old were analyzed. The median age was 58 years. Most patients had performance status 1 (16/25), stage IV disease (18/25) and adenocarcinoma-histology (16/25). Cisplatin and docetaxel were given on day 1 and irinotecan on day 2; the cycle was repeated every 3 weeks. The objective response rate was 39.1% (95% confidence interval: 18.7-59.5%). The median survival time and actual 2-, 3-, and 5-year survival rates were 14.3 months, 32%, 20%, and 8%, respectively. Of note, only 6 patients were treated with gefitinib at the recurrence after triplet chemotherapy; of these, 4 (67%) achieved a partial response, which might result in favorable survival. Grade 3/4 toxicities consisted of neutropenia (100%), neutropenic fever (56%), nausea/vomiting (40%), and diarrhea (16%); no cases of treatment-related death occurred. Triplet chemotherapy showed impressive survival data in our clinical trial, but proved too toxic for use in treating patients with NSCLC in the clinical practice.

DOI： 10.18926/AMO/32866

Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial Reviewed

Tetsuya Mitsudomi, Satoshi Morita, Yasushi Yatabe, Shunichi Negoro, Isamu Okamoto, Junji Tsurutani, Takashi Seto, Miyako Satouchi, Hirohito Tada, Tomonori Hirashima, Kazuhiro Asami, Nobuyuki Katakami, Minoru Takada, Hiroshige Yoshioka, Kazuhiko Shibata, Shinzoh Kudoh, Eiji Shimizu, Hiroshi Saito, Shinichi Toyooka, Kazuhiko Nakagawa, Masahiro Fukuoka

LANCET ONCOLOGY 11 ( 2 ) 121 - 128 2010.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background Patients with non-small-cell lung cancer harbouring mutations in the epidermal growth factor receptor (EGFR) gene respond well to the EGFR-specific tyrosine kinase inhibitor gefitinib. However, whether gefitinib is better than standard platinum doublet chemotherapy in patients selected by EGFR mutation is uncertain.
Methods We did an open label, phase 3 study (WJTOG3405) with recruitment between March 31, 2006, and June 22, 2009, at 36 centres in Japan. 177 chemotherapy-naive patients aged 75 years or younger and diagnosed with stage IIIB/IV non-small-cell lung cancer or postoperative recurrence harbouring EGFR mutations (either the exon 19 deletion or L858R point mutation) were randomly assigned, using a minimisation technique, to receive either gefitinib (250 mg/day orally; n=88) or cisplatin (80 mg/m(2), intravenously) plus docetaxel (60 mg/m(2), intravenously; n=89), administered every 21 days for three to six cycles. The primary endpoint was progression-free survival. Survival analysis was done with the modified intention-to-treat population. This study is registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.
Findings Five patients were excluded (two patients were found to have thyroid and colon cancer after randomisation, one patient had an exon 18 mutation, one patient had insufficient consent, and one patient showed acute allergic reaction to docetaxel). Thus, 172 patients (86 in each group) were included in the survival analyses. The gefitinib group had significantly longer progression-free survival compared with the cisplatin plus docetaxel goup, with a median progression-free survival compared with the cisplatin plus docetaxel goup, with a median progression-free survival time of 9.2 months (95% CI 8.0-13.9) versus 6.3 months (5.8-7.8; HR 0.489, 95% CI 0.336-0.710, log-rank p<0.0001). Myelosuppression, alopecia, and fatigue were more frequent in the cisplatin plus docetaxel group, but skin toxicity, liver dysfunction, and diarrhoea were more frequent in the gefitinib group. Two patients in the gefitinib group developed interstitial lung disease (incidence 2.3%), one of whom died.
Interpretation Patients with lung cancer who are selected by EGFR mutations have longer progression-free survival if they are treated with gefitinib than if they are treated with cisplatin plus docetaxel.

DOI： 10.1016/S1470-2045(09)70364-X

[Treatment strategy and outcomes of invading apical lung cancer]. Reviewed

Toyooka S, Sou J, Sugimoto R, Yamane M, Oto T, Yoshimasu T, Okamura Y, Sano Y, Date H, Miyoshi S

Kyobu geka. The Japanese journal of thoracic surgery 63 ( 1 ) 57 - 64 2010.1

The estrogen receptor influences microtubule-associated protein tau (MAPT) expression and the selective estrogen receptor inhibitor fulvestrant downregulates MAPT and increases the sensitivity to taxane in breast cancer cells Reviewed

Hirokuni Ikeda, Naruto Taira, Fumikata Hara, Takeo Fujita, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka, Tomohiro Nogami, Tadahiko Shien, Hiroyoshi Doihara, Shinichiro Miyoshi

BREAST CANCER RESEARCH 12 ( 3 ) R43 2010

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Introduction: Microtubule-associated protein tau (MAPT) inhibits the function of taxanes and high expression of MAPT decreases the sensitivity to taxanes. The relationship between estrogen receptor (ER) and MAPT in breast cancer is unclear. In this study, we examined the correlation of MAPT expression with the sensitivity of human breast cancer cells to taxanes, and the relationship between ER and MAPT.
Methods: The correlation between MAPT expression and sensitivity to taxanes was investigated in 12 human breast cancer cell lines. Alterations in cellular sensitivity to taxanes were evaluated after knockdown of MAPT expression. ER expression was knocked down or stimulated in MAPT-and ER-positive cell lines to examine the relationship between ER and MAPT. The cells were also treated with hormone drugs (tamoxifen and fulvestrant) and taxanes.
Results: mRNA expression of MAPT did not correlate with sensitivity to taxanes. However, expression of MAPT protein isoforms of less than 70 kDa was correlated with a low sensitivity to taxanes. Downregulation of MAPT increased cellular sensitivity to taxanes. MAPT protein expression was increased by stimulation with 17-beta-estradiol or tamoxifen, but decreased by ER downregulation and by fulvestrant, an ER inhibitor. The combination of fulvestrant with taxanes had a synergistic effect, whereas tamoxifen and taxanes had an antagonistic effect.
Conclusions: Expression of MAPT protein isoforms of less than 70 kDa is correlated with a low sensitivity to taxanes in breast cancer cells. ER influences MAPT expression and fulvestrant increases the sensitivity to taxanes in MAPT-and ER-positive breast cancer cells.

DOI： 10.1186/bcr2598

Volume reduction surgery for pulmonary emphysema

Sugimoto, S., Oto, T., Soh, J., Yamane, M., Toyooka, S., Miyoshi, S.

Japanese Journal of Chest Diseases 69 ( SUPPL. ) 2010

CT fluoroscopy-guided biopsy of 1,000 pulmonary lesions performed with 20-gauge coaxial cutting needles: diagnostic yield and risk factors for diagnostic failure. Reviewed International journal

Hiraki T, Mimura H, Gobara H, Iguchi T, Fujiwara H, Sakurai J, Matsui Y, Inoue D, Toyooka S, Sano Y, Kanazawa S

Chest 136 ( 6 ) 1612 - 1617 2009.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Although conventional CT scan-guided needle biopsy is an established diagnostic method for pulmonary lesions, few large studies have been conducted on the diagnostic outcomes of CT fluoroscopy-guided lung biopsy. We have conducted a retrospective analysis to evaluate the diagnostic outcomes of 1,000 CT fluoroscopy-guided lung biopsies performed with 20-gauge coaxial cutting needles. METHODS: We determined the diagnostic yield of CT fluoroscopy-guided lung biopsies performed with 20-gauge coaxial cutting needles for 1,000 lesions in 901 patients. Independent risk factors for diagnostic failure (ie, nondiagnostic, false-positive, and false-negative results) were determined with multivariate logistic regression analysis. RESULTS: The biopsy results were nondiagnostic in 0.6% of the lesions (6 of 1,000 lesions). The sensitivity and specificity for the diagnosis of malignancy was 94.2% (741 of 787 lesions) and 99.1% (211 of 213 lesions), respectively; diagnostic accuracy was 95.2% (952 of 1,000 lesions). For lesions measuring <or= 1.0 cm, the diagnostic accuracy was 92.7% (140 of 151 lesions). The significant independent risk factors for diagnostic failure were as follows: the acquisition of two or fewer specimens (odds ratio [OR], 2.43; p = 0.007), lesions in the lower lobe (OR, 2.50; p = 0.003), malignant lesions (OR, 7.16; p = 0.007), and lesions measuring <or= 1.0 cm (OR, 3.85; p = 0.016) and >or= 3.1 cm (OR, 4.32; p = 0.007). CONCLUSIONS: CT fluoroscopy-guided lung biopsy performed with 20-gauge coaxial cutting needles resulted in a high diagnostic yield, even in the case of small lesions. Factors such as the acquisition of two or fewer specimens, lesions in the lower lobe, malignant lesions, and lesions measuring <or= 1.0 cm or >or= 3.1 cm significantly increased the rate of diagnostic failure.

DOI： 10.1378/chest.09-0370

Percutaneous computed tomography-guided lung biopsy and pleural dissemination: an assessment by intraoperative pleural lavage cytology. Reviewed

Sano Y, Date H, Toyooka S, Oto T, Yamane M, Hiraki T, Gobara H, Mimura H, Kanazawa S

Cancer 115 ( 23 ) 5526 - 5533 2009.12

Extracorporeal membrane oxygenation bridging to living-donor lobar lung transplantation. Reviewed

Miyoshi K, Oto T, Okazaki M, Yamane M, Toyooka S, Goto K, Sano Y, Sano S, Miyoshi S

The Annals of thoracic surgery 88 ( 5 ) e56 - 7 2009.11

Usefulness of cumulative smoking dose for identifying the EGFR mutation and patients with non-small-cell lung cancer for gefitinib treatment. Reviewed

Jida M, Toyooka S, Mitsudomi T, Takano T, Matsuo K, Hotta K, Tsukuda K, Kubo T, Yamamoto H, Yamane M, Oto T, Sano Y, Kiura K, Yatabe Y, Ohe Y, Date H, Miyoshi S

Cancer science 100 ( 10 ) 1931 - 1934 2009.10

肺尖部肺癌に対する外科的戦略肺尖部胸壁浸潤肺癌に対する治療外科治療を中心として

豊岡伸一, 宗淳一, 山根正修, 大藤剛宏, 吉増達也, 岡村吉隆, 佐野由文, 三好新一郎

日本臨床外科学会雑誌 70 ( 増刊 ) 337 - 337 2009.10

Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells. Reviewed

Soh J, Okumura N, Lockwood WW, Yamamoto H, Shigematsu H, Zhang W, Chari R, Shames DS, Tang X, MacAulay C, Varella-Garcia M, Vooder T, Wistuba II, Lam S, Brekken R, Toyooka S, Minna JD, Lam WL, Gazdar AF

PloS one 4 ( 10 ) e7464 2009.10

原発性肺癌に対する内照射後に気管支狭窄を繰り返した1例

渡邉元嗣, 大藤剛宏, 岡崎幹生, 豊岡伸一, 佐野由文, 三好新一郎

日本臨床外科学会雑誌 70 ( 増刊 ) 812 - 812 2009.10

ブタ胸管のシーリングによって証明された、縦隔リンパ節郭清におけるハーモニックの有用性

岡崎幹生, 豊岡伸一, 大谷真二, 山根正修, 大藤剛宏, 佐野由文, 三好新一郎

肺癌 49 ( 5 ) 671 - 671 2009.10

肺腺癌におけるKRAS遺伝子変化の生物学的活性および予後に対する効果の検討

宗淳一, 豊岡伸一, 山本寛斉, 重松久之, 山根正修, 大藤剛宏, 佐野由文, 三好新一郎

肺癌 49 ( 5 ) 624 - 624 2009.10

当院における縦隔原発非セミノーマ胚細胞腫瘍に対する集学的治療

二宮崇, 木浦勝行, 瀧川奈義夫, 佐野由文, 大藤剛宏, 豊岡伸一, 山根正修, 堀田勝幸, 田端雅弘, 谷本光音, 三好新一郎, 伊達洋至

肺癌 49 ( 5 ) 645 - 645 2009.10

術前induction治療後の手術手技術前放射線同時併用化学療法後の肺切除手術手技

佐野由文, 豊岡伸一, 大藤剛宏, 山根正修, 木浦勝行, 田端雅弘, 瀧川奈義夫, 堀田勝幸, 武本充広, 三好新一郎

肺癌 49 ( 5 ) 574 - 574 2009.10

局所進行非小細胞肺癌に対する集学的治療の現状と展望縦隔リンパ節転移を伴う非小細胞肺癌に対する術前放射線同時併用化学療法の治療成績

豊岡伸一, 木浦勝行, 武本充広, 山根正修, 大藤剛宏, 枝園和彦, 堀田勝幸, 頼冠名, 瀧川奈義夫, 田端雅弘, 佐野由文, 伊達洋至, 三好新一郎

肺癌 49 ( 5 ) 578 - 578 2009.10

生体肺移植のドナー手術における安全性の検討

佐野由文, 大藤剛宏, 豊岡伸一, 山根正修, 岡崎幹生, 石原恵, 三好新一郎

移植 44 ( 総会臨時 ) 315 - 315 2009.9

肺高血圧症crisisに対するVA-ECMOをbridgeとした両側生体肺移植

三好健太郎, 大藤剛宏, 岡崎幹生, 山根正修, 豊岡伸一, 佐野由文, 三好新一郎

移植 44 ( 総会臨時 ) 316 - 316 2009.9

小児期から青年期における胸部悪性腫瘍の臨床的特徴と外科的治療

佐野由文, 豊岡伸一, 大藤剛宏, 山根正修, 木浦勝行, 田端雅弘, 瀧川奈義夫, 堀田勝幸, 三好新一郎

日本癌治療学会誌 44 ( 2 ) 535 - 535 2009.9

Clinical outcomes of short hook wire and suture marking system in thoracoscopic resection for pulmonary nodules Reviewed

Kentaroh Miyoshi, Shinichi Toyooka, Hideo Gobara, Takahiro Oto, Hidefumi Mimura, Yoshifumi Sano, Susumu Kanazawa, Hiroshi Date

EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY 36 ( 2 ) 378 - 382 2009.8

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Objective: The short hook wire and suture marking system is a device for localization of small pulmonary nodules in thoracoscopic resection. We and other authors have shown the feasibility of the marking procedure. In this study, we reviewed our recent experience to examine the problems for resecting procedure using the device and determine if the system negatively impacts the survival rates for lung cancers. Methods: Between November 1996 and March 2007, a total of 125 pulmonary nodular lesions in 108 patients were intended for thoracoscopic resection after localization with computed tomography-guided short hook wire and suture placement. We reviewed the major problems during surgery among all cases and prognosis in 64 patients with primary lung cancer. Results: One hundred and seventeen lesions (93.6%) were successfully resected by intitial resection with no major complication. However, we experienced missing events, the major problem during surgery, which was defined as temporarily missing lesions or hook wires. Eight missing events (6.4%) consisting of five unresected lesions and three remaining hook wires occurred after initial wedge resection. All the missing lesions and one remaining hook wire were recovered by additional resection. No specific factors of lesions, including location, diameter, distance from the pleural surface, and opacification were related to incidence of the 'missing event'. Five-year survival of patients with stage IA lung cancer was 90.0% with no local recurrence. Conclusions: Our localization method assured a consistent quality of resection regardless of the lesion characteristics and a reasonable prognosis for patients with primary lung cancer. The short hook wire and suture system provides acceptable utility in thoracoscopic surgery. (C) 2009 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ejcts.2009.03.039

上皮成長因子受容体遺伝子変異は喫煙・性別とは独立に肺腺癌患者のゲフィチニブ治療における予後に関係する

豊岡伸一, 高野利実, 高坂貴行, 堀田勝幸, 松尾恵太郎, 市原周治, 藤原義朗, 宗淳一, 大谷弘樹, 木浦勝行, 青江啓介, 谷田部恭, 大江裕一郎, 光冨徹哉, 伊達洋至

肺癌 49 ( 4 ) 409 - 415 2009.8

Language：Japanese Publisher：(NPO)日本肺癌学会

目的.ゲフィチニブ投与患者では上皮成長因子受容体(EGFR)変異例で予後が良いことが報告されている。一方、喫煙、性差はEGFR変異に影響し、さらに、肺癌の予後因子であることが示唆されている。本研究では、EGFR変異、性差、喫煙が、ゲフィチニブ治療を受けた肺腺癌患者の生存期間に与える影響を検討した。対象と方法.ゲフィチニブにより治療された肺腺癌患者362例において、EGFR変異、性差、喫煙が全生存期間(OS)および無増悪生存期間(PFS)に及ぼす影響を評価した。結果.EGFR変異は169例(46.7%)に認めた。多変量解析では、変異例で野生型例に比べOSおよびPFSが有意に長かった(P<0.001)。EGFR変異の有無による群別で性差、喫煙量は、OSおよびPFSの延長とは関連がなかった。一方、性別、および、喫煙により分類した群別での解析では、EGFR変異は、OS、PFSの延長と有意な関連を認めた(P<0.001)。結論.本検討から、ゲフィチニブ投与を行う患者を選択する際、EGFR変異は重要な指標であると考えられる。(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2009&ichushi_jid=J01244&link_issn=&doc_id=20090924340013&doc_link_id=%2Fec7jaluc%2F2009%2F004904%2F013%2F0409-0415%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2009%2F004904%2F013%2F0409-0415%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

非小細胞肺癌完全切除症例に対する術後補助化学療法の多施設共同臨床III相試験(カルボプラチン+パクリタキセルとUFTとの無作為化比較臨床試験(SLCG04-01))の中間解析

米谷卓郎, 野崎要, 小副川敦, 平井文彦, 隠土薫, 濱武基陽, 瀬戸貴司, 杉尾賢二, 一瀬幸人, 伊達洋至, 豊岡伸一

肺癌 49 ( 4 ) 501 - 501 2009.8

Right but not left ventricular function recovers early after living-donor lobar lung transplantation in patients with pulmonary arterial hypertension. Reviewed

Toyooka S, Kusano KF, Goto K, Masaomi Y, Oto T, Sano Y, Fuke S, Okazaki M, Ohe T, Kasahara S, Sano S, Date H

The Journal of thoracic and cardiovascular surgery 138 ( 1 ) 222 - 226 2009.7

Language：English Publishing type：Research paper (scientific journal) Publisher：MOSBY-ELSEVIER

Objective: The aim of this study was to evaluate right and left ventricular functions in patients with pulmonary arterial hypertension after living-donor lobar lung transplantation compared with those without hypertension.Methods: Thirty-three recipients of living-donor lobar lung transplantation were divided into two groups: those with pulmonary arterial hypertension (PAH group; n = 12) and those without (non-PAH group; n = 21). Their systolic pulmonary artery pressure was 93.1 +/- 6.7 mm Hg versus 31.4 +/- 2.9 mm Hg, respectively. Right and left ventricular ejection fractions, systolic pulmonary artery pressure, and cardiac index were serially measured by radionuclide ventriculography and right heart catheterization, respectively.Results: Pretransplant right and left ventricular ejection fractions were lower in the PAH group (29.8% +/- 7.0%, 49.9% +/- 6.6%) than in the non-PAH group (49.7% +/- 3.3%, 65.2% +/- 1.9%) (P = .010, .068). Two months after living-donor lobar lung transplantation, right ventricular ejection fraction and systolic pulmonary artery pressure in the PAH group (57.3% +/- 5.1%, 25.7 +/- 1.8 mm Hg) improved dramatically, equal to those in the non-PAH group. In contrast, left ventricular ejection fraction and cardiac index in the PAH group (50.9% +/- 3.7%, 2.66 +/- 0.12 L . min(-1) . m(-2)) were still significantly lower than in the non-PAH group (65.4% +/- 2.8%, 3.13 +/- 0.15 L . min(-1) . m(-2)) (P = .0038, .037). At 6 to 12 months, the PAH group demonstrated a significant rise in left ventricular ejection fraction and cardiac index that reached similar values in the non-PAH group measured at 2 months. These values were stable for up to 3 years.Conclusions: Right ventricular function recovered early after living-donor lobar lung transplantation in the PAH group. In contrast, recovery of left ventricular function required 6 to 12 months. Improved cardiac function was sustained for up to 3 years, suggesting long-term durability of cardiac function recovery after living-donor lobar lung transplantation.

DOI： 10.1016/j.jtcvs.2009.02.038

生体肺移植ドナー手術の認容性について岡山大学病院における93例の経験より

佐野由文, 大藤剛宏, 山根正修, 岡崎幹生, 三好健太郎, 吉田修, 大谷真二, 山本澄治, 柿下大一, 岡崎恵, 豊岡伸一

移植 44 ( 3 ) 270 - 271 2009.6

生体肺移植後Calcineurin inhibitor起因性薬物性肝障害と、白血球貪食症候群

大藤剛宏, 山根正修, 三好健太郎, 大谷真二, 柿下大一, 堀志郎, 脇直久, 山本澄治, 吉田修, 岡崎恵, 岡崎幹生, 豊岡伸一, 佐野由文

移植 44 ( 3 ) 266 - 267 2009.6

VA-ECMOをbridgeとした両側生体肺移植

三好健太郎, 大藤剛宏, 大谷真二, 山本澄治, 柿下大一, 堀志郎, 脇直久, 岡崎幹生, 山根正修, 豊岡伸一, 岡崎恵, 佐野由文

移植 44 ( 3 ) 271 - 271 2009.6

慢性血栓塞栓性肺高血圧症に対して緊急成人間生体-肺葉移植+術後予定ECMOを施行し、救命した1例

岡崎幹生, 大藤剛宏, 山根正修, 豊岡伸一, 佐野由文

移植 44 ( 3 ) 269 - 270 2009.6

Recurrent lung cancer in the mediastinum noticed after a living-donor lobar lung transplantation. Reviewed

Toyooka S, Waki N, Okazaki M, Kato K, Yamane M, Oto T, Sano Y, Date H

Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia 15 ( 2 ) 119 - 122 2009.4

再発胸腺腫に対する静脈再建を伴う腫瘍摘出術 Balloon Occlusion法を併用した一時的バイパス法

佐野由文, 豊岡伸一, 岡崎幹生, 吉田修, 大藤剛宏, 山根正修, 笠原真悟

日本呼吸器外科学会雑誌 23 ( 3 ) 362 - 362 2009.4

Nissen手術を要した食道裂孔ヘルニア合併肺癌に対する肺切除例の検討

岡崎幹生, 豊岡伸一, 岡田真典, 枝園和彦, 田尾裕之, 山根正修, 大藤剛宏, 佐野由文

日本呼吸器外科学会雑誌 23 ( 3 ) 481 - 481 2009.4

CTによる追加検査においてサイズの縮小が見られたブラより発生したFDG-PET陽性原発性肺癌(FDG-PET positive primary lung cancer arising from bulla reduced in size followed by CT)

古川公之, 岡崎幹生, 豊岡伸一, 大藤剛宏, 佐野由文

日本呼吸器外科学会雑誌 23 ( 3 ) 410 - 410 2009.4

当科非小細胞肺癌切除例におけるIASLC提案新TNM分類の検討

三好健太郎, 豊岡伸一, 岡崎幹生, 山根正修, 大藤剛宏, 佐野由文

日本呼吸器外科学会雑誌 23 ( 3 ) 419 - 419 2009.4

Ex-vivo肺灌流回路における灌流液中サイトカインと吸着膜の肺機能に与える影響

柿下大一, 大藤剛宏, 大谷真二, 山本澄治, 脇直久, 吉田修, 堀志郎, 岡崎幹生, 山根正修, 豊岡伸一, 佐野由文

日本呼吸器外科学会雑誌 23 ( 3 ) 381 - 381 2009.4

肺・気管移植の基礎と臨床生体肺移植におけるLung Allocation Scoreの有用性について

大藤剛宏, 山根正修, 大谷真二, 柿下大一, 堀志郎, 脇直久, 吉田修, 山本澄治, 三好健太郎, 岡崎幹生, 豊岡伸一, 佐野由文

日本呼吸器外科学会雑誌 23 ( 3 ) 351 - 351 2009.4

肺癌の手術と化学療法 pN2非小細胞肺癌に対する術前放射線同時併用化学療法の成績

豊岡伸一, 木浦勝行, 武本充広, 山根正修, 大藤剛宏, 堀田勝幸, 頼冠名, 瀧川奈義夫, 田端雅弘, 伊達洋至, 佐野由文

日本呼吸器外科学会雑誌 23 ( 3 ) 349 - 349 2009.4

Impact of EGFR mutation analysis in non-small cell lung cancer. Reviewed

Yamamoto H, Toyooka S, Mitsudomi T

Lung cancer (Amsterdam, Netherlands) 63 ( 3 ) 315 - 321 2009.3

Bronchial healing after living-donor lobar lung transplantation. Reviewed

Toyooka S, Yamane M, Oto T, Sano Y, Okazaki M, Date H

Surgery today 39 ( 11 ) 938 - 943 2009

EGFR mutation, but not sex and smoking, is independently associated with favorable prognosis of gefitinib-treated patients with lung adenocarcinoma Reviewed

Toyooka S, Takano T, Kosaka T, Hotta K, Matsuo K, Ichihara S, Fujiwara Y, Soh J, Otani H, Kiura K, Aoe K, Yatabe Y, Ohe Y, Mitsudomi T, Date H

Japanese Journal of Lung Cancer 49 ( 4 ) 409 - 415 2009

Living-donor lobar lung transplantation for pulmonary complications after hematopoietic stem cell transplantation. Reviewed

Yamane M, Sano Y, Toyooka S, Okazaki M, Date H, Oto T

Transplantation 86 ( 12 ) 1767 - 1770 2008.12

Sirolimus ameliorated post lung transplant chylothorax in lymphangioleiomyomatosis. Reviewed

Ohara T, Oto T, Miyoshi K, Tao H, Yamane M, Toyooka S, Okazaki M, Date H, Sano Y

The Annals of thoracic surgery 86 ( 6 ) e7 - 8 2008.12

EGFR変異とUracil-Tegafurによる肺腺癌術後補助療法の関連性についての検討

末久弘, 豊岡伸一, 堀田勝幸, 内田亜希子, 宗淳一, 藤原義朗, 松尾恵太郎, 大内田守, 高田穣, 木浦勝行, 伊達洋至

岡山医学会雑誌 120 ( 3 ) 265 - 269 2008.12

Language：Japanese Publisher：岡山医学会

完全切除された肺腺癌患者に補助療法としてUracil-Tegafur(UFT)を投与した場合における、EGFR変異の予後判定因子としての可能性を検討した。また、in vitro系のEGFR遺伝子導入細胞株における5-FUの効果も検討した。UFT投与群68例、手術のみの経過観察群119例であった。EGFR変異は187例中79例に認め、49例がエクソン19欠失変異、30例がエクソン21点突然変異であった。女性、非喫煙者に有意に変異が多かった。単変量解析では、UFT投与群が経過観察群よりも、EGFR変異群が野生群よりも予後がよい傾向であった。多変量解析では、術後補助療法が独立して有意に予後を延長していた。EGFR変異群では術後補助療法による予後延長の効果は認めなかった。EGFR変異型細胞株は5-FU低感受性を有することが示唆された。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2008&ichushi_jid=J00175&link_issn=&doc_id=20081205250002&doc_link_id=10.4044%2Fjoma.120.265&url=https%3A%2F%2Fdoi.org%2F10.4044%2Fjoma.120.265&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Age-related methylation in normal colon mucosa differs between the proximal and distal colon in patients who underwent colonoscopy Reviewed

Joichiro Horii, Sakiko Hiraoka, Jun Kato, Keita Harada, Kenji Kuwaki, Hideyuki Fujita, Shinichi Toyooka, Kazuhide Yamamoto

CLINICAL BIOCHEMISTRY 41 ( 18 ) 1440 - 1448 2008.12

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Objectives: To examine the difference in the methylation status ill normal colon mucosa between the proximal and distal colon. in relation to the correlation between the methylation status of normal mucosa and characteristics of neoplasia.
Design and methods: Paired biopsy specimens of normal mucosa from the proximal and distal colon of 82 patients who underwent colonoscopy were obtained. The methylation status of the promoter region of estrogen receptor 1 (ESR1) and myogenic differentiation 1 (MYOD1) was examined.
Results: Normal mucosa was more highly methylated ill the distal than in the proximal colon in both ESR1 and MYOD1 loci (p<0.0001 and p = 0.0009, respectively). Advanced characteristics of polyps in the distal colon were frequently observed in patients with lower methylation of ESR1 in the distal colon normal mucosa.
Conclusions: Methylation levels in normal mucosa differ between the proximal and distal colon, and lower methylation of ESR1 in the distal colon normal mucosa may correlate with advanced features of neoplasia in the distal colon. (c) 2008 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clinbiochem.2008.08.089

The aberrant promoter methylation of BMP3b and BMP6 in malignant pleural mesotheliomas. Reviewed

Kimura K, Toyooka S, Tsukuda K, Yamamoto H, Suehisa H, Soh J, Otani H, Kubo T, Aoe K, Fujimoto N, Kishimoto T, Sano Y, Pass HI, Date H

Oncology reports 20 ( 5 ) 1265 - 1268 2008.11

Genetic predictors of MEK dependence in non-small cell lung cancer. Reviewed International journal

Pratilas CA, Hanrahan AJ, Halilovic E, Persaud Y, Soh J, Chitale D, Shigematsu H, Yamamoto H, Sawai A, Janakiraman M, Taylor BS, Pao W, Toyooka S, Ladanyi M, Gazdar A, Rosen N, Solit DB

Cancer research 68 ( 22 ) 9375 - 9383 2008.11

Language：English Publishing type：Research paper (scientific journal)

Hyperactivated extracellular signal-regulated kinase (ERK) signaling is common in human cancer and is often the result of activating mutations in BRAF, RAS, and upstream receptor tyrosine kinases. To characterize the mitogen-activated protein kinase/ERK kinase (MEK)/ERK dependence of lung cancers harboring BRAF kinase domain mutations, we screened a large panel of human lung cancer cell lines (n = 87) and tumors (n = 916) for BRAF mutations. We found that non-small cell lung cancers (NSCLC) cells with both V600E and non-V600E BRAF mutations were selectively sensitive to MEK inhibition compared with those harboring mutations in epidermal growth factor receptor (EGFR), KRAS, or ALK and ROS kinase fusions. Supporting its classification as a "driver" mutation in the cells in which it is expressed, MEK inhibition in (V600E)BRAF NSCLC cells led to substantial induction of apoptosis, comparable with that seen with EGFR kinase inhibition in EGFR mutant NSCLC models. Despite high basal ERK phosphorylation, EGFR mutant cells were uniformly resistant to MEK inhibition. Conversely, BRAF mutant cell lines were resistant to EGFR inhibition. These data, together with the nonoverlapping pattern of EGFR and BRAF mutations in human lung cancer, suggest that these lesions define distinct clinical entities whose treatment should be guided by prospective real-time genotyping. To facilitate such an effort, we developed a mass spectrometry-based genotyping method for the detection of hotspot mutations in BRAF, KRAS, and EGFR. Using this assay, we confirmed that BRAF mutations can be identified in a minority of NSCLC tumors and that patients whose tumors harbor BRAF mutations have a distinct clinical profile compared with those whose tumors harbor kinase domain mutations in EGFR.

DOI： 10.1158/0008-5472.CAN-08-2223

Frequent p16 inactivation by homozygous deletion or methylation is associated with a poor prognosis in Japanese patients with pleural mesothelioma. Reviewed

Kobayashi N, Toyooka S, Yanai H, Soh J, Fujimoto N, Yamamoto H, Ichihara S, Kimura K, Ichimura K, Sano Y, Kishimoto T, Date H

Lung cancer (Amsterdam, Netherlands) 62 ( 1 ) 120 - 125 2008.10

EGFR遺伝子異常を伴う肺癌細胞株におけるTAE226の抗腫瘍効果

大谷弘樹, 豊岡伸一, 渡辺信之, 治田賢, 高岡宗徳, 久保孝文, 山本寛斉, 山根正修, 大藤剛宏, 大橋圭明, 荻野敦子, 木浦勝行, 猶本良夫, 佐野由文

日本癌治療学会誌 43 ( 2 ) 798 - 798 2008.10

高齢者肺癌に対する新たな治療戦略高齢者肺癌に対する新たな治療戦略としてのラジオ波焼灼術(RFA)

佐野由文, 山根正修, 豊岡伸一, 大藤剛宏, 岡崎幹生, 金澤右

日本癌治療学会誌 43 ( 2 ) 293 - 293 2008.10

ゲフィチニブ未使用肺癌におけるMET遺伝子増幅について

久保孝文, 山本寛斉, 宗淳一, 藤井徹也, 大内田守, 瀧川奈義夫, 木浦勝行, 清水憲二, 伊達洋至, 豊岡伸一

肺癌 48 ( 5 ) 508 - 508 2008.10

日本人胸膜中皮腫におけるP16遺伝子異常の意義遺伝子診断・治療の可能性

小林成行, 豊岡伸一, 柳井広之, 宗淳一, 藤本伸一, 市原周治, 木村賢太郎, 市村浩一, 佐野由文, 岸本卓巳, 伊達洋至

日本癌治療学会誌 43 ( 2 ) 640 - 640 2008.10

肺癌におけるPIK3CA遺伝子異常と機能解析

山本寛斉, 重松久之, 野村将春, ロックウッド・ウィリアム, 佐藤光夫, 奥村直樹, 宗淳一, 鈴木実, ウィストゥバ・イグナシオ, フォン・クワン, リー・ヒュエイ, 豊岡伸一, 伊達洋至, ラム・ワン, ミンナ・ジョン, ガズダー・アディ

日本癌治療学会誌 43 ( 2 ) 797 - 797 2008.10

【肺癌のUp-To-Date】肺癌手術の実際

山根正修, 岡崎幹生, 枝園和彦, 大藤剛宏, 佐野由文, 豊岡伸一

THE LUNG-perspectives 16 ( 4 ) 469 - 473 2008.10

Language：Japanese Publisher：(株)メディカルレビュー社

肺癌、特に早期の非小細胞肺癌に対する治療において外科的切除は重要な位置を占める。医学の進歩により胸腔鏡を用いた手術、また、非浸潤肺癌に対する積極的縮小手術、術前導入療法、術後補助療法の付加など手術を取り巻く環境も次第に変化している。本稿では岡山大学で行っている肺癌手術を中心とした肺癌への取り組みについて述べる。(著者抄録)

術前治療後肺切除時の有茎大網被覆術に伴う消化器合併症の検討

枝園和彦, 豊岡伸一, 岡崎幹生, 山根正修, 羽藤慎二, 伊野英男, 大藤剛宏, 内藤稔, 土井原博義, 佐野由文

日本臨床外科学会雑誌 69 ( 増刊 ) 663 - 663 2008.10

原発性肺癌に対するCTガイド下肺生検の功罪

佐野由文, 岡崎幹生, 山根正修, 豊岡伸一, 大藤剛宏

日本臨床外科学会雑誌 69 ( 増刊 ) 664 - 664 2008.10

移植後のPrimary graft failureをいかに克服するか? marginal donorからDCDまで海外の肺移植におけるDCDの現状と対策

大藤剛宏, 山根正修, 吉田修, 大谷真二, 柿下大一, 堀志郎, 脇直久, 山本澄治, 犬飼倫子, 森田麻由美, 横山千恵, 岡崎恵, 角南直美, 岡崎幹生, 豊岡伸一, 佐野由文

移植 43 ( 総会臨時 ) 170 - 170 2008.9

ゲフィチニブ未使用肺癌におけるMET遺伝子増幅について(METGene Amplification in Lung Cancers Untreated With Gefitinib)

久保孝文, 山本寛斉, 宗淳一, 大内田守, 瀧川奈義夫, 木浦勝行, 清水憲二, 伊達洋至, 豊岡伸一

日本癌学会総会記事 67回 275 - 275 2008.9

Native lung-sparing lobar transplantation for pulmonary emphysema. Reviewed

Yamane M, Okutani D, Sugimoto S, Toyooka S, Aoe M, Okazaki M, Sano Y, Date H

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 27 ( 9 ) 1046 - 1049 2008.9

The allelic distribution of a single nucleotide polymorphism in the PDCD5 gene locus of Japanese non-small cell lung cancer patients. Reviewed

Nanba K, Toyooka S, Soh J, Tsukuda K, Yamamoto H, Sakai A, Ouchida M, Kobayashi N, Matsuo K, Koide N, Kusaka K, Shimizu K, Date H

Molecular medicine reports 1 667 - 671 2008.9

生体肺移植後の長期予後について

佐野由文, 山根正修, 豊岡伸一, 岡崎幹生, 岡崎恵, 大藤剛宏, 伊達洋至

移植 43 ( 総会臨時 ) 398 - 398 2008.9

Sirolimus amelioration of clinical symptoms of recurrent lymphangioleiomyomatosis after living-donor lobar lung transplantation. Reviewed

Sugimoto R, Nakao A, Yamane M, Toyooka S, Okazaki M, Aoe M, Seyama K, Date H, Oto T, Sano Y

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 27 ( 8 ) 921 - 924 2008.8

縦隔巨大軟骨肉腫に対して外科的切除を施行し得た1例

平野豊, 枝園和彦, 古川公之, 野上智弘, 山本寛斉, 岡崎幹生, 山根正修, 豊岡伸一, 大藤剛宏, 佐野由文

岡山医学会雑誌 120 ( 2 ) 246 - 246 2008.8

左肺全摘、大網充填術後に胃の通過障害を来した1例

枝園和彦, 豊岡伸一, 岡崎幹生, 山根正修, 羽藤慎二, 大藤剛宏, 内藤稔, 土井原博義, 佐野由文

岡山医学会雑誌 120 ( 2 ) 249 - 249 2008.8

Non-BAC component but not epidermal growth factor receptor gene mutation is associated with poor outcomes in small adenocarcinoma of the lung. Reviewed

Kobayashi N, Toyooka S, Ichimura K, Soh J, Yamamoto H, Matsuo K, Otani H, Jida M, Kubo T, Tsukuda K, Kiura K, Sano Y, Date H

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 3 ( 7 ) 704 - 710 2008.7

DNA methylation in lung cancer. Reviewed

Toyooka S, Matsuo K, Gazdar AF

The New England journal of medicine 358 ( 23 ) 2513; author reply 2514 2008.6

Mutational and epigenetic evidence for independent pathways for lung adenocarcinoma

TOYOOKA Shinichi, DATE Hiroshi

120 ( 1 ) 7 - 11 2008.5

組織型が非常に稀な悪性胸膜中皮腫の1例

山本寛斉, 豊岡伸一, 肥後貴子, 岡崎幹生, 田尾裕之, 河本純一, 山根正修, 大藤剛宏, 佐野由文, 伊達洋至

岡山医学会雑誌 120 ( 1 ) 119 - 119 2008.5

ゲフィチニブ単剤療法が施行された肺非小細胞癌における予後因子としての血清KL-6

藤原義朗, 木浦勝行, 瀧川奈義夫, 豊岡伸一, 堀田勝幸, 宗淳一, 宮原信明, 谷本安, 金廣有彦, 田端雅弘, 加藤勝也, 伊達洋至, 谷本光音

日本呼吸器学会雑誌 46 ( 増刊 ) 131 - 131 2008.5

悪性中皮腫の診断・治療の進歩悪性中皮腫に対する当院の治療成績と問題点

藤井昌学, 瀧川奈義夫, 木浦勝行, 豊岡伸一, 大谷真二, 佐野由文, 田端雅弘, 谷本光音, 伊達洋至

気管支学 30 ( Suppl. ) S98 - S98 2008.5

IIIB期非小細胞肺癌に対する外科的治療は妥当か?

佐野由文, 豊岡伸一, 岡崎幹生, 田尾裕之, 山根正修, 大藤剛宏

日本呼吸器外科学会雑誌 22 ( 3 ) 549 - 549 2008.4

A novel strategy for treatment of metastatic pulmonary tumors: radiofrequency ablation in conjunction with surgery. Reviewed

Sano Y, Kanazawa S, Mimura H, Gobara H, Hiraki T, Fujiwara H, Yamane M, Toyooka S, Oto T, Date H

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 3 ( 3 ) 283 - 288 2008.3

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Introduction: Local treatment that includes surgical resection of metastatic pulmonary tumors is controversial because of the biologic features and invasiveness of these tumors. We report our experience with a premeditated treatment involving combined computed tomography-guided radiofrequency ablation and surgical resection in three patients with metastatic pulmonary tumors.Methods: Three patients underwent radiofrequency ablation in conjunction with surgical resection. The first was a 67-year-old man with pulmonary metastases of bronchial adenoid cystic carcinoma. We performed partial resection of five tumors in the right lung and ablated a tumor in the left lung. The second was a 66-year-old man with pulmonary metastases of renal cell carcinoma. He underwent radiofrequency ablation for three tumors in the right upper and middle lobes, and right lower lobectomy for tumors in that lobe. The third was a 55-year-old man with pulmonary metastases of high-grade sarcoma of the right thigh. We performed partial resection of five tumors in the left lung and ablated a tumor in the right lung.Results: Two patients had metastatic lesions on both sides of the lung; we performed surgical resection on one side and radiofrequency ablation contralaterally to avoid bilateral thoracotomy. The third patient underwent surgical resection and radiofrequency ablation to avoid highly invasive right pneumonectomy. All patients survived for more than 1 1/2 years after combination therapy.Conclusions: Premeditated treatment involving a combination of radiofrequency ablation and surgical resection can be a useful option in patients with metastatic pulmonary tumors, improving curability and avoiding highly invasive procedures.

DOI： 10.1097/JTO.0b013e3181645443

Dry small pleural dissemination of adenocarcinoma of the lung preoperatively detected by PET/CT: a report of two cases. Reviewed

Okutani D, Yamane M, Toyooka S, Oto T, Aoe M, Sano Y, Date H

Acta medica Okayama 62 ( 1 ) 55 - 58 2008.2

Long-term follow-up of living-donor single lobe transplantation for idiopathic pulmonary arterial hypertension in a child. Reviewed

Toyooka S, Sano Y, Yamane M, Oto T, Okazaki M, Kusano KF, Date H

The Journal of thoracic and cardiovascular surgery 135 ( 2 ) 451 - 452 2008.2

Epidermal growth factor receptor mutation, but not sex and smoking, is independently associated with favorable prognosis of gefitinib-treated patients with lung adenocarcinoma. Reviewed

Toyooka S, Takano T, Kosaka T, Hotta K, Matsuo K, Ichihara S, Fujiwara Y, Soh J, Otani H, Kiura K, Aoe K, Yatabe Y, Ohe Y, Mitsudomi T, Date H

Cancer science 99 ( 2 ) 303 - 308 2008.2

Postoperative perforation in the bronchus intermedius membrane after a primary lung cancer resection Reviewed

Yuji Hirarni, Shinichi Toyooka, Yoshifumi Sano, Hiroshi Date

EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY 33 ( 1 ) 130 - 132 2008.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

We experienced 4 cases of postoperative perforation in the bronchus intermedius membrane (PBIM) after primary lung cancer resection. Three patients had undergone a right lower lobectomy and 1 patient had undergone a right upper lobectomy; as part of a systemic lymph node dissection, the subcarinal lymph node (Station 7) was dissected in all cases. Leakages were detected on postoperative days 3, 10, 11, and 26, respectively. The clinical signs of PBIM included the appearance of sputum like pleural effusion, decreased oxygenation, elevated inflammatory markers, pneumothorax, and infected pleural effusion. PBIM was confirmed by bronchofiberscopy. Direct suturing of the perforated membrane, followed by rapping with an omental flap was performed in 1 case; completion bitobectomies, followed by rapping of the bronchial stump with an omental flap or an intercostal muscle flap were performed in 2 cases; and a completion pneumonectomy, followed by rapping of the bronchial stump with an omental flap was performed in 1 case. All 4 of the cases were successfully treated. (c) 2007 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ejcts.2007.09.038

Current status and potential of living-donor lobar lung transplantation. Reviewed

Date H, Yamane M, Toyooka S, Okazaki M, Aoe M, Sano Y

Frontiers in bioscience : a journal and virtual library 13 1433 - 1439 2008.1

女性縦隔卵黄嚢腫の1切除例

大谷弘樹, 豊岡伸一, 森秀暁, 山根正修, 青江基, 佐野由文, 木浦勝行, 伊達洋至

岡山医学会雑誌 119 ( 3 ) 337 - 337 2008.1

Bronchial mucoepidermoid carcinoma with recurrent hemoptysis in a pregnant woman: report of a case. Reviewed

Tao H, Sano Y, Yamane M, Toyooka S, Oto T, Date H

Surgery today 38 ( 9 ) 850 - 852 2008

Favorable outcomes after living-donor lobar lung transplantation in ventilator-dependent patients. Reviewed

Toyooka S, Yamane M, Oto T, Sano Y, Okazaki M, Hanazaki M, Goto K, Date H

Surgery today 38 ( 12 ) 1078 - 1082 2008

P28-05 PIK3CA mutations and gene copy number in human lung cancers

Gazdar Adi F.

The Journal of the Japanese Association for Chest Surgery 22 ( 3 ) 517 - 517 2008

SP1 呼吸器外科の研究はどうあるべきか(第25回呼吸器外科学会総会)

一瀬幸人, 岡田守人, 豊岡伸一, 間野博行, 豊岡伸一, 間野博行

日本呼吸器外科学会雑誌 22 ( 3 ) 354 - 355 2008

W5-6 悪性中皮腫に対する当院の治療成績と問題点(悪性中皮腫の診断・治療の進歩,ワークショップ5,第31回日本呼吸器内視鏡学会学術集会)

藤井昌学, 瀧川奈義夫, 木浦勝行, 豊岡伸一, 大谷真二, 佐野由文, 田端雅弘, 谷本光音, 伊達洋至

気管支学 30 S98 2008

The impact of sex and smoking status on the mutational spectrum of epidermal growth factor receptor gene in non small cell lung cancer. Reviewed

Toyooka S, Matsuo K, Shigematsu H, Kosaka T, Tokumo M, Yatabe Y, Ichihara S, Inukai M, Suehisa H, Soh J, Kiura K, Fong KM, Lee H, Wistuba II, Gazdar AF, Mitsudomi T, Date H

Clinical cancer research : an official journal of the American Association for Cancer Research 13 ( 19 ) 5763 - 5768 2007.10

肺リンパ脈管筋腫症による生体肺移植後の難治性胸腹水に対するSirolimusの投与経験

大原利章, 佐野由文, 三好健太郎, 田尾裕之, 山根正修, 豊岡伸一, 大藤剛宏, 岡崎恵, 伊達洋至

移植 42 ( 総会臨時 ) 240 - 240 2007.10

EGFR変異とUFTによる肺腺癌術後補助療法の関連性についての検討

末久弘, 豊岡伸一, 堀田勝幸, 内田亜希子, 宗淳一, 藤原義朗, 松尾恵太郎, 大内田守, 高田穣, 木浦勝行, 伊達洋至

肺癌 47 ( 5 ) 513 - 513 2007.10

肺非小細胞癌における治療前血清KL-6値とゲフィチニブ単剤療法の治療効果の関連

藤原義朗, 木浦勝行, 瀧川奈義夫, 豊岡伸一, 堀田勝幸, 宗淳一, 田端雅弘, 加藤勝也, 伊達洋至, 谷本光音

肺癌 47 ( 5 ) 629 - 629 2007.10

抗悪性腫瘍薬の至適投与法確立を目指して非小細胞肺癌(NSCLC)症例における、腫瘍EGFR遺伝子変異の殺細胞性抗癌剤治療効果への影響の検討

堀田勝幸, 木浦勝行, 豊岡伸一, 瀧川奈義夫, 宗淳一, 藤原義朗, 田端雅弘, 伊達洋至, 谷本光音

肺癌 47 ( 5 ) 450 - 450 2007.10

ゲフィチニブにて治療したNSCLC患者の血清KL-6値の予後的意義(Prognostic value of serum KL-6 level in NSCLC patients treated with gefitinib)

藤原義朗, 木浦勝行, 瀧川奈義夫, 豊岡伸一, 堀田勝幸, 宗淳一, 田端雅弘, 加藤勝也, 伊達洋至, 谷本光音

日本癌治療学会誌 42 ( 2 ) 370 - 370 2007.9

Risk factors for recurrence and unfavorable prognosis in patients with stage I non-small cell lung cancer and a tumor diameter of 20 mm or less. Reviewed

Kobayashi N, Toyooka S, Soh J, Ichimura K, Yanai H, Suehisa H, Ichihara S, Yamane M, Aoe M, Sano Y, Date H

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2 ( 9 ) 808 - 812 2007.9

Epidermal growth factor receptor mutation status and adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. Reviewed

Suehisa H, Toyooka S, Hotta K, Uchida A, Soh J, Fujiwara Y, Matsuo K, Ouchida M, Takata M, Kiura K, Date H

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 25 ( 25 ) 3952 - 3957 2007.9

早期肺癌に対する治療戦略末梢小型肺癌に対するラジオ波焼灼術(RFA)の有用性の検討

佐野由文, 平木隆夫, 郷原英夫, 三村秀文, 金澤右, 山根正修, 豊岡伸一, 大藤剛宏, 伊達洋至

日本癌治療学会誌 42 ( 2 ) 262 - 262 2007.9

日本人の悪性胸膜中皮腫におけるP16遺伝子のホモ欠失とp16発現の不活化(Homozygous deletions of Pffigene and inactivation of p16 expression in Japanese malignant pleural mesothelioma)

小林成行, 豊岡伸一, 市原周治, 宗淳一, 市村浩一, 柳井広之, 藤本伸一, 岸本卓巳, 末久弘, 伊達洋至

日本癌学会総会記事 66回 130 - 130 2007.8

Living-donor lobar lung transplantation for pulmonary arterial hypertension after failure of epoprostenol therapy. Reviewed

Date H, Kusano KF, Matsubara H, Ogawa A, Fujio H, Miyaji K, Okazaki M, Yamane M, Toyooka S, Aoe M, Sano Y, Hanazaki M, Goto K, Kasahara S, Sano S, Ohe T

Journal of the American College of Cardiology 50 ( 6 ) 523 - 527 2007.8

扁桃腫瘤で発見された再発肺腺癌

武田洋正, 瀧川奈義夫, 木浦勝行, 大橋圭明, 大澤昌宏, 田端雅弘, 谷本光音, 豊岡伸一, 伊達洋至

肺癌 47 ( 4 ) 387 - 387 2007.8

Long-term improvement in pulmonary function after living donor lobar lung transplantation. Reviewed

Yamane M, Date H, Okazaki M, Toyooka S, Aoe M, Sano Y

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 26 ( 7 ) 687 - 692 2007.7

EGFR mutation status in pleural fluid predicts tumor responsiveness and resistance to gefitinib. Reviewed

Soh J, Toyooka S, Ichihara S, Suehisa H, Kobayashi N, Ito S, Yamane M, Aoe M, Sano Y, Kiura K, Date H

Lung cancer (Amsterdam, Netherlands) 56 ( 3 ) 445 - 448 2007.6

Aberrant promoter methylation in pleural fluid DNA for diagnosis of malignant pleural effusion. Reviewed

Katayama H, Hiraki A, Aoe K, Fujiwara K, Matsuo K, Maeda T, Murakami T, Toyooka S, Sugi K, Ueoka H, Tanimoto M

International journal of cancer. Journal international du cancer 120 ( 10 ) 2191 - 2195 2007.5

The effect of gefitinib on B-RAF mutant non-small cell lung cancer and transfectants. Reviewed

Toyooka S, Uchida A, Shigematsu H, Soh J, Ogino A, Takata M, Kiura K, Ouchida M, Kosaka T, Aoe M, Mitsudomi T, Date H

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2 ( 4 ) 321 - 324 2007.4

EGFR変異とUFTによる肺腺癌術後補助療法の関連性についての検討

末久弘, 豊岡伸一, 堀田勝幸, 内田亜希子, 宗淳一, 木浦勝行, 浅野博昭, 藤原義朗, 松尾恵太郎, 青江基, 高田穣, 清水信義, 伊達洋至

日本呼吸器外科学会雑誌 21 ( 3 ) 404 - 404 2007.4

Aberrant promoter methylation of insulin-like growth factor binding protein-3 gene in human cancers Reviewed

Kunitoshi Tomii, Kazunori Tsukuda, Shinichi Toyooka, Hideaki Dote, Tadashi Hanafusa, Hiroaki Asano, Minoru Naitou, Hiroyoshi Doihara, Takumi Kisimoto, Hideki Katayama, Harvery I. Pass, Hiroshi Date, Nobuyoshi Shimizu

INTERNATIONAL JOURNAL OF CANCER 120 ( 3 ) 566 - 573 2007.2

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

Insulin-like growth factor binding protein-3 (IGFBP-3) is postulated to be a mediator of growth suppression signals. Here, we examined the methylation status of IGFBP-3 to correlate to clinicopathological factors in human cancers. The methylation status of IGFBP-3 was determined by bisulfite DNA sequencing and was correlated with expression semi-quantified by real-time RT-PCR to develop a methylation-specific PCR (MSP) assay for IGFBP-3. Using the MSP assay, we examined the methylation status of IGFBP-3 in gastric cancer (GC), colorectal cancer (CRC), breast cancer (BC) and malignant mesothelioma (MM). IGFBP-3 methylation was detected in 6 of 13 (46%) and 16 of 24 (67%) GC cell lines and tumors, respectively; 4 of 8 (50%) and 15 of 26 (58%) CRC cell lines and tumors, respectively; 3 of 11 (27%) and 7 of 39 (18%) BC cell lines and tumors, respectively and 1 of 5 (20%) and 18 of 56 (32%) MM cell lines and tumors, respectively. Interestingly, the methylation status of MM specimens from Japanese patients (75%, 12 out of 16 patients) was significantly higher than those from the USA (15%, 6 out of 40 patients) (p < 0.0001), suggesting the presence of ethnic differences in the IGFBP-3 methylation status. We also found that IGFBP-3 methylation was preferentially present in GCs arising in the lower-third of the stomach (p = 0.079). In summary, our results showed that IGFBP-3 methylation played an important role in the silencing of its expression, suggesting that IGFBP-3 may act as a tumor suppressor gene in several human cancers examined. (c) 2006 Wiley-Liss, Inc.

DOI： 10.1002/ijc.22341

PS-032-3 肺癌におけるEGFR遺伝子変異のタイプとその臨床病理学的特徴(基礎研究6, 第24回日本呼吸器外科学会総会号)

重松久之, 鈴木実, 豊岡伸一, 木村秀樹, 藤澤武彦, 伊達洋至

日本呼吸器外科学会雑誌 21 ( 3 ) 404 - 404 2007

Cytomegalovirus infection in lung transplantation; current status, detection, prophylactic treatment

Motoi Aoe, H. Tao, M. Yamane, S. Toyooka, Y. Sano, M. Okazaki, H. Date

Kyobu geka. The Japanese journal of thoracic surgery 60 ( 11 ) 988 - 992 2007

Language：Japanese Publishing type：Research paper (scientific journal)

The control of the postoperative infectious disease is one of the important elements in transplantation. Among them, the control of the cytomegalovirus (CMV) infection may be said the most important in the management of the transplant recipient who is under the immunosuppression. This time, we review the status of the pre-transplant CMV infection in the donors and recipients of both brain-death and living-related lung transplantation that we performed, and report our prophylactic treatment for CMV infection and its results. The CMV positive rate of the recipients and donors of the lung transplantation that we experienced in Okayama University was 87%. We experienced 4 cases that developed CMV infection after lung transplantation. However, there is no case that died of a CMV-related infectious disease after lung transplantation to date. By the CMV mismatch transplant, it seemed that the frequency of the postoperative CMV disease was high in comparison with the transplant of recipient CMV (+). But, the control of the CMV infection after lung transplantation is thought to be possible if we give a proper prophylactic treatment even in CMV mismatch transplantation.

Extensive traumatic pneumomediastinum. without injuries of organs in the thorax: report of a case

D. Okutani, M. Aoe, M. Yamane, S. Hatoh, S. Toyooka, Y. Sano, H. Date

Kyobu geka. The Japanese journal of thoracic surgery 60 ( 10 ) 942 - 945 2007

Language：Japanese Publishing type：Research paper (scientific journal)

A 57-year-old man was accidentally hit by concrete blocks weighing 3 tons on his right side, and was admitted to a hospital. The radiologic findings taken immediately after trauma demonstrated pneumo-mediastinum, subcutaneous emphysema with multiple rib fractures and right clavicle fracture. At computed tomography (CT) scan 16 hours after trauma, pneumomediastinum and subcutaneous emphysema turned out to be worsened with an increased bilateral pleural effusion. An emergency thoracotomy revealed no abnormalities of trachea or esophagus, and neither bronchoscopy or esophagogastroscopy, showed injuries anywhere inside. The chest cavities and mediastinum were washed well with 3 liters of saline solution. The patient had a good course after surgery without any complications, and was discharged at the 18th hospital day. Mediastinal drainage by an emergency operation should always be a choice to a patient having a progressively worsening pneumomediastinum which might cause tachycardia, low blood pressure, and severe dyspnea due to compression of blood vessels and trachea.

The impact and role of EGFR gene mutation on non-small cell lung cancer Reviewed

Shinichi Toyooka, Junichi Soh, Hisayuki Shigematsu, Motoi Aoe, Hiroshi Date

CANCER CHEMOTHERAPY AND PHARMACOLOGY 58 S25 - S31 2006.11

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Mutations in the epidermal growth factor receptor (EGFR) gene have been reported in non-small cell lung cancer (NSCLC), especially in patients with adenocarcinomas, women, never smokers, and East Asians. These factors were recognized as predictors of gefitinib response in the Iressa Dose Evaluation in Advanced Lung Cancer study. Despite some contradictory arguments, somatic mutations in EGFR have been demonstrated to be a useful biomarker for predicting the clinical outcome of treatment with gefitinib or erlotinib, indicating the necessity of validated assays for clinical applications. Mutations in EGFR and KRAS are established carcinogenic mechanisms responsible for NSCLC. Recent studies have demonstrated that epigenetic alteration is another critical mechanism in lung carcinogenesis. Notably, EGFR and KRAS mutations are mutually exclusive, suggesting the presence of two independent pathways for the development of adenocarcinoma; however, the relationship between mutation and epigenetic alteration is not known. To address these issues, we examined the EGFR mutation status in Japanese patients with NSCLC by direct sequencing exons 18-21 of EGFR; the results were then correlated with clinicopathological factors and previously investigated epigenetic alterations. In this article, we mainly focus on: (1) the relationship between EGFR mutations and clinicopathological factors, (2) the relationship between EGFR mutations and response to gefitinib, (3) the development of a sensitive assay for detecting the major EGFR mutations, and (4) differences in the evolution of epigenetic alterations between EGFR- or KRAS-mediated tumorigenesis. The present results provide important data for translational research and will further our understanding of the molecular pathogenesis of NSCLC, leading to the establishment of molecular targeting strategies for the treatment of NSCLC.

DOI： 10.1007/s00280-006-0312-8

肺癌診断のフロントライン肺癌手術症例における術前、術中診断方法(特に胸腔鏡下生検)について

青江基, 越宗龍一郎, 市原周治, 末久弘, 宗淳一, 柿下大一, 堀志郎, 奥谷大介, 平見有二, 山根正修, 豊岡伸一, 佐野由文, 伊達洋至

日本臨床外科学会雑誌 67 ( 増刊 ) 267 - 267 2006.10

胸水中EGFR遺伝子変異がゲフィチニブによる生存延長効果の予測因子になりうるか

宗淳一, 豊岡伸一, 浅野博昭, 青江基, 佐野由文, 清水信義, 伊達洋至, 青江啓介, 片山英樹, 杉和郎, 木浦勝行

肺癌 46 ( 6 ) 783 - 784 2006.10

性別・喫煙歴が肺癌におけるEGFR遺伝子変異部位に及ぼす影響についての検討

豊岡伸一, 松尾恵太郎, 重松久之, 徳毛誠樹, 犬飼道雄, 市原周治, 末久弘, 宗淳一, 木浦勝行, 山根正修, 青江基, 佐野由文, 伊達洋至

日本癌学会総会記事 65回 454 - 454 2006.9

CT腫瘍径20mm以下、臨床病期1A原発性非小細胞肺癌における再発危険因子の検討

小林成行, 豊岡伸一, 宗淳一, 山根正修, 青江基, 佐野由文, 伊達洋至

The Japanese Journal of THORACIC AND CARDIOVASCULAR SURGERY 54 ( Suppl. ) 384 - 384 2006.9

非小細胞肺癌におけるゲフィチニブの臨床効果とHER2、EGFR遺伝子異常の関係

豊岡伸一, 宗淳一, 市原周治, 末久弘, 犬飼道雄, 重松久之, 山根正修, 青江啓介, 青江基, 佐野由文, 清水信義, 伊達洋至

The Japanese Journal of THORACIC AND CARDIOVASCULAR SURGERY 54 ( Suppl. ) 480 - 480 2006.9

胸水中EGFR遺伝子変異検索に基づいた肺癌個別化治療の可能性

宗淳一, 豊岡伸一, 青江啓介, 浅野博昭, 市原周治, 末久弘, 重松久之, 山根正修, 青江基, 佐野由文, 杉和郎, 清水信義, 伊達洋至

The Japanese Journal of THORACIC AND CARDIOVASCULAR SURGERY 54 ( Suppl. ) 340 - 340 2006.9

非小細胞肺癌におけるゲフィチニブの臨床効果とHER2、EGFR遺伝子異常の関係

宗淳一, 豊岡伸一, 市原周二, 青江啓介, 山根正修, 青江基, 佐野由文, 藤原義朗, 堀田勝之, 木浦勝行, 伊達洋至

日本癌学会総会記事 65回 234 - 234 2006.9

gefitinib抵抗性肺癌におけるT790M変異の存在と臨床的意義

犬飼道雄, 豊岡伸一, 浅野博昭, 市原周治, 宗淳一, 山根正修, 青江基, 佐野由文, 清水信義, 伊達洋至

日本癌治療学会誌 41 ( 2 ) 671 - 671 2006.9

変異型EGFR発現非小細胞肺癌細胞株のRas12V導入によるgefitinib耐性化

内田亜希子, 平野世紀, 北尾洋之, 頼冠名, 荻野敦子, 豊岡伸一, 瀧川奈義夫, 田端雅弘, 高田穣, 木浦勝行, 谷本光音

日本癌学会総会記事 65回 234 - 234 2006.9

非喫煙歴による術後再発非小細胞肺癌患者の長期生存予測(Never-smoking history predicts long-term survival in patients with non-small cell lung cancer with postoperative recurrence)

藤原義朗, 木浦勝行, 田端雅弘, 瀧川奈義夫, 谷本安, 堀田勝幸, 松尾恵太郎, 豊岡伸一, 佐野由文, 青江基, 伊達洋至, 谷本光音

日本癌治療学会誌 41 ( 2 ) 671 - 671 2006.9

OKT3が有用であった生体肺移植後のステロイド抵抗性急性拒絶反応の検討

杉本誠一郎, 伊達洋至, 杉本龍士郎, 吉田修, 豊岡伸一, 青江基, 岡部和倫, 佐野由文

日本呼吸器外科学会雑誌 20 ( 3 ) 812 - 812 2006.5

術後再発非小細胞肺癌に対するGefitinib治療効果とEGFR遺伝子変異・コピー数異常の検討

市原周治, 豊岡伸一, 徳毛誠樹, 宗淳一, 藤原義朗, 重松久之, 末久弘, 青江啓介, 青江基, 佐野由文, 岡部和倫, 杉和郎, 木浦勝行, 伊達洋至, 清水信義

日本呼吸器外科学会雑誌 20 ( 3 ) 794 - 794 2006.5

腫瘍径20mm以下のc-1A肺腺癌症例における早期再発予測因子

小林成行, 豊岡伸一, 宗淳一, 青江基, 岡部和倫, 佐野由文, 伊達洋至, 清水信義

日本呼吸器外科学会雑誌 20 ( 3 ) 939 - 939 2006.5

Enriched PCR法による胸水中EGFR遺伝子変異検索に基づいた肺癌個別化治療の可能性

宗淳一, 豊岡伸一, 浅野博昭, 市原周治, 重松久之, 青江啓介, 青江基, 佐野由文, 岡部和倫, 杉和郎, 伊達洋至, 清水信義

日本呼吸器外科学会雑誌 20 ( 3 ) 794 - 794 2006.5

非小細胞肺癌切除症例におけるEGFR遺伝子変異と臨床病理学的因子の検討

豊岡伸一, 市原周治, 徳毛誠樹, 小林成行, 脇直久, 宗淳一, 末久弘, 浅野博昭, 重松久之, 青江基, 岡部和倫, 佐野由文, 伊達洋至, 清水信義

日本呼吸器外科学会雑誌 20 ( 3 ) 843 - 843 2006.5

Infrequent existence of simian virus 40 large T antigen DNA in malignant mesothelioma in Japan Reviewed

Keisuke Aoe, Akio Hiraki, Tomoyuki Murakami, Shinichi Toyooka, Narayan Shivapurkar, Adi F. Gazdar, Naoko Sueoka, Koji Taguchi, Toshiaki Kamei, Hiroyasu Takeyama, Kazuro Sugi, Takumi Kishimoto

Cancer Science 97 ( 4 ) 292 - 295 2006.4

Language：English Publishing type：Research paper (scientific journal)

Malignant mesothelioma is the most common primary pleural neoplasm. Association of simian virus 40 (SV40) with malignant mesothelioma has been reported, suggesting that SV40 plays an important role in the origin of a subset of these tumors. However, significant geographic variation is present as to how often this association occurs. As no study concerning SV40 in malignant mesothelioma has been reported from Japan, we examined the frequency of SV40 infection in Japanese malignant mesothelioma cases. In pleural malignant mesothelioma tissue from 35 patients in Japan, we sought the presence of SV40 large T antigen DNA using real-time polymerase chain reaction (PCR), as well as expression of the viral protein using immunohistological methods. Real-time PCR demonstrated that two of 35 mesotheliomas contained DNA sequences encoding portions of SV40 large T antigen. None of the 35 malignant mesothelioma specimens showed immunoreactivity for SV40 large T antigen. SV40 infection does not appear to have a major role in the development of malignant mesothelioma in Japan. © 2006 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2006.00171.x

Relationship between epidermal growth factor receptor gene mutations and the severity of adverse events by gefitinib in patients with advanced non-small cell lung cancer. Reviewed International journal

Fujiwara Y, Kiura K, Toyooka S, Takigawa N, Tokumo M, Hotta K, Aoe M, Tabata M, Matsuo K, Date H, Tanimoto M

Lung cancer (Amsterdam, Netherlands) 52 ( 1 ) 99 - 103 2006.4

Language：English Publishing type：Research paper (scientific journal) Publisher：1

PURPOSE: Recent reports have demonstrated that mutation of epidermal growth factor receptor (EGFR) gene is predictive factor for tumor responsiveness to gefitinib suggesting the importance of EGFR status for the treatment of the patients with non-small cell lung cancer (NSCLC). However, the relationship between EGFR mutation and adverse events of gefitinib is still unknown. The aim of this study was to evaluate its correlation. PATIENTS AND METHODS: Twenty-six tumor samples from Japanese NSCLC patients who received gefitinib in Okayama University Hospital between November 2000 and October 2004 were examined exons 18-21 of EGFR using direct sequence method. We retrospectively reviewed the clinical records and compared EGFR mutation status with adverse events during gefitinib treatment. RESULTS: Of all 26 patients, EGFR mutation (exon 19 in-frame deletion, 6; exon 21 L858R, 5), were detected in 11 patients (42.3%). The principal adverse event was skin rash (89%), diarrhea (39%), and liver injury (39%). Grade 3 or more adverse events were not common. EGFR mutation status was correlated with neither its frequency nor severity of adverse events during gefitinib treatment including skin rash, diarrhea, liver injury, and interstitial lung disease. As expected, objective response rate of those with EGFR mutations was significantly higher than those without EGFR mutations (78% versus 21%, P<0.001). CONCLUSION: Our study did not demonstrate the presence of close relationships between EGFR mutation status and adverse events during gefitinib treatment.

DOI： 10.1016/j.lungcan.2005.12.004

Other Link： http://orcid.org/0000-0003-1761-6314

Mutations of epidermal growth factor receptor and K-ras genes in adenosquamous carcinoma of the lung. Reviewed

Toyooka S, Yatabe Y, Tokumo M, Ichimura K, Asano H, Tomii K, Aoe M, Yanai H, Date H, Mitsudomi T, Shimizu N

International journal of cancer 118 ( 6 ) 1588 - 1590 2006.3

肺高血圧症の治療の現状と移植適応両側生体部分肺移植後に肺リンパ脈管筋腫症再発を来たした一例

杉本龍士郎, 伊達洋至, 杉本誠一郎, 青江基, 豊岡伸一, 岡部和倫, 岡崎恵, 佐野由文

移植 41 ( 1 ) 57 - 58 2006.2

Mutational and epigenetic evidence for independent pathways for lung adenocarcinomas arising in smokers and never smokers. Reviewed

Toyooka S, Tokumo M, Shigematsu H, Matsuo K, Asano H, Tomii K, Ichihara S, Suzuki M, Aoe M, Date H, Gazdar AF, Shimizu N

Cancer research 66 ( 3 ) 1371 - 1375 2006.2

切除肺癌における再発と腫瘍マーカーの検討

増田紘子, 豊岡伸一, 宗淳一, 原田昌明, 末久弘, 青江基, 佐野由文, 岡部和倫, 伊達洋至, 清水信義

岡山医学会雑誌 117 ( 3 ) 258 - 258 2006.1

LTC-1 Bilateral phrenic nerve paralysis after livingdonor lobar lung transplantation : A case report(Lung Transplant Conference)

Sano Yoshifumi, Aoe Motoi, Toyooka Shinichi, Shigematsu Hisayuki, Okazaki Megumi, Date Hiroshi

The Journal of the Japanese Association for Chest Surgery 20 ( 3 ) 981 - 981 2006

P-501 原発性肺癌の孤立性転移性副腎腫瘍に対する腹腔鏡下副腎摘出術4例の検討(一般示説71 症例(2),世界をリードする呼吸器外科医に!,第23回日本呼吸器外科学会総会)

青江基, 井野川英利, 佐藤仁, 重松久之, 豊岡伸一, 佐野由文, 岡部和倫, 伊達洋至, 清水信義

日本呼吸器外科学会雑誌 20 ( 3 ) 966 - 966 2006

P-530 特発性喉頭・気管狭窄の2例(一般示説75 気道疾患,世界をリードする呼吸器外科医に!,第23回日本呼吸器外科学会総会)

脇直久, 豊岡伸一, 青江基, 伊達洋至, 清水信義

日本呼吸器外科学会雑誌 20 ( 3 ) 973 - 973 2006

OP20-2 Matched Pair Analysisを用いた原発性肺癌における開胸下肺葉切除術と胸腔鏡下肺葉切除術との比較(一般口演20 胸腔鏡,世界をリードする呼吸器外科医に!,第23回日本呼吸器外科学会総会)

重松久之, 豊岡伸一, 青江基, 岡部和倫, 佐野由文, 伊達洋至

日本呼吸器外科学会雑誌 20 ( 3 ) 828 - 828 2006

RP-022 肺転移性腫瘍の手術適応を考える : 多発例と単発例の臨床的比較(要望口演05 胚細胞性腫瘍・多発肺転移,世界をリードする呼吸器外科医に!,第23回日本呼吸器外科学会総会)

佐野由文, 重松久之, 豊岡伸一, 青江基, 岡部和倫, 伊達洋至

日本呼吸器外科学会雑誌 20 ( 3 ) 798 - 798 2006

多発肺癌におけるEGFR遺伝子の変異と増幅

市原周治, 豊岡伸一, 徳毛誠樹, 宗淳一, 末久弘, 浅野博昭, 富井邦年, 青江基, 佐野由文, 岡部和倫, 伊達洋至, 清水信義

肺癌 45 ( 5 ) 527 - 527 2005.11

原発性肺癌手術症例における術後気管支断端瘻発生症例の検討

青江基, 重松久之, 佐藤仁, 市原周治, 宗淳一, 豊岡伸一, 佐野由文, 岡部和倫, 伊達洋至, 清水信義

肺癌 45 ( 5 ) 640 - 640 2005.11

EGFR遺伝子変異と臨床病理学的因子の検討

原田昌明, 豊岡伸一, 市村浩一, 徳毛誠樹, 宗淳一, 末久弘, 青江基, 岡部和倫, 佐野由文, 伊達洋至, 清水信義

The Japanese Journal of THORACIC AND CARDIOVASCULAR SURGERY 53 ( Suppl.II ) 410 - 410 2005.9

EGFR遺伝子L858R変異を有するGefitinib非感受性肺癌の2例

豊岡伸一, 徳毛誠樹, 木浦勝行, 市原周治, 細川忍, 青江基, 佐野由文, 岡部和倫, 大橋圭明, 田端雅弘, 伊達洋至, 清水信義

日本癌治療学会誌 40 ( 2 ) 347 - 347 2005.9

切除肺癌における再発と腫瘍マーカーの検討

増田紘子, 豊岡伸一, 宗淳一, 原田昌明, 末久弘, 青江基, 佐野由文, 岡部和倫, 伊達洋至, 清水信義

The Japanese Journal of THORACIC AND CARDIOVASCULAR SURGERY 53 ( Suppl.II ) 544 - 544 2005.9

肺癌における病期とリンパ節郭清術前リンパ節転移の評価

豊岡伸一, 宗淳一, 末久弘, 青江基, 岡部和倫, 佐野由文, 伊達洋至, 清水信義

The Japanese Journal of THORACIC AND CARDIOVASCULAR SURGERY 53 ( Suppl.II ) 211 - 211 2005.9

当科における季節別に見た肺癌手術成績

宗淳一, 豊岡伸一, 末久弘, 青江基, 岡部和倫, 佐野由文, 伊達洋至, 清水信義

The Japanese Journal of THORACIC AND CARDIOVASCULAR SURGERY 53 ( Suppl.II ) 540 - 540 2005.9

EGFR mutation陽性肺非小細胞癌におけるgefitinibの有害反応に関する検討

藤原義朗, 豊岡伸一, 瀧川奈義夫, 田端雅弘, 徳毛誠樹, 青江基, 木浦勝行, 谷本光音

日本癌治療学会誌 40 ( 2 ) 522 - 522 2005.9

Antitumor effect of gefitinib ('Iressa') on esophageal squamous cell carcinoma cell lines in vitro and in vivo Reviewed

F Hara, M Aoe, H Doihara, N Taira, T Shien, H Takahashi, S Yoshitomi, K Tsukuda, S Toyooka, T Ohta, N Shimizu

CANCER LETTERS 226 ( 1 ) 37 - 47 2005.8

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

High expression of epidermal growth factor receptor (EGFR) is thought to be correlated with cell proliferation, invasion, metastasis, resistance to chemoradiotherapy, and poor prognosis in Various kinds of human cancers. Blockade of EGFR signal transduction can be a promising strategy for cancer therapy. Approximately 40-70% of esophageal squamous cell carcinomas (ESCCs) show high expression of EGFR. In this study, we examined the antitumor effect of gefitinib, an EGFR tyrosine kinase inhibitor, against ESCC cells in vitro and in vivo. In three ESCC cell lines (TE8, T.T and T.Tn), cell proliferation had been inhibited in a dose-dependent manner and IC(50) Values (respectively, 8.49, 18.9 and 17.3 mu M). Gefitinib inhibited EGF-induced autophosphorylation of EGFR and its downstream signaling pathways, Ras/Raf/MAPK and PI3K/Akt, and caused G(1) arrest of cell cycle and apoptosis confirmed with flow cytometry. We examined the effect of gefitinib on nude mice bearing established TE8 and T.T xenografts. Gefitimb (100 or 200 mg/kg once-daily, p.o.) showed antitumor activity in a dose-dependent manner, resulting in a significantly improved survival of treated mice as compared with untreated mice. Immunohistochemical examination of the harvested tumor was performed to examine the status of phosphorylated EGFR, PCNA, Factor VIII and apoptosis. We found inhibition of EGFR phosphorylation, cell cycle arrest (by PCNA staining), decrease of microvessel density (Factor VIII) and induction of apoptosis by TUNEL staining. In conclusion, our findings demonstrate that gefitinib is effective for growth inhibition of ESCC cell lines in vitro and in vivo and suggest that gefitinib may be one of the new therapeutic options for ESSC. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.canlet.2004.12.025

Promoter hypermethylation profile of ovarian epithelial neoplasms Reviewed

PB Makarla, MH Saboorian, R Ashfaq, KO Toyooka, S Toyooka, JD Minna, AF Gazdar, JO Schorge

CLINICAL CANCER RESEARCH 11 ( 15 ) 5365 - 5369 2005.8

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Ovarian carcinomas are believed to arise de novo from surface epithelium, but the actual molecular pathogenesis is unknown. The aim of this study was to compare the promoter hypermethylation profiles of ovarian epithelial neoplasms to better understand the role of epigenetic silencing in carcinogenesis.
Experimental Design: We analyzed the DNA promoter methylation status of eight tumor suppressor and cancer-related genes (p16, RAR beta, E-cadherin H-cadherin, APC, GSTP1, MGMT, RASSF1A) in 23 benign cystadenomas, 23 low malignant potential (LMP) tumors, and 23 invasive carcinomas by methylation-specific PCR.
Results: Benign cystadenomas exhibited promoter hypermethylation in only two genes, p16 (13%) and E-cadherin (13%). LMP tumors also showed p16 (22%) and E-cadherin (17%) methylation, in addition to RAR beta (9%) and H-cadherin (4%). All eight genes were hypermethylated in invasive cancers at a frequency of 9% to 30%. The mean methylation index was highest in invasive tumors [0.20 versus 0.065 (LMP) and 0,033 (cystadenomas); P = 0.001]. Promoter methylation of at least one gene was most commonly observed among invasive cancers [78% versus 44% (LMP; P = 0.03) and 26% (cystadenomas; P = 0.0009)]. Three genes exhibited higher methylation frequencies in invasive tumors: RASSF1A (30% versus 0%; P = 0.0002), H-cadherin (22% versus 2%; P = 0.013), and APC (22% versus 0%; P = 0.003).
Conclusions: Promoter hypermethylation is a frequent epigenetic event that occurs most commonly in invasive epithelial ovarian carcinomas. The profile of aberrant methylation suggests that an accumulation of events at specific genes may trigger malignant transformation of some benign cystaclenomas and LMP tumors.

EGFR mutation and response of lung cancer to gefitinib. Reviewed

Toyooka S, Kiura K, Mitsudomi T

The New England journal of medicine 352 ( 20 ) 2136; author reply 2136 2005.5

primary pericardial synovial sarcomaの1手術例

宗淳一, 青江基, 豊岡伸一, 岡部和倫, 佐野由文, 伊達洋至, 清水信義

日本呼吸器外科学会雑誌 19 ( 3 ) 373 - 373 2005.5

Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in gastrointestinal tumour Reviewed

H. Dote, S. Toyooka, K. Tsukuda, M. Yano, T. Ota, M. Murakami, M. Naito, M. Toyota, A. F. Gazdar, N. Shimizu

British Journal of Cancer 92 ( 6 ) 1117 - 1125 2005.3

Language：English Publishing type：Research paper (scientific journal)

The human DOC-2/DAB2 interactive protein (hDAB2IP) gene is a novel member of the Ras GTPase-activating family and has been demonstrated to be a tumour-suppressor gene inactivated by methylation in several cancers. In this study, we analysed the methylation and expression status of hDAB2IP in gastrointestinal tumours. The promoter region of hDAB2IP was divided into two regions (m2a and m2b) based on our previous report, and the methylation status was determined by bisulphite DNA sequencing in gastric cancer cell lines. The gene expression was semiquantified by real-time RT-PCR, and the results indicated that the m2b promoter region might be an authentic methylation-mediated key regulator of the gene expression. Based on the sequence data, we developed a methylation-specific PCR (MSP) for the m2a and m2b regions and applied it to the samples. Methylation-specific PCR revealed aberrant methylation in the m2a region in eight of 12 gastric cancer cell lines (67%), 16 of 35 gastric cancer tissues (46%) and 29 of 60 colorectal cancer tissues (48%), and in the m2b region in eight of 12 cell lines (67%), I 5 of 35 gastric cancer tissues (43%) and 28 of 60 colorectal cancer tissues (47%). On the other hand, seven (12%) and I I (19%) of 59 gastrointestinal nonmalignant mucosal specimens showed methylation in the m2a and m2b regions, respectively, suggesting that hDAB2IP methylation might play a causative role in carcinogenesis. The 5-aza-2′-deoxycytidine treatment restored the gene expression in the m2b-methylated cell lines, confirming that the methylation caused gene downregulation. We also examined the relationship between hDAB2IP methylation and the clinicopathological features in patients with primary tumours, and determined that methylation in the m2b region was associated with location of the tumour in the stomach. In summary, our results demonstrated that hDAB2IP methylation is frequently present in gastrointestinal tumours and that the resulting gene silencing plays an important role in gastrointestinal carcinogenesis. © 2005 Cancer Research UK.

DOI： 10.1038/sj.bjc.6602458

Promoter methylation downregulates CDX2 expression in colorectal carcinomas Reviewed

Hiroshi Kawai, Kunitoshi Tomii, Shinichi Toyooka, Masaaki Yano, Masakazu Murakami, Kazunori Tsukuda, Nobuyoshi Shimizu

Oncology Reports 13 ( 3 ) 547 - 551 2005.3

Language：English Publishing type：Research paper (scientific journal)

CDX2 (caudal type homeobox transcription factor 2) is a homeobox protein, which is expressed in intestinal epithelium. CDX2 has been considered to play a role as a tumor suppressor gene in colorectal cancer because its expression is lacking in colorectal carcinomas, but preserved in adenomas. The point mutations have been found to account for loss of CDX2 expression, but the main mechanism responsible for CDX2 gene inactivation is less understood. We analyzed methylation and expression status of CDX2 in colorectal cancer cell lines and primary tumors. There are two CpG-rich sites in promoter region of CDX2 gene, -1570 to -1200 and -220 to +880. By COBRA (combined bisulfite restriction analysis) assay, the upper CpG-rich site was heavily methylated in all cell lines, but the lower CpG-rich site was methylated in limited cell lines. Bisulfite sequencing analysis and RT-PCR revealed that methylation of the lower CpG site was associated with down-regulation of CDX2. In addition, gene expression was restored in COLO201, a methylated cell line with 5-aza-2′-deoxycytidine, confirming that methylation caused gene down-regulation. We also examined CDX2 promoter methylation of primary tumors by MSP (methylated-allele specific PCR) assay and found that nearly 40% of cases have a methylated CDX2 gene. Our results demonstrate that CDX2 methylation is frequently present in colorectal cancers and may play a key role in inactivating CDX2 expression.

Somatic mutations of the HER2 kinase domain in lung adenocarcinomas Reviewed

H Shigematsu, T Takahashi, M Nomura, K Majmudar, M Suzuki, H Lee, Wistuba, I, KM Fong, S Toyooka, N Shimizu, T Fujisawa, JD Minna, AF Gazdar

CANCER RESEARCH 65 ( 5 ) 1642 - 1646 2005.3

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Mutations in the epidermal growth factor receptor gene (EGFR) in lung cancers predict for sensitivity to EGFR kinase inhibitors. HER2 (also known as NEU, EGFR2, or ERBB2) is a member of the EGFR family of receptor tyrosine kinases and plays important roles in the pathogenesis of certain human cancers, and mutations have recently been reported in lung cancers. We sequenced the tyrosine kinase domain of HER2 in 671 primary non-small. cell lung cancers (NSCLC), 80 NSCLC cell lines, and 55 SCLCs and other neuroendocrine lung tumors as well as 85 other epithelial cancers (breast, bladder, prostate, and colorectal cancers) and compared the mutational status with clinicopathologic features and the presence of EGFR or KRAS mutations. HER2 mutations were present in 1.6% (11 of 671) of NSCLC and were absent in other types of cancers. Only one adenocarcinoma cell line (NCI-H1781) had a mutation. All HER2 mutations were in-frame insertions in exon 20 and target the identical corresponding region as did EGFR insertions. HER2 mutations were significantly more frequent in never smokers (3.2%, 8 of 248; P = 0.02) and adenocarcinoma histology (2.8%, 11 of 394; P = 0.003). In 394 adenocarcinoma cases, HER2 mutations preferentially targeted Oriental ethnicity (3.9%) compared with other ethnicities (0.7%), female gender (3.6%) compared with male gender (1.9%) and never smokers (4.1%) compared with smokers (1.4%). Mutations in EGFR, HER2, and KRAS genes were never present together in individual tumors and cell lines. The remarkable similarities of mutations in EGFR and HER2 genes involving tumor type and subtype, mutation type, gene location, and specific patient subpopulations targeted are unprecedented and suggest similar etiologic factors. EGFR, HER2, and KRAS mutations are mutually exclusive, suggesting different pathways to lung cancer in smokers and never smokers.

Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers Reviewed

H Shigematsu, L Lin, T Takahashi, M Nomura, M Suzuki, Wistuba, II, KM Fong, H Lee, S Toyooka, N Shimizu, T Fujisawa, ZD Feng, JA Roth, J Herz, JD Minna, AF Gazdar

JOURNAL OF THE NATIONAL CANCER INSTITUTE 97 ( 5 ) 339 - 346 2005.3

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS INC

Background. Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity. However, the role of such mutations in the pathogenesis of lung cancers is unclear. Methods: We sequenced exons 18-21 of the EGFRTK domain from genomic DNA isolated from 617 non-small-cell lung cancers (NSCLCs) and 524 normal lung tissue samples from the same patients and 36 neuroendocrine lung tumors collected from patients in Japan, Taiwan, the United States, and Australia and from 243 other epithelial cancers. Mutation status was compared with clinicopathologic features and with the presence of mutations in KRAS, a gene in the EGFR signaling pathway that is also frequently mutated in lung cancers. All statistical tests were two sided. Results: We detected a total of 134 EGFR TK domain mutations in 130 (21%) of the 617 NSCLCs but not in any of the other carcinomas, nor in nonmalignant lung tissue from the same patients. In NSCLC patients, EGFR TK domain mutations were statistically significantly more frequent in never smokers than ever smokers (51% versus 10%), in adenocarcinomas versus cancer of other histologies (40% versus 3%), in patients of East Asian ethnicity versus other ethnicities (30% versus 8%), and in females versus males (42% versus 14%; all P<.001). EGFR TK domain mutation status was not associated with patient age at diagnosis, clinical stage, the presence of bronchioloalveolar histologic features, or overall survival. The EGFR TK domain mutations we detected were of three common types: in-frame deletions in exon 19, single missense mutations in exon 21, and in-frame duplications/insertions in exon 20. Rare missense mutations were also detected in exons 18, 20, and 21. KRAS gene mutations were present in 50 (8%) of the 617 NSCLCs but not in any tumors with an EGFR TK domain mutation. Conclusions: Mutations in either the EGFR TK domain or the KRAS gene can lead to lung cancer pathogenesis. EGFR TK domain mutations are the first molecular change known to occur specifically in never smokers.

DOI： 10.1093/jnci/dji055

Aberrant methylation profile of human malignant mesotheliomas and its relationship to SV40 infection Reviewed

Makoto Suzuki, Shinichi Toyooka, Narayan Shivapurkar, Hisayuki Shigematsu, Kuniharu Miyajima, Takao Takahashi, Victor Stastny, Andrea L. Zern, Takehiko Fujisawa, Harvey I. Pass, Michele Carbone, Adi F. Gazdar

Oncogene 24 ( 7 ) 1302 - 1308 2005.2

Language：English Publishing type：Research paper (scientific journal)

Malignant mesothelioma (MM) is associated with asbestos exposure and the presence of SV40 viral sequences. Recently, we reported that SV40 infection of human mesothelial cells (HM) causes aberrant methylation of the tumor suppressor gene (TSG) RASSF1A. We investigated methylation of 12 genes by methylation-specific PCR in 63 MMs, six MM cell lines, and two foci of SV40-infected HM. Methylation percentages of the tested genes ranged from 3 to 65%. The frequencies of HPP1, RASSF1A, Cyclin D2, and RRAD methylation, and the value of the methylation index, were significantly higher in SV40 sequence-positive MMs than in SV40-negative MMs. Methylation of TMS1 and HIC-1 was associated with shortened survival. SV40-infected HM showed progressive aberrant methylation of seven genes (RASSF1A, HPP1, DcR1, TMS1, CRBP1, HIC-1, and RRAD) during serial passage. Our results demonstrate a relationship between SV40 and methylation of multiple genes in MM, indicating that the virus plays a role in the pathogenesis of MM. © 2005 Nature Publishing Group. All rights reserved.

DOI： 10.1038/sj.onc.1208263

Aberrant methylation of HIN-1 (high in normal-1) is a frequent event in many human malignancies Reviewed

H Shigematsu, M Suzuki, T Takahashi, K Miyajima, S Toyooka, N Shivapurkar, GE Tomlinson, D Mastrangelo, HI Pass, E Brambilla, UG Sathyanarayana, B Czerniak, T Fujisawa, N Shimizu, AF Gazdar

INTERNATIONAL JOURNAL OF CANCER 113 ( 4 ) 600 - 604 2005.2

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

HIN-1 (high in normal-1) is a putative cytokine with growth inhibitory activities and is downregulated by aberrant methylation in breast cancers. We studied HIN-1 methylation status in many types of adult and pediatric malignancies and cell lines. We examined the expression of HIN-1 mRNA in 52 cell lines and the promoter methylation status in the cell lines and in over 800 primary tumors representing 17 tumor types using methylation specific PCR. Promoter methylation was observed in 73% of breast cancer, 67% of nonsmall cell lung cancer (NSCLC), 30% of small cell lung cancer (SCLC) and 57% of malignant mesothelioma (MM) cell lines, and methylation was completely correlated with loss of expression. Expression negative cell lines restored HIN-1 expression after treatment with 5-aza-2'-deoxycytidine. Promoter methylation of HIN-1 was found in 90% of retinoblastomas, 73% of Wilms' tumors, 61% of rhabdomyosarcomas, 57% of breast cancers, 52% of prostate cancers, 40% of MMs, 28% of NSCLCs and 27% of lymphomas. Methylation frequencies in colorectal cancers, cervical cancers, bronchial carcinoids, SCLCs, neuroblastomas, osteosarcomas, leukemia, medulloblastomas and bladder cancers were lower (4-21%), while hepatoblastomas lacked methylation. HIN-1 methylation was rarely detected in nonmalignant tissues (8 of 165, 5%). Aberrant methylation of HIN-1 with loss of expression is a common event and may contribute to the pathogenesis of many types of human malignancies.

DOI： 10.1002/ijc.20622

再発肺癌に対するラジオ波焼灼療法 (RFA) の有用性について(再発肺癌の治療, 第22回日本呼吸器外科学会総会)

佐野由文, 豊岡伸一, 青江基, 岡部和倫, 伊達洋至, 金澤右, 清水信義

日本呼吸器外科学会雑誌 19 ( 3 ) 316 - 316 2005

Atypical adenomatous hyperplasia 合併・非合併多発肺腺癌における臨床病理学的因子の検討(肺癌 (8), 第22回日本呼吸器外科学会総会)

豊岡伸一, 永井完治, 西條天基, 似鳥純一, 萩原優, 菱田智之, 塩野知志, 吉田純司, 西村光世, 伊達洋至, 清水信義, 石井源一郎, 西脇裕

日本呼吸器外科学会雑誌 19 ( 3 ) 427 - 427 2005

肺移植後に骨粗鬆症関連の骨病変を発症した症例の検討(肺移植, 第22回日本呼吸器外科学会総会)

青江基, 豊岡伸一, 岡部和倫, 佐野由文, 伊達洋至, 清水信義

日本呼吸器外科学会雑誌 19 ( 3 ) 352 - 352 2005

Unilateral chronic rejection after living-donor lobar lung transplantation

The Journal of the Japanese Association for Chest Surgery 19 ( 3 ) 281 - 281 2005

W11-2 気管支鏡, 胸腔鏡を使った対策(<ワークショップ11>肺切除後合併症と対策)(第28回日本呼吸器内視鏡学会総会)

青江基, 豊岡伸一, 岡部和倫, 佐野由文, 伊達洋至, 清水信義

気管支学 27 ( 3 ) 197 - 197 2005

The relationship between aberrant methylation and survival in non-small-cell lung cancers Reviewed

S. Toyooka, M. Suzuki, R. Maruyama, K. O. Toyooka, K. Tsukuda, Y. Fukuyama, T. Iizasa, M. Aoe, H. Date, T. Fujisawa, N. Shimizu, A. F. Gazdar

British Journal of Cancer 91 ( 4 ) 771 - 774 2004.8

Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Publishing Group

The present study examined the relationship between methylation of five genes (p16INK4a, RASSF1A, APC, RARβ and CDH13) and patient survival in 351 cases of surgically resected lung cancers. While there was no relationship between the other genes and survival, p16INK4a methylation was significantly related to unfavourable prognosis in lung adenocarcinomas. © 2004 Cancer Research UK.

DOI： 10.1038/sj.bjc.6602013

Less frequent promoter hypermethylation of DLC-1 gene in primary breast cancers Reviewed

A Teramoto, K Tsukuda, M Yano, S Toyooka, H Dote, H Doihara, N Shimizu

ONCOLOGY REPORTS 12 ( 1 ) 141 - 144 2004.7

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

Absence or low expression of DLC-1, a tumor suppressor gene, in breast cancers has been shown recently. LOH of 8p12-p22, on which DLC-1 is located, is frequent in breast cancers, but the correlation between low expression of DLC-1 and LOH has not been confirmed. To determine the implication of aberrant methylation, one of the most frequent mechanisms of silencing the tumor suppressor or cancer-related genes, we examined the methylation status of DLC-1 promoter region in breast cancer cell lines and primary breast tumors. The hypermethylation status was examined by MSP and 25% of cell lines harbored a methylated allele. The gene silencing by methylation was also confirmed by the reexpression of DLC-1 by the 5-aza-2'-deoxycytidine treatment in DLC-1 hypermethylated cell line. But the methylation of DLC-1 gene was less frequently shown in primary breast cancers (10%). These data suggest that hypermethylation is responsible for silencing of DLC-1 gene in a limited portion of breast cancers.

DNA methylation of multiple genes and clinicopathological relationship of non-small cell lung cancers Reviewed

T Hanabata, K Tsukuda, S Toyooka, M Yano, M Aoe, Nagahiro, I, Y Sano, H Date, N Shimizu

ONCOLOGY REPORTS 12 ( 1 ) 177 - 180 2004.7

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

Aberrant methylation of 5'CpG islands is thought to play an important role in the inactivation of tumor suppressor genes in several types of cancers. In non-small cell lung cancer (NSCLC), several genes are known to be frequently methylated and the correlation of their methylation with clinical features has been studied. We determined the methylation of p16, CDH13 and RAR-beta which were reported to be methylated frequently in NSCLCs and HPP-1 which was known to be methylated in other types of cancers. The correlation between methylation and clinicopathological features were examined. The frequencies of methylation in NSCLCs were 20% for p16, 37% for CDH13, 34% for RAR-beta, and 13% for HPP1. The methylation of p16 is correlated with smoking history and methylation of HPP1 was significantly more frequent in adenocarcinomas than in squamous cell carcinomas. This is the first description of aberrant methylation of the HPP1 gene in lung cancers and our data support the previous reports on methylation in NSCLCs and association with smoking.

SYT-SSX fusion genes in synoviat sarcoma of the thorax Reviewed

M Yano, S Toyooka, K Tsukuda, H Dote, Y Morimoto, N Ohata, K Ichimura, M Aoe, H Date, N Shimizu

LUNG CANCER 44 ( 3 ) 391 - 397 2004.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI IRELAND LTD

Synovial sarcoma (SS) is characterized by a chromosomal translocation resulting in the expression of an SYT-SSX chimeric transcript, usually SYT-SSX1 or SYT-SSX2. Synovial sarcoma typically originates in the limbs, and its location in the thorax is rare. Synovial sarcomas are usually classified into three histologic subtypes: biphasic, monophasic and poorly differentiated tumors. The detection of the characteristic chimeric transcript often contributes to a histopathological diagnosis, especially when the tumor arises in an unusual location. Previous studies have shown that SYT-SSX1 is the most common SYT-SSX fusion transcript in biphasic synovial sarcomas of the limbs. Here, we report two cases of synovial sarcoma originating in the thorax. The presence of SYT-SSX2 chimeric transcripts was confirmed by reverse transcript polymerase chain reaction (RT-PCR) and a direct sequencing analysis in both cases. The tumor in case 1 originated from the pericardium, which is an exceedingly rare site for primary synovial sarcoma; only three other cases of synovial sarcoma originating in the pericardium have been previously reported. Case 2 exhibited a biphasic synovial sarcoma of the mediastinum containing an SYT-SSX2 fusion transcript, which is a rare fusion type in biphasic synovial sarcomas of the limbs. We reviewed previous reports of thoracic synovial sarcomas containing an analysis of the SYT-SSX fusion transcript and found that case 2 in the present study was the first description of a biphasic synovial sarcoma of the thorax with an SYT-SSX2 fusion transcript. However, the number of reported cases was not sufficient to conclude that SYT-SSX2 fusion in biphasic synovial sarcoma of the thorax is, indeed, rare. Further genetic analysis is needed to fully understand the biological and clinical features of synovial sarcoma originating in the thorax. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2003.11.011

The relationship between NY-ESO-1 mRNA expression and clinicopathological features in non-small cell lung cancer Reviewed

J Konishi, S Toyooka, M Aoe, Y Omura, K Washio, K Tsukuda, N Shimizu

ONCOLOGY REPORTS 11 ( 5 ) 1063 - 1067 2004.5

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

Tumor-associated antigens recognized by cellular or humoral effectors of the immune system are potential targets for antigen-specific cancer immunotherapy. NY-ESO-1 is one of the most immunogenic cancer/testis (CT) antigens and emerges as the potential candidate for specific immunotherapy. We studied mRNA expression status of NY-ESO-1 in 63 cases of NSCLCs using the real-time reverse transcription PCR to examine the relationship between its expression and clinicopathological features. NY-ESO-1 expression was present in 20 (32%) of 63 NSCLC cases and significantly increased with the advancement of disease stage in TNM classification (P=0.013), especially related to lymph node metastasis (P=0.020). Moreover, frequency of NY-ESO-1 expression was related to the degree of pathological differentiation (P=0.035). The quantity of NY-ESO-1 expression by real-time RT-PCR was not correlated with any clinicopathological factor. Our results demonstrate that the NY-ESO-1 expression was frequently present in primary NSCLC, especially advanced cases with lymph node metastasis. In addition, the high incidence of NY-ESO-1 expression in NSCLC suggests the possibility of a specific immunotherapy for NSCLC.

Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types Reviewed

N Shivapurkar, S Toyooka, KO Toyooka, J Reddy, K Miyajima, M Suzuki, H Shigematsu, T Takahashi, G Parikh, HI Pass, PM Chaudhary, AF Gazdar

INTERNATIONAL JOURNAL OF CANCER 109 ( 5 ) 786 - 792 2004.5

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

TNF-related apoptosis-inducing ligand (TRAIL) selectively induces programmed cell death (apoptosis) in various cancer cells but not in normal cells. TRAIL is known to bind to 4 different receptors, 2 proapoptotic (DR4 and DRS), and 2 potentially antiapoptotic receptors lacking death domains (DcRI and DcR2) Aberrant promoter methylation and resultant silencing of tumor suppressor genes play an important role in the pathogenesis of many tumor types. Recently aberrant methylation of TRAIL decoy receptors was reported in pediatric tumor cell lines and neuroblastomas. We examined the methylation and expression status of TRAIL receptor genes in cancers of breast, lung, mesothelioma, prostate, bladder, cervix, ovary, brain and in hematopoietic malignancies. Aberrant methylation of DcR1 or DcR2 was present in 70% of primary breast cancers, 31% of primary lung cancers, in 63% of primary malignant mesothelioma (MM), in 60% of prostate cancer, in 42% of bladder cancer, in 100% of cervical cancer, in 43% of ovarian cancer, in 41% of lymphoma, in 26% of leukemia and in 56% of multiple myeloma. Methylation of DR4 and DR5 was rare in all the tumor types examined. Methylation of all the 4 receptors was rare in non malignant tissues. In cell lines, aberrant methylation of DcR1 was present in 11 of 23 (48%) breast, 10 of 27 (37%) lung and 3 of 7 (43%) MM, whereas aberrant methylation of DcR2 was present in 17 of 23 (74%) breast, 13 of 27 (48%) lung and 5 of 7 (71%) MM. The concordance between loss of gene expression and aberrant methylation ranged from 70-100%. Treatment with 5-aza-2'-deoxycytidine restored DcR1 and DcR2 expression in 9 methylated cell lines confirming that aberrant methylation was the cause for silencing of DcRI and DcR2 expression. Our results demonstrate that DcRI and DcR2 genes are frequently methylated in various tumor types, and that the role of decoy receptors in tumor pathogenesis needs to be re-evaluated. (C) 2004 Wiley-Liss, Inc.

DOI： 10.1002/ijc.20041

Mutation analysis of the BRAF codon 599 in malignant pleural mesothelioma by enriched PCR-RFLP Reviewed

H Dote, K Tsukuda, S Toyooka, M Yano, HI Pass, N Shimizu

ONCOLOGY REPORTS 11 ( 2 ) 361 - 363 2004.2

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

BRAF encodes a RAS-regulated serine/threonine kinase that mediates the pathway for cell growth and malignant transformation. Point mutations of BRAF were reported recently in 66% of melanomas, over 30% of thyroid papillary and low-grade ovarian cancers, and a smaller percentage of other human cancers. Mutations in malignant cells were reported to occur only in exons 11 and 15. Among these mutations, BRAF V599E is most frequent and proved to invert its transcript to the dominant active form. To exclude the interference of co-existing normal cells in clinical samples, we developed a new enriched PCR-RFLP assay for detecting mutations of BRAF codon 599 mutation. The sensitivity of this assay was examined to find that one mutant allele among C, 102 wild-type alleles could be detected. We applied this method for 53 cases of primary malignant pleural mesotheliomas (MPMs) and 6 cell lines and found no mutations in these samples. Our results demonstrate that the developed enriched PCR-RFLP is a sensitive assay to detect BRAF codon 599 mutation. However, it may be a rare type of mutation in MPMs. Our new assay is useful and can be applied for screening of BRAF codon 599 mutation in various kinds of clinical samples.

Primary Thymic Adenocarcinoma with Production of Carbohydrate Antigen 19-9 and Carcinoembryonic Antigen Reviewed

Takahiko Misao, Yosuke Yamamoto, Hideharu Nakano, Shinichi Toyooka, Masataka Yamane, Katashi Satoh

Japanese Journal of Thoracic and Cardiovascular Surgery 52 ( 1 ) 30 - 32 2004

Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Association for Thoracic Surgery

A 59-year-old male, whose chest X-ray showed an abnormal shadow, visited us for further study. Laboratory examination showed the elevated level for both carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) in serum, and the chest X-ray and computed tomography showed an anterior mediastinal mass. Under a diagnosis of thymic malignancy, extended thymectomy with combined resection of the pleura and pericardium was performed. Histopathological findings showed a well-differentiated adenocarcinoma of the thymus, in which CA19-9 and CEA were positive immuno-histochemically. The level of serum CA19-9 and CEA returned to normal ranges postoperatively, however, the tumor recurred in local site with re-elevation of these tumor markers at the 20th month after surgery. He died at 4th month after the first recurrence despite the intensive chemotherapy. We report an extremely rare case of primary thymic adenocarcinoma with the production of CA19-9 and CEA.

DOI： 10.1007/s11748-004-0058-3

P-143 肺癌細胞におけるDNMT1と癌抑制遺伝子の関連について(基礎研究2)(一般示説15)

鈴木実, 砂長則明, 豊岡伸一, 木村秀樹, 藤澤武彦

日本呼吸器外科学会雑誌 18 ( 3 ) 372 - 372 2004

P-594 非小細胞肺癌株におけるビスフォスフォネート製剤の直接増殖抑制効果の評価と検討(肺癌10)(一般示説60)

越宗龍一郎, 原文堅, 青江基, 豊岡伸一, 大谷裕, 平見有二, 花畑哲郎, 永広格, 佐野由文, 伊達洋至, 清水信義

日本呼吸器外科学会雑誌 18 ( 3 ) 485 - 485 2004

Establishment and validation of quantitative real-time pcr assay for aberrant methylation of 14-3-3û gene in breast and lung carcinoma

Ubaradka G. Sathyanarayana, Makoto Suzuki, Shinichi Toyooka, Asha Padar, Kiyomi O. Toyooka, Andrea L. Zern, Kuniharu Miyajima, Takashi Takahashi, Elizabeth Brambilla, Adi F. Gazdar

Cancer Genomics and Proteomics 1 ( 1 ) 1 - 8 2004

Language：English Publishing type：Research paper (scientific journal) Publisher：International Institute of Anticancer Research

Background: 14-3-3Û gene has been shown to be responsible for G2 cell cycle checkpoint control by p53 in response to DNA damage in human cells. In order to increase the potential utility of 14-3-3Û gene as a molecular marker in tumor analysis and prognosis, we established and validated a quantitative real-time MSP assay and correlated our findings with the standard MSP assay. Materials and Methods: We examined the expression of 14-3-3 Û gene by reverse transcription PCR (RT-PCR) in breast and lung cancer cell lines and control non-malignant tissue samples. To elucidate the mechanism of gene silencing, we studied the methylation patterns in cell lines, tumors and non-malignant control tissues of breast and lung using previously reported MSP assay. For fluorescence based quantitative Real-Time PCR assay, we designed primers and probe specific to 14-3-3Û gene, validated the assay in cell lines and non-malignant control tissues of breast and lung and extended the study to primary tumors and corresponding nonmalignant tissues. Results: The concordances between the standard MSP assay and the real-time assay were 95-100%. The overall concordances between standard MSP and real-time assay in 60 cell lines were 97%. By real-time assay, the differences in methylation frequencies between malignant and non-malignant breast and between malignant and nonmalignant lung tissues
between NSCLC and SCLC cell lines between MSP (-) and MSP (+) samples and between MSP (+) and MSP (++) samples were statistically significant. The mean real-time values for MSP (-), MSP (+) and MSP (++) samples were 2, 28 and 53 respectively. Conclusion: We conclude that promoter methylation is a valid pathway for silencing of 14-3- 3Û gene in primary breast and lung carcinomas. The real-time assay to distinguish the extent and degree of methylation of 14- 3-3Û gene among malignant and non-malignant tissues would potentially enhance the utility of this marker in breast and lung cancer analysis and prognosis.

Alterations in the Mitochondrial Displacement Loop in Lung Cancers Reviewed

Makoto Suzuki, Shinichi Toyooka, Kuniharu Miyajima, Toshihiko Iizasa, Takehiko Fujisawa, Nebiyou B. Bekele, Adi F. Gazdar

Clinical Cancer Research 9 ( 15 ) 5636 - 5641 2003.11

Language：English Publishing type：Research paper (scientific journal)

Purpose: Alterations of the noncoding displacement (D) loop of mitochondrial DNA are present in many cancers. These alterations include numerical changes in a homopolymeric C tract (PCT) at positions 303-309 and single base substitutions (SBS). We determined the frequency of D-loop alterations in lung cancer cell lines and tumors, and related them to clinicopathologic features. Experimental Design: We sequenced the entire D-loop of 28 lung cancer cell lines [12 small cell lung cancer (SCLC) and 16 non-small cell lung cancer (NSCLC)] and matched B-lymphoblastoid cell lines. In 55 resected NSCLCs and corresponding nonmalignant lungs we determined the length of the PCT. Results: In nonmalignant cell lines and tissues the most frequent PCT repeat number was seven (36 of 83
43%) with a range of six to nine. Alterations, often multiple, were present in 17 of 28 (61%) of the cell lines, including 8 of 12 SCLC (67%) and 9 of 16 NSCLC (56%) lines. They consisted of SBS in 8 of 28 lines (29%), all of which were homoplasmic, and PCT changes in 14 of 28 (50%) lines, 8 of which were homoplasmic. Of interest, 95% (40 of 42) of the SBS were present within the two hypervariable regions in the D-loop. Because SBS were more frequent if PCT changes were present, only the PCT number was determined in resected samples. PCT changes were present in 11 of 55 (20%) of the NSCLC tumors. Changes were never noted in tumors when the PCT number in the nonmalignant tissue was seven, and only two tumor cell lines had changes when the PCT number in the matched lymphoblastoid cell line was seven. These changes were higher in squamous cell carcinomas (8 of 25
32%) than in adenocarcinomas (3 of 30
10%
P = 0.04) and in large tumors (T3 and T4
7 of 20
35%) compared with smaller tumors (T1 and T2
4 of 35
11%
P = 0.04). Smoking history, gender, age, and stage were not related to frequency of PCT change. Conclusions: Our findings indicate that D-loop alterations are frequent in lung cancers and their cell lines, and that these changes are weakly associated with certain clinical parameters. In tumors PCT changes were only present when the corresponding nonmalignant lung demonstrated a variation from the most common repeat number of seven.

Aberrant methylation of multiple genes in the upper aerodigestive tract epithelium of heavy smokers Reviewed

S Zochbauer-Muller, S Lam, S Toyooka, AK Virmani, KO Toyooka, S Seidl, JD Minna, AF Gazdar

INTERNATIONAL JOURNAL OF CANCER 107 ( 4 ) 612 - 616 2003.11

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

An important method for silencing tumor suppressor genes in cancers is by aberrant methylation (referred to as methylation) of CpG islands in gene promoter regions. In lung cancer, methylation of the genes retinoic acid receptor beta-2 (RARbeta-2), CDH13 (H-cadherin), p16(INK4a) (p16), RASSFIA (RAS association domain family 1) is frequent. Thus, we investigated methylation of these genes in 4 different types of specimens (oropharyngeal brushes, sputum samples, bronchial brushes and bronchioloalveolar lavage [BAL] samples) of the upper aerodigestive tract epithelium from heavy smokers without evidence of cancer but with morphometric evidence of sputum atypia and compared the frequencies of methylation in the different types of specimens. In addition, we also analyzed sputum samples from 30 never smokers for methylation of these genes. Our major findings are: (i) At least one gene was methylated in one or more specimens from 48% of the smokers. However, methylation was statistically significant less frequently in never smokers compared to smokers. (ii) In general, methylation occurred more frequently in samples from the central airways (sputum, bronchial brushes) compared to the peripheral airways (BAL) and only occasionally in the oropharynx. (iii) RARbeta-2 was the most frequently methylated gene, whereas the frequency of methylation for the other genes was lower. (iv) Data from sputum samples and bronchial brushes were comparable. Our findings suggest that detection of methylation should be investigated as an intermediate marker for lung cancer risk assessment and response to chemopreventive regimens. (C) 2003 Wiley-Liss, Inc.

DOI： 10.1002/ijc.11458

The effect of epidermal growth factor receptor antisense morpholino oligomer on non-small cell lung cancer cell line Reviewed

K Washio, M Aoe, S Toyooka, H Mushiake, K Tsukuda, N Shimizu

ONCOLOGY REPORTS 10 ( 6 ) 1967 - 1971 2003.11

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

Overexpression of the epidermal growth factor receptor (EGFR) has been identified as a common component of various cancer types including lung cancer. Recently morpholino oligonucleotides appeared as a promising modification for antisense applications with few toxic effects and their stability. We investigated the effect of EGFR antisense morpholino oligomer on non-small cell lung cancer (NSCLC) cell line by evaluating EGFR mRNA, protein product and cell proliferation. The EGFR antisense morpholino oligomer was designed to target the translation start site in the EGFR mRNA. The four base-mismatch morphlino oligomer was designed as a control for EGFR antisense morpholino oligomer. These morpholino oligomers were introduced into NCI-H125 cell line which showed overexpression of EGFR. The EGFR mRNA and protein expression were quantified by real time RT-PCR and ELISA, respectively. The significant repression in both EGFR mRNA and protein expression was observed for three days after single treatment with EGFR antisense morpholino oligomer. Furthermore, the growth of NCI-H125 cell line was significantly inhibited with treatment by EGFR antisense morpholino oligomer. Our results indicate that EGFR antisense morpholino oligomer represses the EGFR expression at both mRNA and protein level and inhibits the proliferation of NSCLC cell line suggesting that it may be a promising strategy as one of antisense therapies for NSCLC.

Detection of codon 61 point mutations of the K-ras gene in lung and colorectal cancers by enriched PCR. Reviewed

Toyooka S, Tsukuda K, Ouchida M, Tanino M, Inaki Y, Kobayashi K, Yano M, Soh J, Kobatake T, Shimizu N, Shimizu K

Oncology reports 10 ( 5 ) 1455 - 1459 2003.9

悪性中皮腫に対するin vitro及びin vivoのGefitinib(Iressa)の抗腫瘍効果(Antitumor effect by Gefitinib(Iressa)against malignant mesothelioma in vitro and in vivo)

原文堅, 青江基, 豊岡伸一, 平成人, 枝園忠彦, 高畠大典, 吉冨誠二, 高橋寛敏, 石部洋一, 小笠原豊, 土井原博義, 清水信義

日本癌治療学会誌 38 ( 2 ) 767 - 767 2003.9

Epigenetic down-regulation of death-associated protein kinase in lung cancers Reviewed

S Toyooka, KO Toyooka, K Miyajima, JL Reddy, M Toyota, UG Sathyanarayana, A Padar, MS Tockman, S Lam, N Shivapurkar, AF Gazdar

CLINICAL CANCER RESEARCH 9 ( 8 ) 3034 - 3041 2003.8

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Death-associated protein kinase (DAPK) is a pro-apoptotic serine/threonine kinase involved in apoptosis. Aberrant methylation of DAPK was reported in lung cancers by methylation-specific PCR. However, we were unable to relate methylation with gene silencing with the same methodology. Our goals were to develop a methodology that related methylation with gene silencing and use it to study the state of the gene in lung cancers.
Experimental Design and Results: Using a semiquantitative real-time reverse transcription-PCR, DAPK expression was lower in lung cancers than in corresponding nonmalignant bronchial epithelial cells in five of six primary short-term cultures. In continuous cell lines, mRNA expression was down-regulated, as well as compared with nonmalignant bronchial epithelial cells, and its protein was not detected by Western blotting in 17 of 23 (74%) cell lines. We investigated methylation status of 5' flanking region of DAPK by combined bisulfite restriction analysis and bisulfited DNA sequencing. Aberrant methylation was detected in 21 of 48 (44%) cell lines, 2 of 6 primary cultured tumors, and 14 of 38,(37%) primary lung cancers, although varying degrees of methylation were noticed. Furthermore, bisufite sequence data suggested that aberrant methylation might occur selectively at some CpG dinucleotides in cell lines which had absent expression. Treatment with 5-aza-2'-deoxycytidine restored DAPK expression in heavily methylated cell lines tested, and histone deacetylase inhibitor trichostatin A alone restored DAPK expression in some methylated cell lines as well.
Conclusions: Our major. findings are: (a) DAPK expression is frequently down-regulated in lung cancers; (b) aberrant methylation of DAPK is frequent in lung cancers, although considerable heterogeneity of methylation is present, and some specific CpG dinucleotides are often methylated in expression negative lung cancers; and (c) besides methylation and histone deacetylation, there may be other mechanisms for down-regulation of DAPK expression.

Aberrant methylation of TMS1 in small cell, non small cell lung cancer and breast cancer Reviewed

A Virmani, A Rathi, K Sugio, UG Sathyanarayana, S Toyooka, FC Kischel, Tonk, V, A Padar, T Takahashi, JA Roth, DM Euhus, JD Minna, AF Gazdar

INTERNATIONAL JOURNAL OF CANCER 106 ( 2 ) 198 - 204 2003.8

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

TMSI (target of methylation-induced silencing) is a CpG island-associated gene that functions in the regulation of apoptosis and encodes a caspase recruitment domain, a recently described motif found in apoptotic signaling molecules. Recent evidence suggests that silencing of genes in the apoptotic pathway contribute to human carcinogenesis. We examined the DNA methylation status of the TMSI promoter in lung and breast tumor tissues, tumor cell lines and nonmalignant tissues by methylation-specific polymerase chain reaction (MSP) and its mRNA expression by reverse transcription PCR. Aberrant methylation of TMSI was present in 70% (40 of 57) of small cell lung cancer (SCLC) cell lines and 41% (13 of 32) of SCLC tumor tissues, 48% (29 of 6 1) of non small cell lung cancer (NSCLC) cell lines and 40% (28 of 70) of NSCLC tumor tissues and 46% (12 of 26) of breast cancer cell lines and 32% (20 of 63) of breast tumor tissues. Methylation was absent in the peripheral blood lymphocytes and buccal epithelium from healthy volunteers, as well as in nonmalignant lung tissues and was rare in nonmalignant breast tissues 7% (2 of 30). DNA methylation was confirmed by sequence analysis and the methylation status correlated inversely with TMSI RNA expression in 18 cell lines tested. RNA expression was restored by treatment with the demethylating agent S-aza-2'-deoxycytidine, in 4 of 4 methylated cell lines that lacked the TMSI transcript. Our results suggest that methylation of TMSI may play a role in the pathogenesis of small cell and non small lung and breast cancers. (C) 2003 Wiley-Liss, Inc.

DOI： 10.1002/ijc.11206

Epigenetic inactivation of laminin-5-encoding genes in lung cancers Reviewed

Ubaradka G. Sathyanarayana, Shinichi Toyooka, Asha Padar, Takashi Takahashi, Elizabeth Brambilla, John D. Minna, Adi F. Gazdar

Clinical Cancer Research 9 ( 7 ) 2665 - 2672 2003.7

Language：English Publishing type：Research paper (scientific journal)

Purpose: We investigated the loss of expression of three laminin-5 (LN5)-encoding genes in lung cancer cell lines and elucidated the mechanism of inactivation of the genes in lung cancer cell lines and tumors. Experimental Design: We examined the expression of LN5-encoding genes by reverse transcription-PCR in 49 lung cancer cell lines. To elucidate the mechanism of gene silencing, we treated expression-negative cell lines (two for each gene) with a demethylating agent and examined the restoration of expression by reverse transcription-PCR. We dissected out the methylation patterns of CpG sites unique to the promoter regions of LN5-encoding genes by bisulfite genomic sequencing of expression-negative cell lines. We designed methylation-specific primers and validated the methylation status of the promoter regions in lung cancer cell lines using methylation-specific PCR. We further studied the methylation patterns of primary non-small cell lung cancer [NSCLC (n = 36)], small cell lung cancer [SCLC (n = 26)], and carcinoids (n = 24) tumors. Results: We observed frequent losses of expression in NSCLC (20-60%) and SCLC (65-86%) cell lines. Expression of one or more genes was lost in 90% of SCLC cell lines and 65% of NSCLC cell lines. Treatment of expression-negative cell lines with demethylating agent restored expression in all of the cases. Methylation of LN5-encoding genes was present more frequently in SCLC cell lines (60-80%) than in NSCLC cell lines (15-60%), and at least one gene was methylated in 95% of SCLC and 60% of NSCLC cell lines. The concordances between loss of expression and methylation in 40 lung cancer cell lines for the three genes (90-95%) were statistically significant. Methylation was more frequent in SCLC tumors (58-77%) than in NSCLC tumors (22-42%) and carcinoids (13-33%), and at least one gene was methylated in 92% of SCLC tumors, 47% of NSCLC tumors, and 33% of carcinoids. Conclusions: Our results demonstrate frequent epigenetic inactivation of LN5-encoding genes in lung cancers, and these findings are of biological interest and are potentially of clinical importance.

Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer Reviewed

S Toyooka, R Maruyama, KO Toyooka, D McLerran, ZD Feng, Y Fukuyama, AK Virmani, S Zochbauer-Muller, K Tsukuda, K Sugio, N Shimizu, K Shimizu, H Lee, CY Chen, KM Fong, M Gilcrease, JA Roth, JD Minna, AF Gazdar

INTERNATIONAL JOURNAL OF CANCER 103 ( 2 ) 153 - 160 2003.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

Aberrant methylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of lung cancers. There are major smoke exposure, histology, geography and gender-related changes in non-small cell lung cancer (NSCLC). We investigated smoking-related, histologic, geographic and gender differences in the methylation profiles of resected NSCLCs. We examined 514 cases of NSCLC and 84 corresponding nonmalignant lung tissues from 4 countries (USA, Australia, Japan and Taiwan) for the methylation status of 7 genes known to be frequently methylated in lung cancers [p16, RASSF1A (RAS association domain family 1), APC, RARbeta, CDH13, MGMT and GSTPI]. Multivariate analyses were used for data analysis. Adenocarcinoma was the major histologic type in women and never smokers; analyses that involved smoke exposure and gender were limited to this histology. Our major findings are a) methylation status of any single gene was largely independent of methylation status of other genes; b) the rates of methylation of p 16 and APC and the mean Methylation Index (MI), a reflection of the overall methylation status, were significantly higher in ever smokers than in never smokers; c) the mean MI of tumors arising in former smokers was significantly lower than the mean of current smokers; d) the methylation rates of APC, CDH13 and RARbeta were significantly higher in adenocarcinomas than in squamous cell carcinomas; e) methylation rates of MGMT and GSTP1 were significantly higher in the USA and Australian cases than in those from Japan and Taiwan; and (f) no significant gender-related differences in methylation patterns were noted. Our findings demonstrate important smoke exposure, histologic type and geography-related differences in the methylation profiles of NSCLC tumors. (C) 2002 Wiley-Liss, Inc.

DOI： 10.1002/ijc.10787

日本人非小細胞癌におけるDNAメチル化と臨床病理学的因子の検討

豊岡伸一, 鈴木実, 丸山理一郎, 福山康朗, 飯笹俊彦, 藤沢武彦, 清水信義

日本呼吸器外科学会雑誌 17 ( 3 ) 281 - 281 2003

c-N0肺癌切除例の検討 : 縦隔鏡検査の適応について

三竿貴彦, 豊岡伸一, 中野秀治, 久保孝文, 林達朗

日本呼吸器外科学会雑誌 17 ( 3 ) 390 - 390 2003

A case of pancreatic adenocarcinoma with novel K-ras mutation and long term survival. Reviewed

Toyooka S, Tsukuda K, Mizuta M, Soh J, Shirakawa K, Shimizu K, Shimizu N

The American journal of gastroenterology 97 ( 7 ) 1852 - 1853 2002.7

Differential expression of FEZ1/LZTS1 gene in lung cancers and their cell cultures Reviewed

S Toyooka, Y Fukuyama, Wistuba, II, MS Tockman, JD Minna, AF Gazdar

CLINICAL CANCER RESEARCH 8 ( 7 ) 2292 - 2297 2002.7

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: The FEZ1/LZTS1 (FEZ1) gene, located on chromosome 8p22 (8p22), was identified recently as a candidate tumor suppressor gene. Because loss of heterozygosity at 8p21-22 is a frequent event in lung cancers, we studied FEZ1 alteration in short-term cultures of resected lung cancer tumors and cell lines.
Experimental Design: We examined FEZ1 expression in 17 non-small cell lung cancer (NSCLC), 19 small cell lung cancer (SCLC) cell lines, and 6 pairs of short-term cultures of resected NSCLCs and accompanying nonmalignant bronchial cells (NBECs) by reverse transcription-PCR and Western blotting. To investigate the mechanism for silencing, cells were cultured with 5-aza-2'-deoxycytidine or trichostatin A. We screened for genomic mutations by PCR-single-strand conformational polymorphism.
Results: Thirteen of 17 NSCLC (76%) and 3 of 19 SCLC (16%) of cell lines showed absent expression (P = 0.001). Of the paired NSCLC-NBEC cultures, 3 of 6 showed loss of expression in tumor cell cultures. In the cell lines retaining expression, the amplicon products in SCLCs were more intense than those of NSCLCs and NBECs. Expression of FEZ1 was not restored by 5aza-2'-deoxycytidine and trichostatin A. Although FEZ1 expression was moderately correlated with loss of heterozygosity of specific microsatellite makers at 8p21-22 in NSCLC cell lines, it was strongly correlated to D8S261 and LPL loci in SCLC cell lines. No mutation was found within cording region of FEZ1 by PCR-single-strand conformational polymorphism.
Conclusions: We found differential FEZ1 expression in NSCLC and SCLC cell lines, and the absent expression in 3 of 6 short-term cultures of NSCLC tumors. FEZ1 may be related to tumorigenesis of lung cancer.

Aberrant methylation of the CDH13 (H-cadherin) promoter region in colorectal cancers and adenomas Reviewed

S Toyooka, KO Toyooka, K Harada, K Miyajima, P Makarla, UG Sathyanarayana, J Yin, F Sato, N Shivapurkar, SJ Meltzer, AF Gazdar

CANCER RESEARCH 62 ( 12 ) 3382 - 3386 2002.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Expression of the cadherin family member CDH13 (H-cadherin) is reduced in several human tumors, and it has been hypothesized that this gene functions as a tumor suppressor gene. Previously, we reported that the 5' region of CDH13 is frequently methylated in breast and lung cancers. Here we confirmed the promoter activity of 5' region of CDH13 by luciferase assay and examined its aberrant methylation in colorectal cancers, cell lines, and adenomas. Methylation status was investigated by methylation-specific PCR (MSP) and by bisulfite DNA sequencing of cloned DNA of PCR amplicons. In cell lines, we examined the correlation between methylation status and mRNA expression by reverse transcription-PCR. Aberrant methylation of CDH13 was present in 7 of 13 (54%) cell lines, and expression was absent in 6 of 13 (46%) cell lines. CDH13 expression was present in six cell lines that showed only the unmethylated form by MSP and in one cell line that showed both the methylated and unmethylated forms. Treatment with 5-aza-2'-deoxycytidine restored CDH13 expression in methylated cell lines. In surgically resected samples, 17 of 35 (49%) cases of primary colorectal cancer, 2 of 33 (6%) cases of corresponding nonmalignant colorectal mucosa, and 8 of 19 (42%) adenomas were methylated. Sequence data after bisulfite treatment indicated that primary cancers and two cell lines with loss of expression were highly methylated compared with nonmalignant colorectal epithelial cells, especially at the attachment sites of primers for NISP, although there was heterogeneity in methylation status. Our results suggest that CDH13 expression is frequently silenced by aberrant methylation in colorectal cancers and adenomas and that methylation of CDH13 commences at an early stage of multistep colorectal tumorigenesis.

Differential inactivation of caspase-8 in lung cancers Reviewed

Narayan Shivapurkar, Shinichi Toyooka, Michael T. Eby, Chun Xian Huang, Ubaradka G. Sathyanarayana, H. Thomas Cunningham, Jyotsna L. Reddy, Elizabeth Brambilla, Takashi Takahashi, John D. Minna, Preet M. Chaudhary, Adi F. Gazdar

Cancer Biology and Therapy 1 ( 1 ) 65 - 69 2002

Language：English Publishing type：Research paper (scientific journal) Publisher：Landes Bioscience

Caspase-8 (CASP8) is an apoptosis inducing cysteine protease which is activated through the formation of a death-inducing signaling complex when death receptors are complexed to their specific ligands. Recent reports indicate that CASP8 expression is lost via a combination of promoter methylation and allelic loss in a subset of neuroblastomas. We investigated the state of the gene in lung tumors and cell lines. RT-PCR studies indicated that gene expression was lost in most (27 of 34, 79%) of small cell lung carcinoma (SCLC) cell lines, but expression was retained in all 22 non-SCLC (NSCLC) lines tested. Loss of gene expression at the RNA level was associated with absent protein expression by Western blotting and lack of CASP8 enzymatic activity. Methylation of the promoter region of the CASP8 gene was present in 16 of 27 (59%) of the SCLC lines lacking gene expression. All methylated cell lines lacked the presence of an unmethylated allele indicating biallelic methylation or loss of non-methylated allele. Promoter methylation was absent in all SCLC and NSCLC cell lines retaining gene expression, and all of these lines had the unmethylated form of the gene. One non-expressing SCLC cell line, NCI-H82, had a homozygous deletion at 2q33 encompassing the chromosomal location of the CASP8 gene. The mechanism of gene inactivation in the remaining 10 of 27 (37%) non-expressing SCLC cell lines is unknown. Using five polymorphic markers for 2q33 a high frequency of allelic loss was present in SCLC lines. Analyses of fresh tumors showed that 15 of 43 (35%) of the SCLC, seven of 40 (18%) of bronchial carcinoids and none of 44 NSCLC tumors had CASP8 promoter methylation. Because only approximately 60% of SCLC cell lines lacking CASP8 expression were methylated, extrapolating from the cell line data, we estimate that approximately 58% of SCLC and 30% of bronchial carcinoids lack CASP8 expression. Thus, CASP8 expression is absent in a subset of both high grade (SCLC) and low grade (carcinoid) neuroendocrine lung tumors but not in NSCLC, which usually lack neuroendocrine features. CASP8 may function as a tumor suppressor gene in neuroendocrine lung tumors.

DOI： 10.4161/cbt.1.1.45

DNA methylation profiles of lung tumors Reviewed

Shinichi Toyooka, Kiyomi O. Toyooka, Riichiroh Maruyama, Arvind K. Virmani, Luc Girard, Kuniharu Miyajima, Kenichi Harada, Yutaka Ariyoshi, Takashi Takahashi, Kenji Sugio, Elisabeth Brambilla, Michel Gilcrease, John D. Minna, Adi F. Gazdar

Molecular Cancer Therapeutics 1 ( 1 ) 61 - 67 2001.11

Language：English Publishing type：Research paper (scientific journal)

Aberrant methylation of CpG islands in promoter regions of tumor cells is one of the major mechanisms for silencing of tumor suppressor genes. We determined the frequency of aberrant promoter methylation of the p16, adenomatous polyposis coli (APC), H-cadherin (CDH13), glutathione S-transferase P1 (GSTP1), O6-methylguanine-DNA-methyltransferase (MGMT), retinoic acid receptor β-2 (RARβ), E-cadherin (CDH1), and RAS association domain family 1A (RASSF1A) genes in 198 tumors consisting of small cell lung cancers [SCLCs (n = 43)], non-small cell lung cancers [NSCLCs (n = 115)], and bronchial carcinoids (n = 40). The profile of methylated genes in the two neuroendocrine tumors (SCLC and carcinoids) were very different from that of NSCLC. However, whereas the overall pattern of aberrant methylation of carcinoids was similar to that of SCLC, carcinoids had lower frequencies of methylation for some of the genes tested. There were also significant differences in the methylation profiles between the two major types of NSCLC, adenocarcinoma and squamous cell carcinoma. We performed cluster analysis and found that SCLCs clustered with other SCLCs and carcinoids but not with NSCLCs, whereas the NSCLCs tended to cluster together. Within NSCLCs, adenocarcinomas and squamous cell carcinomas clustered with their respective histological types. Finally, we compared the methylation profiles of SCLC and NSCLC tumors and their respective cell lines (n = 44). In general, methylation frequencies were higher in tumor cell lines, but these differences were seldom significant. Thus, tumor cell lines appear to be suitable models to study aberrant DNA methylation. We conclude that SCLC, carcinoids, squamous cell carcinomas, and adenocarcinomas of the lung have unique profiles of aberrant methylation. Our findings should help us understand differences in the pathogenetic mechanisms of lung cancers. © 2001 American Association for Cancer Research.

Loss of expression and aberrant methylation of the CDH13 (H-cadherin) gene in breast and lung carcinomas Reviewed

KO Toyooka, S Toyooka, AK Virmani, UG Sathyanarayana, DM Euhus, M Gilcrease, JD Minna, AF Gazdar

CANCER RESEARCH 61 ( 11 ) 4556 - 4560 2001.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Expression of some members of the cadherin family is reduced in several human tumors, and CDH13 (B-cadherin), located on chromosome 16q24.2-3, may function as a tumor suppressor gene. In human tumors, loss of expression of many tumor suppressor genes occurs by aberrant promoter region methylation. We examined the methylation status of the CDH13 promoter in breast and lung cancers and correlated it with mRNA expression using methylation-specific PCR and reverse transcription-PCR Methylation was frequent in primary breast tumors (18 of 55, 33%) and cell lines (7 of 20, 35%). In lung cancers, methylation was present more frequently in non-small cell lung cancer tumors (18 of 42, 43%) and cell lines (15 of 30, 50%) than in small cell Lung cancer cell Lines (6 of 30, 20%; P = 0.03). Only the methylated or unmethylated forms of the gene were present in most (73 of 80, 91%) tumor cell lines. CDH13 expression was present in 24 of 30 (80%) of nonmethylated tumor lines, All 18 methylated lines tested lacked expression irrespective of whether the unmethylated form was present, confirming biallelic inactivation in methylated lines, Gene expression was restored in all five methylated cell lines tested after treatment with the demethylating agent 5 ' -aza-2-deoxycytidine. Our results demonstrate frequent aberrant methylation of CDH13 in breast and lung cancers accompanied by loss of gene expression, although expression may occasionally be lost by other mechanisms.

Three cases report of duplication of alimentary tract Reviewed

Shinichi Toyooka, Kazutoyo Shirakawa, Shinji Hato, Osanori Sogabe, Hiroya Maeda, Minoru Mizuta, Takashi Ohya, Ichizo Suemitsu

Japanese Journal of Gastroenterological Surgery 30 ( 1 ) 88 - 91 1997

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Society of Gastroenterological Surgery

We have treated three cases of alimentary tract duplication in the last four years. Case 1 involved a 34-year-old man who had complained of abdominal pain since early childhood. On X-ray examination, an intra-abdominal calcification was detected. Although a definite diagnosis was not made, a laparotomy was performed because of the history of frequent severe abdominal pain. This led to diagnosis of duplication of the ileum. In case 2 a 13-year-old boy complained of abdominal pain and melena. Laparotomy was performed under a suspected diagnosis of Meckel's diverticulitis. A diagnosis of duplication of the ileum was then made. Case 3 involved a 67-year-old man who had undergone total gastrectomy because of gastric cancer. The operative findings included a tumor the size of a child's head was attached to the S-colon. We resected the tumor and made a diagnosis of duplication of the S-colon. The preoperative diagnosis of alimentary tract duplication is difficult. This potential diagnosis should be borne in mind for a patient who complains of abdominal symptoms with an unknown cause.

DOI： 10.5833/jjgs.30.88

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