Faculty Profiles - TOYOOKA Shinichi

Papers - TOYOOKA Shinichi

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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

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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

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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

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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

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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

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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

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

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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

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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

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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

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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

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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

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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

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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

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Papers - TOYOOKA Shinichi