Faculty Profiles - SUZAWA Ken

Papers - SUZAWA Ken

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Prognostic Analysis of Pathological Stage I Lung Adenocarcinoma Harboring Major EGFR Mutations. International journal

Shinkichi Takamori, Makoto Endo, Akira Hamada, Shuta Ohara, Shota Fukuda, Yasuaki Tomioka, Satoshi Takamori, Atsushi Osoegawa, Kotaro Nomura, Kosuke Fujino, Mao Yoshikawa, Ken Suzawa, Kazuhiko Shien, Kenichi Suda, Fumihiko Kinoshita, Kazuki Hayasaka, Hirotsugu Notsuda, Taichi Nagano, Kyoto Matsudo, Asato Hashinokuchi, Taichi Matsubara, Shinya Katsumata, Satoshi Shiono, Junichi Soh, Yasuhisa Ohde, Mototsugu Shimokawa

Clinical lung cancer 2024.12

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

BACKGROUND: While Epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma (LUAD) has favorable outcomes with targeted therapy, early-stage prognosis remains influenced by pathological factors and central nervous system (CNS) recurrence. The study aimed to clarify prognostic factors in pathological stage (pStage) I EGFR mutation-positive LUAD. METHODS: Between 2015 and 2018, 2,191 pStage I LUAD cases with known EGFR status (excluding EGFR testing after recurrence) who received anatomical resection were included from multiple institutions in Japan. Univariate and multivariate analyses of disease-free survival (DFS) and overall survival (OS) were performed. RESULTS: 1,073 (49.0%) cases harbored EGFR mutations, including 419 (19.1%) with 19del and 529 (24.1%) with L858R. In cases with major EGFR mutation (n = 948), multivariate analysis showed that the absence of noninvasive area (NIA) (hazard ratio [HR]: 1.778, 95% confidence interval [CI]: 1.174-2.692, P = .0065), pStage (IA2 vs. IA1, HR: 2.079, 95% CI: 1.129-3.827, P = .0345; IA3 vs. IA1, HR: 4.009, 95% CI: 2.088-7.696, P = .0001; IB vs. IA1, HR: 5.280, 95% CI: 2.871-9.709, P < .0001), and presence of lymphatic invasion (HR: 1.855, 95% CI: 1.103-3.119, P = .0197) were independent predictors of shorter DFS, and only advanced pStage was an independent predictor of CNS recurrence (relative risk for pStage IA3 or more: 9.729, P < .0001). CONCLUSION: In EGFR mutation-positive pStage I LUAD, those without NIA, with higher pStage and lymphatic invasion were independent predictive factors for DFS, and pStage ≥ IA3 was an independent predictor of CNS recurrence.

DOI： 10.1016/j.cllc.2024.12.011

Prognostic impact of PD-L1 expression in surgically resected EGFR-mutant lung adenocarcinoma: A real-world database study in Japan (CReGYT-01 EGFR study). Reviewed International journal

Kotaro Nomura, Kazuki Takada, Fumihiko Kinoshita, Satoshi Muto, Taichi Matsubara, Yasunobu Kouki, Shinya Katsumata, Akira Hamada, Naoki Haratake, Kosuke Fujino, Mao Yoshikawa, Ken Suzawa, Kazuhiko Shien, Kenichi Suda, Shuta Ohara, Shota Fukuda, Hiroyuki Suzuki, Tatsuro Okamoto, Fumihiko Hirai, Keiju Aokage, Satoshi Shiono, Junichi Soh, Masahiro Tsuboi, Mototsugu Shimokawa, Yasuhisa Ohde

International journal of cancer 2024.11

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

The expression of programmed cell death-ligand 1 (PD-L1) and mutation in epidermal growth factor receptor (EGFR) are biomarkers used for perioperative treatment of lung adenocarcinoma. However, the clinical significance of PD-L1 expression in surgically resected EGFR-mutant lung adenocarcinoma remains unclear. We conducted a real-world database of patients with surgically resected lung adenocarcinoma from 2015 to 2018 was constructed across 21 centers in Japan. The association among PD-L1 expression, EGFR mutations, and prognosis was evaluated. Among 847 patients, PD-L1 expression was negative (tumor proportion score [TPS] < 1%) in 429 (51%), weakly positive (TPS = 1%-49%) in 275 (32%), and strongly positive (TPS ≥50%) in 143 (17%) patients. EGFR mutations were detected in 331 (39%) patients. PD-L1 expression was associated with poor recurrence-free survival (RFS) (p < .001) in both EGFR-mutant and wild-type patients. However, in EGFR-mutant patients, PD-L1 expression was not associated with overall survival (OS) (p = .506). Multivariable analysis confirmed an association between PD-L1 expression and RFS but not OS. Furthermore, in EGFR-mutant patients treated with EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment post-relapse, PD-L1 expression was not associated with overall response rate (p = .714), disease control rate (p = .554), or progression-free survival (p = .660). In conclusion, PD-L1 expression predicted poor RFS-independent EGFR status but did not show any association with OS in EGFR-mutant patients. The efficacy of post-relapse EGFR-TKI treatment was independent of PD-L1 expression. The significance of PD-L1 expression in perioperative EGFR-TKI therapy should be evaluated.

DOI： 10.1002/ijc.35270

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

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

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

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

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

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

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

Authorship：Corresponding author 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

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

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

Impact of central nervous system metastasis after complete resection of lung adenocarcinomas harboring common EGFR mutation - A real-world database study in Japan: The CReGYT-01 EGFR study. Reviewed International journal

Shinya Katsumata, Mototsugu Shimokawa, Akira Hamada, Naoki Haratake, Kotaro Nomura, Kosuke Fujino, Mao Yoshikawa, Ken Suzawa, Kazuhiko Shien, Kenichi Suda, Shuta Ohara, Shota Fukuda, Fumihiko Kinoshita, Kazuki Hayasaka, Hirotsugu Notsuda, Shinkichi Takamori, Satoshi Muto, Yusuke Takanashi, Kiyomichi Mizuno, Akikazu Kawase, Takamitsu Hayakawa, Keigo Sekihara, Michihito Toda, Somei Matsuo, Kyoshiro Takegahara, Masaki Hashimoto, Kenta Nakahashi, Makoto Endo, Hiroki Ozawa, Ryo Fujikawa, Yasuaki Tomioka, Kei Namba, Taichi Matsubara, Jun Suzuki, Hikaru Watanabe, Kazuki Takada, Hironobu Hoshino, Taisuke Kaiho, Takahide Toyoda, Yasunobu Kouki, Satoshi Shiono, Junichi Soh, Yasuhisa Ohde

European journal of cancer (Oxford, England : 1990) 201 113951 - 113951 2024.2

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

OBJECTIVES: To clarify the impact of central nervous system (CNS) metastasis on performance status (PS) at relapse, on subsequent treatment(s), and on survival of patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutation. METHODS: We conducted the multicenter real-world database study for patients with radical resections for lung adenocarcinomas between 2015 and 2018 at 21 centers in Japan. EGFR mutational status was examined at each center. RESULTS: Of 4181 patients enrolled, 1431 underwent complete anatomical resection for lung adenocarcinoma harboring common EGFR mutations. Three-hundred-and-twenty patients experienced disease relapse, and 78 (24%) had CNS metastasis. CNS metastasis was significantly more frequent in patients with conventional adjuvant chemotherapy than those without (30% vs. 20%, P = 0.036). Adjuvant chemotherapy did not significantly improve relapse-free survival at any pathological stage (adjusted hazard ratio for stage IA2-3, IB, and II-III was 1.363, 1.287, and 1.004, respectively). CNS metastasis did not affect PS at relapse. Subsequent treatment, mainly consisting of EGFR-tyrosine kinase inhibitors (TKIs), could be equally given in patients with or without CNS metastasis (96% vs. 94%). Overall survival after relapse was equivalent between patients with and without CNS metastasis. CONCLUSION: The efficacy of conventional adjuvant chemotherapy may be limited in patients with lung adenocarcinoma harboring EGFR mutations. CNS metastasis is likely to be found in practice before deterioration in PS, and may have little negative impact on compliance with subsequent EGFR-TKIs and survival after relapse. In this era of adjuvant TKI therapy, further prospective observational studies are desirable to elucidate the optimal management of CNS metastasis.

DOI： 10.1016/j.ejca.2024.113951

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

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

Authorship：Corresponding author 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

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

Authorship：Corresponding author 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

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

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

Ken Suzawa, Shinichi Toyooka

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

Authorship：Lead author 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

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

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

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

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

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

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

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

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

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

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

Authorship：Corresponding author 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. Reviewed 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

Clinical features of patients with second primary lung cancer following 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 2022.5

Authorship：Corresponding author 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

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

Authorship：Corresponding author 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

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

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

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

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

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

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

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

Protective effects of anti-HMGB1 monoclonal antibody on lung ischemia reperfusion injury in mice. Reviewed International journal

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

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

During ischemia reperfusion (IR) injury, high mobility group box 1 (HMGB1), a chromatin binding protein, is released from necrotic cells and triggers inflammatory responses. We assessed the therapeutic effect of a neutralizing anti-HMGB1 monoclonal antibody (mAb) on lung IR injury. A murine hilar clamp model of IR was used, where mice were divided into sham and IR groups with intravenous administration of anti-HMGB 1 mAb or control mAb. We analyzed the effect of anti-HMGB1 mAb against IR injury by assessing lung oxygenation, lung injury score, neutrophil infiltration, expression of proinflammatory cytokines and chemokines, levels of mitogen-activated protein kinase (MAPK) signaling, and measurement of apoptotic cells. Anti-HMGB1 mAb significantly decreased the plasma level of HMGB1 elevated by IR. The severity of IR injury represented by oxygenation capacity, lung injury score, and neutrophil infiltration was significantly improved by anti-HMGB1 mAb treatment. The expression of proinflammatory factors, including IL-1β, IL-6, IL-12, TNF-α, CXCL-1, and CXCL-2, and phosphorylation of p38 MAPK were both significantly reduced by anti-HMGB1 mAb treatment. Furthermore, anti-HMGB1 mAb treatment suppressed apoptosis, as determined through TUNEL assays. Overall, anti-HMGB1 mAb ameliorated lung IR injury by reducing inflammatory responses and apoptosis. Our findings indicate that anti-HMGB1 mAb has potential for use as a therapeutic to improve IR injury symptoms during lung transplantation.

DOI： 10.1016/j.bbrc.2021.08.015

Robot-assisted intrathoracic procedure for dumbbell tumour in the prone position. Reviewed International journal

Mikio Okazaki, Tomoyuki Takigawa, Ken Suzawa, Shinichi Toyooka

Interactive cardiovascular and thoracic surgery 33 ( 4 ) 643 - 645 2021.10

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

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

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

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

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

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

Prognostic Significance of Neutrophil-to-Lymphocyte Ratio in Locally Advanced Non-small-cell Lung Cancer Treated with Trimodality Therapy. Reviewed 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 2021.9

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

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

Robot-assisted thoracoscopic lobectomy for severe incomplete interlober fissure. Reviewed 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. Reviewed

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

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

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 2021.7

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

A Simple Prognostic Benefit Scoring System for Sarcoma Patients with Pulmonary Metastases: Sarcoma Lung Metastasis Score. Reviewed International journal

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 28 ( 7 ) 3884 - 3890 2021.7

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

BACKGROUND: Pulmonary metastasectomy could be considered one of the treatment options for disease control in sarcoma patients with pulmonary metastases; however, there is little consensus regarding the suitable criteria for predicting the likely outcomes in these patients. The aim of this study was to establish a prognostic benefit scoring system based on preoperatively examined prognostic factors for sarcoma patients with pulmonary metastases. METHODS: This was a single-center, retrospective cohort study conducted in a cohort of 135 sarcoma patients who underwent a first pulmonary metastasectomy at Okayama University Hospital between January 2006 and December 2015. Based on the results of a multivariable logistic regression analysis performed to determine the factors influencing 3-year mortality, a Sarcoma Lung Metastasis Score was created and its correlation with 3-year survival was analyzed. RESULTS: The results of the multivariate analysis revealed significant differences in the disease-free interval (< 2 years vs. ≥ 2 years; odds ratio (OR) 4.22, 95% confidence interval (CI) 1.67-10.70), maximum tumor diameter (≥ 15 mm vs. < 15 mm; OR 3.86, 95% CI 1.75-8.52), and number of pulmonary metastases (≥ 6 vs. < 6; OR 2.65, 95% CI 1.06-6.620). The Sarcoma Lung Metastasis Score, which was defined as the total score of these three factors, reliably predicted 3-year survival (score: 0, 89.5%; 1, 63.2%; 2, 39.0%; 3, 10.5%). CONCLUSIONS: Our newly proposed simple Sarcoma Lung Metastasis Score appears to be a useful prognostic predictor for sarcoma patients with pulmonary metastases, in that it could be helpful for the selection of appropriate treatments for these patients.

DOI： 10.1245/s10434-020-09272-1

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

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

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. Reviewed

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

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 51 ( 1 ) 127 - 135 2021.1

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

The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis. Reviewed 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

Effect of isoflavones on breast cancer cell development and their impact on breast cancer treatments. Reviewed 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

RET inhibition in novel patient-derived models of RET-fusion positive lung adenocarcinoma reveals a role for MYC upregulation. Reviewed International journal

Takuo Hayashi, Igor Odintsov, Roger S Smith, Kota Ishizawa, Allan J W Liu, Lukas Delasos, Christopher Kurzatkowski, Huichun Tai, Eric Gladstone, Morana Vojnic, Shinji Kohsaka, Ken Suzawa, Zebing Liu, Siddharth Kunte, Marissa S Mattar, Inna Khodos, Monika A Davare, Alexander Drilon, Emily Cheng, Elisa de Stanchina, Marc Ladanyi, Romel Somwar

Disease models & mechanisms 2020.12

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

Multi-kinase RET inhibitors, such as cabozantinib and RXDX-105, are active in lung cancer patients with RET fusions; however, the overall response rates to these two drugs are unsatisfactory compared to other targeted therapy paradigms. Moreover, these inhibitors may have different efficacies against RET rearrangements depending on the upstream fusion partner. A comprehensive preclinical analysis of the efficacy of RET inhibitors is lacking due to a paucity of disease models harboring RET rearrangements. Here we generated two new patient-derived xenograft (PDX) models, one new patient-derived cell line, one PDX-derived cell line, and several isogenic cell lines with RET fusions. Using these models, we re-examined the efficacy and mechanism of action of cabozantinib and found that this RET inhibitor was effective at blocking growth of cell lines, activating caspase 3/7 and inhibiting activation of ERK and AKT. Cabozantinib treatment of mice bearing RET-fusion-positive cell line xenografts and two PDXs significantly reduced tumor proliferation without adverse toxicity. Moreover, cabozantinib was effective at reducing growth of a lung cancer PDX that was not responsive to RXDX-105. Transcriptomic analysis of lung tumors and cell lines with RET alterations showed activation of a MYC signature and this was suppressed by treatment of cell lines with cabozantinib. MYC protein levels were rapidly depleted following cabozantinib treatment. Taken together, our results demonstrate that cabozantinib is an effective agent in preclinical models harboring RET rearrangements with three different 5' fusion partners (CCDC6, KIF5B and TRIM33). Notably, we identify MYC as a protein that is upregulated by RET expression and down-regulated by cabozantinib treatment, opening up potentially new therapeutic avenues for combinatorial targeting RET-fusion driven lung cancers. The novel RET fusion-dependent preclinical models described herein represent valuable tools for further refinement of current therapies and the evaluation of novel therapeutic strategies.

DOI： 10.1242/dmm.047779

Prognostic nutrition index affects the prognosis of patients undergoing trimodality therapy for locally advanced non-small cell lung cancer. Reviewed

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

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

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

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

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

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

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

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

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

Authorship：Corresponding author 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

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 50 ( 8 ) 863 - 871 2020.8

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

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

MAPK Pathway Alterations Correlate with Poor Survival and Drive Resistance to Therapy in Patients with Lung Cancers Driven by ROS1 Fusions. Reviewed 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

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

YES1 activation induces acquired resistance to neratinib in HER2-amplified breast and lung cancers. Reviewed International journal

Tatsuaki Takeda, Hiromasa Yamamoto, Ken Suzawa, Shuta Tomida, Shunsaku Miyauchi, Kota Araki, Kentaro Nakata, Akihiro Miura, Kei Namba, Kazuhiko Shien, Junichi Soh, Tadahiko Shien, Yoshihisa Kitamura, Toshiaki Sendo, Shinichi Toyooka

Cancer science 111 ( 3 ) 849 - 856 2020.3

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

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

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

Authorship：Lead author 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

Acquired BRAF Rearrangements Induce Secondary Resistance to EGFR therapy in EGFR-Mutated Lung Cancers. Reviewed International journal

Morana Vojnic, Daisuke Kubota, Christopher Kurzatkowski, Michael Offin, Ken Suzawa, Ryma Benayed, Adam J Schoenfeld, Andrew J Plodkowski, John T Poirier, Charles M Rudin, Mark G Kris, Neal X Rosen, Helena A Yu, Gregory J Riely, Maria E Arcila, Romel Somwar, Marc Ladanyi

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 14 ( 5 ) 802 - 815 2019.5

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

INTRODUCTION: Multiple genetic mechanisms have been identified in EGFR-mutant lung cancers as mediators of acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKIs), but many cases still lack a known mechanism. METHODS: To identify novel mechanisms of AR, we performed targeted large panel sequencing of samples from 374 consecutive patients with metastatic EGFR-mutant lung cancer, including 174 post-TKI samples, of which 38 also had a matched pre-TKI sample. Alterations hypothesized to confer AR were introduced into drug-sensitive EGFR-mutant lung cancer cell lines (H1975, HCC827, and PC9) by using clustered regularly interspaced short palindromic repeats/Cas9 genome editing. MSK-LX138cl, a cell line with EGFR exon 19 deletion (ex19del) and praja ring finger ubiquitin ligase 2 gene (PJA2)/BRAF fusion, was generated from an EGFR TKI-resistant patient sample. RESULTS: We identified four patients (2.3%) with a BRAF fusion (three with acylglycerol kinase gene (AGK)/BRAF and one with PJA2/BRAF) in samples obtained at AR to EGFR TKI therapy (two posterlotinib samples and two posterlotinib and postosimertinib samples). Pre-TKI samples were available for two of four patients and both were negative for BRAF fusion. Induction of AGK/BRAF fusion in H1975 (L858R + T790M), PC9 (ex19del) and HCC827 (ex19del) cells increased phosphorylation of BRAF, MEK1/2, ERK1/2, and signal transducer and activator of transcription 3 and conferred resistance to growth inhibition by osimertinib. MEK inhibition with trametinib synergized with osimertinib to block growth. Alternately, a pan-RAF inhibitor as a single agent blocked growth of all cell lines with mutant EGFR and BRAF fusion. CONCLUSION: BRAF fusion is a mechanism of AR to EGFR TKI therapy in approximately 2% of patients. Combined inhibition of EGFR and MEK (with osimertinib and trametinib) or BRAF (with a pan-RAF inhibitor) are potential therapeutic strategies that should be explored.

DOI： 10.1016/j.jtho.2018.12.038

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

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

Activation of KRAS Mediates Resistance to Targeted Therapy in MET Exon 14-mutant Non-small Cell Lung Cancer. Reviewed International journal

Ken Suzawa, Michael Offin, Daniel Lu, Christopher Kurzatkowski, Morana Vojnic, Roger S Smith, Joshua K Sabari, Huichun Tai, Marissa Mattar, Inna Khodos, Elisa de Stanchina, Charles M Rudin, Mark G Kris, Maria E Arcila, William W Lockwood, Alexander Drilon, Marc Ladanyi, Romel Somwar

Clinical cancer research : an official journal of the American Association for Cancer Research 25 ( 4 ) 1248 - 1260 2019.2

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

PURPOSE: MET exon 14 splice site alterations that cause exon skipping at the mRNA level (METex14) are actionable oncogenic drivers amenable to therapy with MET tyrosine kinase inhibitors (TKI); however, secondary resistance eventually arises in most cases while other tumors display primary resistance. Beyond relatively uncommon on-target MET kinase domain mutations, mechanisms underlying primary and acquired resistance remain unclear. EXPERIMENTAL DESIGN: We examined clinical and genomic data from 113 patients with lung cancer with METex14. MET TKI resistance due to KRAS mutation was functionally evaluated using in vivo and in vitro models. RESULTS: Five of 113 patients (4.4%) with METex14 had concurrent KRAS G12 mutations, a rate of KRAS cooccurrence significantly higher than in other major driver-defined lung cancer subsets. In one patient, the KRAS mutation was acquired post-crizotinib, while the remaining 4 METex14 patients harbored the KRAS mutation prior to MET TKI therapy. Gene set enrichment analysis of transcriptomic data from lung cancers with METex14 revealed preferential activation of the KRAS pathway. Moreover, expression of oncogenic KRAS enhanced MET expression. Using isogenic and patient-derived models, we show that KRAS mutation results in constitutive activation of RAS/ERK signaling and resistance to MET inhibition. Dual inhibition of MET or EGFR/ERBB2 and MEK reduced growth of cell line and xenograft models. CONCLUSIONS: KRAS mutation is a recurrent mechanism of primary and secondary resistance to MET TKIs in METex14 lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK may represent a potential therapeutic approach in this molecular cohort.

DOI： 10.1158/1078-0432.CCR-18-1640

Acquired MET Exon 14 Alteration Drives Secondary Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in EGFR-Mutated Lung Cancer. Reviewed International journal

Ken Suzawa, Michael Offin, Adam J Schoenfeld, Andrew J Plodkowski, Igor Odintsov, Daniel Lu, William W Lockwood, Maria E Arcila, Charles M Rudin, Alexander Drilon, Helena A Yu, Gregory J Riely, Romel Somwar, Marc Ladanyi

JCO precision oncology 3 2019

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

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

Concurrent Alterations in EGFR-Mutant Lung Cancers Associated with Resistance to EGFR Kinase Inhibitors and Characterization of MTOR as a Mediator of Resistance. Reviewed International journal

Helena A Yu, Ken Suzawa, Emmet Jordan, Ahmet Zehir, Ai Ni, Ryan Kim, Mark G Kris, Matthew D Hellmann, Bob T Li, Romel Somwar, David B Solit, Michael F Berger, Maria Arcila, Gregory J Riely, Marc Ladanyi

Clinical cancer research : an official journal of the American Association for Cancer Research 24 ( 13 ) 3108 - 3118 2018.7

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Purpose: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR-mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR-mutant lung cancer. Clinical data were collected and correlated with somatic mutation data. Erlotinib resistance due to acquired MTOR mutation was functionally evaluated by in vivo and in vitro studies.Results: In 200 EGFR-mutant pretreatment samples, the most frequent concurrent alterations were mutations in TP53, PIK3CA, CTNNB1, and RB1 and focal amplifications in EGFR, TTF1, MDM2, CDK4, and FOXA1 Shorter time to progression on EGFR TKI was associated with amplification of ERBB2 (HR = 2.4, P = 0.015) or MET (HR = 3.7, P = 0.019), or mutation in TP53 (HR = 1.7, P = 0.006). In the 136 posttreatment samples, we identified known mechanisms of acquired resistance: EGFR T790M (51%), MET (7%), and ERBB2 amplifications (5%). In the 38 paired samples, novel acquired alterations representing putative resistance mechanisms included BRAF fusion, FGFR3 fusion, YES1 amplification, KEAP1 loss, and an MTOR E2419K mutation. Functional studies confirmed the contribution of the latter to reduced sensitivity to EGFR TKI in vitro and in vivoConclusions:EGFR-mutant lung cancers harbor a spectrum of concurrent alterations that have prognostic and predictive significance. By utilizing paired samples, we identified several novel acquired alterations that may be relevant in mediating resistance, including an activating mutation in MTOR further validated functionally. Clin Cancer Res; 24(13); 3108-18. ©2018 AACR.

DOI： 10.1158/1078-0432.CCR-17-2961

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

Therapeutic strategies for afatinib-resistant lung cancer harboring HER2 alterations. Reviewed International journal

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)

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

Therapeutic Potential of Afatinib for Cancers with ERBB2 (HER2) Transmembrane Domain Mutations G660D and V659E. Reviewed International journal

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

The oncologist 23 ( 2 ) 150 - 154 2018.2

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

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

Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer. Reviewed International journal

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)

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 docetaxel-resistant 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

Estimation of age-related DNA degradation from formalin-fixed and paraffin-embedded tissue according to the extraction methods. Reviewed International journal

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)

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

Optimal method for quantitative detection of plasma EGFR T790M mutation using droplet digital PCR system. Reviewed International journal

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

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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

Targeting the miR-200c/LIN28B axis in acquired EGFR-TKI resistance non-small cell lung cancer cells harboring EMT features. Reviewed International journal

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 - 40847 2017.1

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

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

Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies. Reviewed International journal

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

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer. Reviewed International journal

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 ) e0171356 2017

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

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 trastuzumab-resistant 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

Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway. Reviewed International journal

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 - 39557 2016.12

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

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

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

Yesl is the key molecule for the resistance to trastuzumab in breast cancer, and dasatinib overcomes the resistance Reviewed

Hiromasa Yamamoto, Tatsuaki Takeda, Hirotaka Kanzaki, Ken Suzawa, Kei Namba, Hiroki Sato, Hidejiro Torigoe, Mototsugu Watanabe, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Yoshihisa Kitamura, Toshiaki Sendo, Shinichi Toyooka

CANCER RESEARCH 76 2016.7

Establishment and molecular characterization of cell lines from Japanese patients with malignant pleural mesothelioma. Reviewed International journal

Ken Suzawa, Hiromasa Yamamoto, Tomoyuki Murakami, Hideki Katayama, Masashi Furukawa, Kazuhiko Shien, Shinsuke Hashida, Kazunori Okabe, Keisuke Aoe, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Yusuke Mimura, Shinichi Toyooka, Shinichiro Miyoshi

Oncology letters 11 ( 1 ) 705 - 712 2016.1

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations. Reviewed International journal

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

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1111/cas.12845

Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib. Reviewed International journal

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 - 84 2015.10

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

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

Distant Bystander Effect of REIC/Dkk-3 Gene Therapy through Immune System Stimulation in a Murine Model of Thoracic Malignancies Reviewed

Ken Suzawa, Kazuhiko Shien, Peng Huang, Masakiyo Sakaguchi, Masami Watanabe, Shinsuke Hashida, Junichi Soh, Hiromasa Yamamoto, Yuho Maki, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Hiromi Kumon, Shinichiro Miyoshi, Shinichi Toyooka

JOURNAL OF THORACIC ONCOLOGY 10 ( 9 ) S599 - S599 2015.9

Anti-tumor effect of Dasatinib in HER2 positive breast cancer with Trastuzumab resistance Reviewed

Tatsuaki Takeda, Hirotaka Kanzaki, Shinichi Toyooka, Mototsugu Watanabe, Tomoaki Ohtsuka, Ken Suzawa, Shinsuke Hashida, Yuho Maki, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Yoshihisa Kitamura, Toshiaki Sendo

CANCER RESEARCH 75 2015.8

Anti-tumor effect of afatinib, an irreversible EGFR/HER2 dual inhibitor, in lung cancers harboring HER2 oncogene Reviewed

Ken Suzawa, Shinichi Toyooka, Masakiyo Sakaguchi, Tomoaki Ohtsuka, Mototsugu Watanabe, Shinsuke Hashida, Yuho Maki, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

CANCER RESEARCH 75 2015.8

Identification of a novel binding protein playing a critical role in HER2 activation in lung cancer cells Reviewed

Tomoaki Ohtsuka, Masakiyo Sakaguchi, Katsuyoshi Takata, Shinsuke Hashida, Mototsugu Watanabe, Ken Suzawa, Yuho Maki, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

CANCER RESEARCH 75 2015.8

Pneumocephalus and chylothorax complicating vertebrectomy for lung cancer. Reviewed International journal

Seiichiro Sugimoto, Masato Tanaka, Ken Suzawa, Hitoshi Nishikawa, Shinichi Toyooka, Takahiro Oto, Toshifumi Ozaki, Shinichiro Miyoshi

The Annals of thoracic surgery 99 ( 4 ) 1425 - 8 2015.4

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

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.

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 International journal

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 - 504 2015.3

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

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 G2/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 G2/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

Asymptomatic but functional paraganglioma of the posterior mediastinum. Reviewed International journal

Ken Suzawa, Hiromasa Yamamoto, Koichi Ichimura, Shinichi Toyooka, Shinichiro Miyoshi

The Annals of thoracic surgery 97 ( 3 ) 1077 - 80 2014.3

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

A 72-year-old woman was referred to our hospital because of a posterior mediastinal tumor. On the basis of detailed imaging tests, including (123)I-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.

DOI： 10.1016/j.athoracsur.2013.06.100

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 : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia 20 Suppl 501 - 4 2014

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

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

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