千葉 眞人; 宗 淳一; 老木 華; 深見 朋; 福田 祥; 小原 秀太; 濱田 顕; 下治 正樹; 武本 智樹; 須田 健一; 光冨 徹哉; 津谷 康大
気管支学462132 - 132(一社)日本呼吸器内視鏡学会2024年03月
Shinya Katsumata; Mototsugu Shimokawa; Akira Hamada; Naoki Haratake; Kotaro Nomura; Kosuke Fujino; Mao Yoshikawa; Ken Suzawa; Kazuhiko Shien; Kenichi Suda; Shuta Ohara; Shota f*ckuda; Fumihiko Kinosh*ta; 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)201113951 - 1139512024年02月
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.
宗 淳一; 下治 正樹; 武本 智樹; 深見 朋世; 老木 華; 福田 祥大; 小原 秀太; 濱田 顕; 千葉 眞人; 伊藤 正興; 須田 健一; 光冨 徹哉; 津谷 康大
肺癌635407 - 407(NPO)日本肺癌学会2023年10月
須田 健一; 老木 華; 福田 祥大; 深見 朋世; 小原 秀太; 濱田 顕; 伊藤 正興; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉; 津谷 康大
肺癌635412 - 412(NPO)日本肺癌学会2023年10月
老木 華; 千葉 眞人; 宗 淳一; 深見 朋世; 福田 祥大; 小原 秀太; 濱田 顕; 伊藤 正興; 下治 正樹; 武本 智樹; 須田 健一; 光冨 徹哉; 津谷 康大
肺癌635530 - 530(NPO)日本肺癌学会2023年10月
宗 淳一; 下治 正樹; 武本 智樹; 深見 朋世; 老木 華; 福田 祥大; 小原 秀太; 濱田 顕; 千葉 眞人; 伊藤 正興; 須田 健一; 光冨 徹哉; 津谷 康大
肺癌635407 - 407(NPO)日本肺癌学会2023年10月
須田 健一; 老木 華; 福田 祥大; 深見 朋世; 小原 秀太; 濱田 顕; 伊藤 正興; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉; 津谷 康大
肺癌635412 - 412(NPO)日本肺癌学会2023年10月
老木 華; 千葉 眞人; 宗 淳一; 深見 朋世; 福田 祥大; 小原 秀太; 濱田 顕; 伊藤 正興; 下治 正樹; 武本 智樹; 須田 健一; 光冨 徹哉; 津谷 康大
肺癌635530 - 530(NPO)日本肺癌学会2023年10月
正確かつ迅速な肺癌診断への挑戦!(Minimal Residul Disease)
須田 健一; 小原 秀太; 宗 淳一; 津谷 康大; 光冨 徹哉
日本癌治療学会学術集会抄録集61回OWS14 - 62023年10月
Akira Hamada; Kenichi Suda; Masaya Nishino; Keiko Obata; Hana Oiki; Tomoyo f*ckami; Shota f*ckuda; Toshio Fujino; Shuta Ohara; Takamasa Koga; Masato Chiba; Masaki Shimoji; Masaoki Ito; Toshiki Takemoto; Junichi Soh; Yasuhiro Tsutani; Tetsuya Mitsudomi
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer2023年09月
INTRODUCTION: Approximately 10% of mutations in the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) are in-frame insertions in exon 20 (X20ins). These tumors usually do not respond to conventional EGFR-tyrosine kinase inhibitors (TKIs). Several novel EGFR-TKIs active for X20ins are in clinical development, including mobocertinib, which was recently approved by the US FDA. However, acquired resistance during treatment with these TKIs still occurs as in the case of EGFR-TKIs of earlier generations. METHODS: We chronically exposed Ba/F3 cells transduced with five most common X20ins (A763_Y764insFQEA, V769_D770insASV, D770_N771insSVD, H773_V774insNPH and H773_V774insH) to mobocertinib in the presence of N-ethyl-N-nitrosourea and searched for secondary EGFR mutations. We evaluated the efficacies of several EGFR X20ins inhibitors, including zipalertinib and sunvozertinib, against cells with acquired resistant mutations. RESULTS: All secondary mutations resulting in acquired resistance to mobocertinib were exclusively C797S in insFQEA and insSVD. However, in the case of other X20ins (insASV, insNPH and insH), T790M or C797S secondary mutations contributed to acquired resistance to mobocertinib. The emergence of T790M was more frequent in cells treated with lower drug concentrations. Sunvozertinib showed good activity against resistant cells with T790M. Cells with C797S were refractory to all EGFR-TKIs, except for erlotinib, which was active for insFQEA with C797S. CONCLUSIONS: T790M or C797S, depending on the original X20ins mutations, conferred acquired resistance to mobocertinib. Sunvozertinib may be the treatment of choice for patients with tumors resistant to mobocertinib because of T790M.
画像上cN3が疑われるも病理学的にcN0であった非小細胞肺がんの2症例
岡本 鴻児; 須田 健一; 小原 秀太; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 津谷 康大
肺癌633255 - 255(NPO)日本肺癌学会2023年06月
ロボット支援下手術に特有に起きる合併症とその対策 ロボット支援下解剖学的肺切除術時の気管支損傷を考察する
宗 淳一; 武本 智樹; 福田 祥大; 小原 秀太; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 津谷 康大
日本呼吸器外科学会雑誌373WS2 - 6(一社)日本呼吸器外科学会2023年06月
原発性肺癌切除例における人工知能解析プログラムを用いた腫瘍体積増大速度の臨床的意義
福田 祥大; 宗 淳一; 小原 秀太; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 津谷 康大
日本呼吸器外科学会雑誌373O51 - 4(一社)日本呼吸器外科学会2023年06月
Uniportal VATS区域切除の実際 難点と克服法を動画から
千葉 眞人; 福田 祥大; 小原 秀太; 濱田 顕; 下治 正樹; 武本 智樹; 須田 健一; 宗 淳一; 光冨 徹哉; 津谷 康大
日本呼吸器外科学会雑誌373O60 - 1(一社)日本呼吸器外科学会2023年06月
多発肺転移をきたした子宮筋腫の2症例
永山 孝郁; 須田 健一; 小原 秀太; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 津谷 康大
日本呼吸器外科学会雑誌373P11 - 6(一社)日本呼吸器外科学会2023年06月
癌免疫療法時代における外科医の役割 肺がん外科領域におけるがん免疫療法の進歩と呼吸器外科医の役割
須田 健一; 濱田 顕; 宗 淳一; 小原 秀太; 千葉 眞人; 武本 智樹; 光冨 徹哉; 津谷 康大
日本外科学会定期学術集会抄録集123回SY - 4(一社)日本外科学会2023年04月
呼吸器外科領域でのロボット支援下手術の克服すべき課題と手技の工夫 局所進行肺癌に対する術前化学放射線療法後ロボット支援下胸腔鏡手術の可能性
宗 淳一; 下治 正樹; 武本 智樹; 福田 祥大; 小原 秀太; 濱田 顕; 千葉 眞人; 須田 健一; 津谷 康大
日本外科学会定期学術集会抄録集123回WS - 6(一社)日本外科学会2023年04月
PD-L1高発現非小細胞肺癌における術前血清フィブリノゲン値の臨床的意義
小原 秀太; 須田 健一; 福田 祥大; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉; 津谷 康大
日本外科学会定期学術集会抄録集123回SF - 3(一社)日本外科学会2023年04月
低侵襲胸腔鏡手術が肺癌治療にもたらしたもの Uniportal VATSの発展と適応拡大
千葉 眞人; 宗 淳一; 福田 祥大; 小原 秀太; 濱田 顕; 下治 正樹; 武本 智樹; 須田 健一; 光冨 徹哉; 津谷 康大
肺癌626540 - 540(NPO)日本肺癌学会2022年11月
Toshio Fujino; Kenichi Suda; Takamasa Koga; Akira Hamada; Shuta Ohara; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Junichi Soh; Tetsuya Mitsudomi
Journal of hematology & oncology15179 - 792022年06月
BACKGROUND: Capmatinib and tepotinib are guideline-recommended front-line treatments for non-small-cell lung cancer (NSCLC) patients with MET exon 14 skipping mutations (METex14). However, the emergence of acquired resistance to capmatinib/tepotinib is almost inevitable partially due to D1228X or Y1230X secondary mutations of the MET. In this study, we explored agents that are active against both D1228X and Y1230X MET to propose an ideal sequential treatment after capmatinib/tepotinib treatment failure in NSCLC patients with METex14. METHODS: The inhibitory effects of 300 drugs, including 33 MET-TKIs, were screened in Ba/F3 cells carrying METex14 plus MET D1228A/Y secondary mutations. The screen revealed four-candidate type II MET-TKIs (altiratinib, CEP-40783, foretinib and sitravatinib). Therefore, we performed further growth inhibitory assays using these four MET-TKIs plus cabozantinib and merestinib in Ba/F3 cells carrying MET D1228A/E/G/H/N/V/Y or Y1230C/D/H/N/S secondary mutations. We also performed analyses using Hs746t cell models carrying METex14 (with mutant allele amplification) with/without D1228X or Y1230X in vitro and in vivo to confirm the findings. Furthermore, molecular dynamics (MD) simulations were carried out to examine differences in binding between type II MET-TKIs. RESULTS: All 6 type II MET-TKIs were active against Y1230X secondary mutations. However, among these 6 agents, only foretinib showed potent activity against D1228X secondary mutations of the MET in the Ba/F3 cell and Hs746t in vitro model and Hs746t in vivo model, and CEP-40783 and altiratinib demonstrated some activity. MD analysis suggested that the long tail of foretinib plays an important role in binding D1228X MET through interaction with a residue at the solvent front (G1163). Tertiary G1163X mutations, together with L1195F/I and F1200I/L, occurred as acquired resistance mechanisms to the second-line treatment foretinib in Ba/F3 cell models. CONCLUSIONS: The type II MET-TKI foretinib may be an appropriate second-line treatment for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at residue D1228 or Y1230.
肺癌周術期治療:最新の話題と今後の展開 肺癌術後におけるcirculating tumor DNA検出の意義
小原 秀太; 須田 健一; 藤野 智大; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉
日本呼吸器外科学会雑誌36Suppl.WS2 - 6(一社)日本呼吸器外科学会2022年05月
COVID-19 pandemicが外科切除の対象となる肺がん患者に与えた影響
須田 健一; 小原 秀太; 藤野 智大; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉
日本呼吸器外科学会雑誌36Suppl.O66 - 2(一社)日本呼吸器外科学会2022年05月
Uniportal VATS気管支形成術の経験と導入における工夫
千葉 眞人; 宗 淳一; 小原 秀太; 藤野 智大; 濱田 顕; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉
日本呼吸器外科学会雑誌36Suppl.O87 - 6(一社)日本呼吸器外科学会2022年05月
縦隔リンパ節郭清を伴う肺葉切除におけるロボット支援手術の特徴と可能性 ハイブリッド・単孔式と比較して
宗 淳一; 小原 秀太; 藤野 智大; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉
日本呼吸器外科学会雑誌36Suppl.O94 - 3(一社)日本呼吸器外科学会2022年05月
当院における肺癌根治切除後の乳び胸合併症例の検討
武本 智樹; 小原 秀太; 藤野 智大; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 宗 淳一; 光冨 徹哉
日本呼吸器外科学会雑誌36Suppl.O101 - 1(一社)日本呼吸器外科学会2022年05月
肺癌周術期合併症と糖尿病との関連
下治 正樹; 須田 健一; 小原 秀太; 藤野 智大; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉
日本呼吸器外科学会雑誌36Suppl.O106 - 6(一社)日本呼吸器外科学会2022年05月
Akira Hamada; Kenichi Suda; Toshio Fujino; Masaya Nishino; Shuta Ohara; Takamasa Koga; Takanobu Kabasawa; Masato Chiba; Masaki Shimoji; Makoto Endoh; Toshiki Takemoto; Junichi Soh; Naoki Yanagawa; Satoshi Shiono; Tetsuya Mitsudomi
JTO clinical and research reports35100321 - 1003212022年05月
Introduction: Recent studies have suggested that including presence or absence of ground-glass opacity (GGO) may improve the tumor descriptor (T descriptor) classification in clinical stage I NSCLC. In this study, we analyzed prognostic implications of presence or absence of GGO, size of the solid component, and predominant histology to identify the true prognostic determinant for early-stage NSCLC. Methods: We retrospectively examined 384 patients with clinical stage I NSCLC (solid: 242, part solid: 142) who underwent complete resection between 2009 and2013. Results: Survival curves of the whole cohort revealed good separation using the current TNM classification. Nevertheless, the part-solid group had a favorable prognosis irrespective of solid component size. Conversely, patients in the solid tumor group with tumors between 3 and 4 cm had a worse prognosis than patients whose tumors were less than or equal to 3 cm. Thus, we propose the following novel T descriptor classification: IA, part-solid tumors; IB, solid tumors less than or equal to 3 cm; and IC, solid tumors between 3 and 4 cm. This novel classification system stratified patient prognosis better than the current classification. On pathologic evaluation, the part-solid group always had better prognoses than the solid group in each subgroup divided by pathologic grade. Conclusions: These results suggest that presence of GGO is the true prognostic determinant of stage I NSCLC, irrespective of the size of the solid component. Our novel T descriptor classification system could more accurately predict prognoses of clinical stage I NSCLC cases.
Uniportal VATSの習得と発展を目指した手術教育プログラム 動物心肺ハイブリッドモデル・VR・オンラインカンファレンスの活用
千葉 眞人; 小原 秀太; 藤野 智大; 濱田 顕; 下治 正樹; 須田 健一; 武本 智樹; 宗 淳一; 光冨 徹哉
日本外科学会定期学術集会抄録集122回SP - 3(一社)日本外科学会2022年04月
同一期間に実施した肺がんハイブリッド手術・単孔式手術・ロボット支援下手術の比較検討
宗 淳一; 小原 秀太; 藤野 智大; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉
日本外科学会定期学術集会抄録集122回SF - 1(一社)日本外科学会2022年04月
インシデント・アクシデント報告から考える手術室におけるノンテクニカルスキルの重要性
武本 智樹; 辰巳 陽一; 小原 秀太; 藤野 智大; 濱田 顕; Chiba Masato; 下治 正樹; 須田 健一; 宗 淳一; 光冨 徹哉
日本外科学会定期学術集会抄録集122回SF - 4(一社)日本外科学会2022年04月
小原 秀太; 須田 健一; 藤野 智大; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉
日本気管食道科学会会報732168 - 168(NPO)日本気管食道科学会2022年04月
小原 秀太; 須田 健一; 光冨 徹哉
近畿大学医学雑誌463-473 - 78近畿大学医学会2021年12月[招待有り]
近年、liquid biopsyのひとつである腫瘍由来血漿中可溶性DNA(circulating tumor DNA:ctDNA)の検出が、進行期肺癌の実臨床でも用いられるようになった。具体的には、EGFR変異検査に用いられるCobas EGFR変異検出キットやMET exon14 skipping変異の検出に用いられるArcher METによる血漿検体の遺伝子解析結果をもってそれぞれの治療薬の投与が可能となっている。さらに本年3月には、包括的ゲノムプロファイリングであるFoundation One Liquidがんゲノムプロファイルも製造販売承認された。しかし、腫瘍量が比較的少ない外科切除を受ける肺がん患者において、ctDNAを含むliquid biopsyが有用であるかについては十分明らかではない。われわれは最近、臨床病期II-IIIA期の肺がん外科切除例を対象に、術前と術後にctDNAを測定するパイロットスタディを実施した。その結果、術前のctDNA陽性は腫瘍径と関連すること、術後のctDNA陽性は分化度と関連すること、再発予測のバイオマーカーとしては、術前のctDNAよりも術後のctDNAのほうが優れていることが示された。本総説ではこのパイロットスタディの結果を紹介すると共に、本領域における現時点でのエビデンスと今後の展望について総括する。(著者抄録)
Akira Hamada; Kenichi Suda; Takamasa Koga; Toshio Fujino; Masaya Nishino; Shuta Ohara; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Junichi Soh; Tetsuro Uchida; Tetsuya Mitsudomi
Lung cancer (Amsterdam, Netherlands)16279 - 852021年11月[査読有り]
OBJECTIVES: The LUX-Lung 8 randomized trial (LL8) demonstrated a prolonged progression-free survival (PFS) in patients with metastatic squamous cell carcinoma (SCC) of the lung after treatment with afatinib compared with erlotinib. A secondary analysis of the LL8 reported that the presence of rare HER2/HER4 mutations may be partly responsible for this result. Patients with HER2 (hazard ratio [HR] 0.06/p-value 0.02) or HER4 (HR 0.21/p-value unreported) mutations had longer PFS after treatment with afatinib. However, the biological function of these mutations is unclear. MATERIALS AND METHODS: Ten HER2 and 13 HER4 point mutations that were detected in the secondary analysis were transduced into the mouse pro-B cell line (Ba/F3) to determine changes in interleukin-3 (IL-3) dependence and sensitivity to six EGFR or pan-HER tyrosine kinase inhibitors (TKIs), including afatinib and erlotinib. The efficacy of the six TKIs was compared using a sensitivity index, defined as the 50% inhibitory concentration divided by trough concentration of each drug at clinically recommended doses. RESULTS: Seven out of 10 Ba/F3 clones expressing HER2 mutations and all 13 Ba/F3 clones expressing HER4 mutations did not grow in the absence of IL-3, indicating these mutations were non-oncogenic. Three Ba/F3 clones expressing the HER2 mutations E395K, G815R, or R929W acquired IL-3-independent growth. The sensitivity indices for afatinib were≤one-fifth of those for erlotinib in all three lines. Other second/third-generation (2G/3G) TKIs showed high efficacy against clones expressing these HER2 mutations. CONCLUSIONS: The majority of HER2/4 mutations detected in lung SCC from LL8 were not oncogenic in the Ba/F3 models, suggesting that the presence of HER2/4 mutations were not responsible for the superior outcomes of afatinib in the LL8 study. However, SCC of the lung in some patients may be driven by rare HER2 mutations, and these patients may benefit from 2G/3G pan-HER-TKI treatment.
Kenichi Suda; Shuta Ohara; Toshio Fujino; Akira Hamada; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Junichi Soh; Tetsuya Mitsudomi
Clinical lung cancer231e60-e68 2021年10月[査読有り]
BACKGROUND: The differential diagnosis of a solitary solid-type lung nodule is diverse. 18F-fluorodeoxyglucose positron emission tomography (PET) has a high sensitivity in the diagnosis of solid-type lung cancers; however, PET-negative, solid-type lung cancers are rarely observed. In this study, we analyzed the clinical/genetic features and prognosis of PET-negative, solid-type lung cancers. PATIENTS AND METHODS: Between January 2007 and February 2020, 709 patients with solid-type lung cancers (tumor size ≥2.0 cm) underwent pulmonary resection. Clinical, genetic, and prognostic features were evaluated in 27 patients (3.8%) with tumors showing negative PET results defined as SUVmax <2.0. RESULTS: All 27 patients had lung adenocarcinoma; 23 had invasive adenocarcinomas and 4 had invasive mucinous adenocarcinomas. The PET-negative group showed high frequencies of females and never-smokers. Recurrence-free survival was significantly better in the PET-negative group compared with PET-positive counterparts extracted using propensity score matching from patients who underwent pulmonary resection during the same period (P=.0052). Furthermore, 83% of PET-negative, solid-type invasive lung adenocarcinoma patients harbored EGFR mutation, which was significantly higher than that of PET-positive, solid-type invasive lung adenocarcinoma patients (38%, n=225) who received EGFR mutation testing in our cohort (P < .0001). PET-negative, solid-type lung adenocarcinoma patients with EGFR mutations had significantly better recurrence-free survival compared with PET-positive, solid-type lung adenocarcinoma patients with EGFR mutations extracted using propensity score matching (P=.0030). CONCLUSION: PET-negative, solid-type lung cancers are characterized with a high incidence of EGFR mutation and a better prognosis compared with PET-positive, solid-type lung cancer.
宗 淳一; 武本 智樹; 小原 秀太; 藤野 智大; 古賀 教将; 濱田 顕; 千葉 眞人; 須田 健一; 光冨 徹哉
日本胸部外科学会定期学術集会74回LOD21 - 4(一社)日本胸部外科学会2021年10月
須田 健一; 濱田 顕; 小原 秀太; 藤野 智大; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉
肺癌616594 - 594(NPO)日本肺癌学会2021年10月
小原 秀太; 宗 淳一; 須田 健一; 藤野 智大; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 光冨 徹哉
肺癌616633 - 633(NPO)日本肺癌学会2021年10月
藤野 智大; 須田 健一; 小原 秀太; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉
肺癌616645 - 645(NPO)日本肺癌学会2021年10月
Toshio Fujino; Kenichi Suda; Kazuko Sakai; Isao Murakami; Shigeki Shimizu; Shuta Ohara; Takamasa Koga; Akira Hamada; Junichi Soh; Kazuto Nishio; Tetsuya Mitsudomi
Clinical Lung Cancer2021年09月[査読有り]
Takamasa Koga; Kenichi Suda; Masaya Nishino; Toshio Fujino; Shuta Ohara; Akira Hamada; Junichi Soh; Vijaya Tirunagaru; Avanish Vellanki; Robert C Doebele; Tetsuya Mitsudomi
Translational lung cancer research1083659 - 36702021年08月[査読有り]
Background: HER2 (ERBB2) activating mutations are present in 2-3% of lung adenocarcinomas; however, no targeted therapy is approved for HER2-altered lung cancers. A novel pan-HER inhibitor, tarloxotinib, is designed to release the active form (tarloxotinib-E) under hypoxic conditions in tumor tissues after being administered as a prodrug. Following the evaluation of the in vitro activity of tarloxotinib-E in HER2-mutant cells, we explored the mechanisms of resistance to tarloxotinib-E in these cells. Methods: Growth inhibitory assays were performed with tarloxotinib-E and its prodrug using Ba/F3 cells expressing one of six HER2 mutations or wild-type (WT) HER2, in addition to H1781 cells with HER2 exon 20 insertions. Resistant clones were established from N-ethyl-N-nitrosourea (ENU)-treated HER2-mutant Ba/F3 cells and H1781 cells by chronic exposure to tarloxotinib-E. Results: Tarloxotinib-E showed potent activity against HER2-mutant Ba/F3 cells and H1781 cells. Furthermore, the half maximal inhibitory concentration (IC50) of tarloxotinib (inactive form) for WT HER2 was 180 times higher than that of tarloxotinib-E, indicating a wide therapeutic window of tarloxotinib. We established 30 resistant clones with secondary mutations of HER2 by ENU mutagenesis, all of which harbored C805S in exon 20. In the analysis of H1781 cells that acquired resistance to tarloxotinib-E, we found that increased HER3 expression was the molecular mechanism of tarloxotinib-E resistance. Conclusions: Tarloxotinib-E exhibited potent activity against cell line models with HER2 mutations. We identified a secondary C805S HER2 mutation and HER3 overexpression as the mechanisms of acquired resistance to tarloxotinib-E.
Takamasa Koga; Kenichi Suda; Toshio Fujino; Shuta Ohara; Akira Hamada; Masaya Nishino; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Takeo Arita; Michael Gmachl; Marco H Hofmann; Junichi Soh; Tetsuya Mitsudomi
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer1681321 - 13322021年05月[査読有り]
INTRODUCTION: KRAS mutations have been recognized as undruggable for many years. Recently, novel KRAS G12C inhibitors, such as sotorasib and adagrasib, are being developed in clinical trials and have revealed promising results in metastatic NSCLC. Nevertheless, it is strongly anticipated that acquired resistance will limit their clinical use. In this study, we developed invitro models of the KRAS G12C cancer, derived from resistant clones against sotorasib and adagrasib, and searched for secondary KRAS mutations as on-target resistance mechanisms to develop possible strategies to overcome such resistance. METHODS: We chronically exposed Ba/F3 cells transduced with KRASG12C to sotorasib or adagrasib in the presence of N-ethyl-N-nitrosourea and searched for secondary KRAS mutations. Strategies to overcome resistance were also investigated. RESULTS: We generated 142 Ba/F3 clones resistant to either sotorasib or adagrasib, of which 124 (87%) harbored secondary KRAS mutations. There were 12 different secondary KRAS mutations. Y96D and Y96S were resistant to both inhibitors. A combination of novel SOS1 inhibitor, BI-3406, and trametinib had potent activity against this resistance. Although G13D, R68M, A59S and A59T, which were highly resistant to sotorasib, remained sensitive to adagrasib, Q99L was resistant to adagrasib but sensitive to sotorasib. CONCLUSIONS: We identified many secondary KRAS mutations causing resistance to sotorasib, adagrasib, or both, invitro. The differential activities of these two inhibitors depending on the secondary mutations suggest sequential use in some cases. In addition, switching to BI-3406 plus trametinib might be a useful strategy to overcome acquired resistance owing to the secondary Y96D and Y96S mutations.
Uniportal VATSにおけるエンブロックな縦隔リンパ節郭清
千葉 眞人; 宗 淳一; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 濱田 顕; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉
日本呼吸器外科学会雑誌353RV9 - 1(NPO)日本呼吸器外科学会2021年05月
【撤回論文】肺葉切除における単孔式手術とロボット支援下手術の利点・欠点を踏まえたベストマッチアプローチ法の検討
宗 淳一; 千葉 眞人; 武本 智樹; 小原 秀太; 藤野 智大; 古賀 教将; 濱田 顕; 西野 将矢; 下治 正樹; 須田 健一; 光冨 徹哉
日本呼吸器外科学会雑誌353O19 - 6(NPO)日本呼吸器外科学会2021年05月
【撤回論文】---当論文については「日本呼吸器外科学会雑誌」35巻3号(2021年発行)の巻末に演題取り下げのお知らせが掲載された。
ロボット支援下肺葉切除時の気管支損傷の2例
武本 智樹; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 宗 淳一; 光冨 徹哉
日本呼吸器外科学会雑誌353V11 - 7(NPO)日本呼吸器外科学会2021年05月
胸腺腫瘍切除例におけるCT値とWHO分類の関連
下治 正樹; 須田 健一; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉
日本呼吸器外科学会雑誌353MO6 - 5(NPO)日本呼吸器外科学会2021年05月
高齢者肺癌葉切除における縦隔リンパ節郭清の意義
西野 将矢; 宗 淳一; 小原 秀太; 藤野 智大; 古賀 教将; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉
日本呼吸器外科学会雑誌353MO70 - 1(NPO)日本呼吸器外科学会2021年05月
左B1+2分岐異常領域に発生した小型肺癌の1切除例
藤野 智大; 須田 健一; 小原 秀太; 西野 将矢; 古賀 教将; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉
日本呼吸器外科学会雑誌353MO90 - 3(NPO)日本呼吸器外科学会2021年05月
「pN陽性」非小細胞肺がんにおけるすりガラス成分の有無の予後因子としての意義
須田 健一; 小原 秀太; 西野 将矢; 古賀 教将; 藤野 智大; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉
日本呼吸器外科学会雑誌353MO99 - 5(NPO)日本呼吸器外科学会2021年05月
Masaya Nishino; Kenichi Suda; Takamasa Koga; Shuta Ohara; Toshio Fujino; Junichi Soh; Vijaya Tirunagaru; Avanish Vellanki; Robert C Doebele; Tetsuya Mitsudomi
Thoracic cancer12101511 - 15162021年05月[査読有り]
BACKGROUND: Approximately 10% of non-small cell lung cancers (NSCLCs) that harbor epidermal growth factor receptor (EGFR) gene mutations have in-frame insertions in exon 20 of the EGFR gene. These tumors do not usually respond to currently available EGFR-tyrosine kinase inhibitors (TKIs). Tarloxotinib is a novel hypoxia-activated prodrug that releases a potent, irreversible pan-ERBB TKI (tarloxotinib-E) under solid tumor hypoxia. METHODS: We examined the efficacy of tarloxotinib-E against several types of Ba/F3 cells with introduced EGFR exon 20 mutations (EGFR A763insFQEA, V769insASV, D770insSVD, H773insH and H773insNPH mutations). We assayed growth inhibition for tarloxotinib (prodrug), tarloxotinib-E (active form), poziotinib, afatinib, and osimertinib in Ba/F3 cells with each EGFR exon 20 mutation. We also explored acquired resistance mechanisms to tarloxotinib-E by establishing cells with resistance to tarloxotinib-E via chronic drug exposure after N-ethyl-N-nitrosourea mutagenesis treatment. RESULTS: Among all tested Ba/F3 cell lines, IC50 was ≥72.1 times higher for tarloxotinib than for tarloxotinib-E, which implies a wide therapeutic window with this prodrug strategy. Tarloxotinib-E was efficacious against all tested Ba/F3 cells except for H773insH, which was less sensitive to all tested EGFR-TKIs. As acquired resistance mechanisms to tarloxotinib-E, we identified either T790M or C797S secondary mutations, depending on the original EGFR exon 20 mutation. CONCLUSIONS: These findings indicate that tarloxotinib-E could be effective for NSCLC with EGFR exon 20 mutations. Our results also show that T790M or C797S mutations can confer acquired resistance to tarloxotinib-E; and suggest that resistance mechanisms are influenced by the baseline EGFR exon 20 mutations.
外科における多施設臨床試験の意義と方向性 肺癌における医師主導治験の経験
濱田 顕; 宗 淳一; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉
日本外科学会定期学術集会抄録集121回NES - 1(一社)日本外科学会2021年04月
肺癌根治術におけるアプローチ法の優劣:特にリンパ節郭清について-RATS、multiple port VATS、single port VATS- 当院におけるUniportal VATSリンパ節郭清の工夫
千葉 眞人; 中野 大哉; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 濱田 顕; 須田 健一; 武本 智樹; 宗 淳一; 光冨 徹哉
日本外科学会定期学術集会抄録集121回DB - 2(一社)日本外科学会2021年04月
ヒト胸郭モデルと豚心肺モデルを用いたハンズオンによる手技の教育と修練システムの構築
武本 智樹; 櫻井 真倫; 神波 奈央子; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 宗 淳一; 光冨 徹哉
日本外科学会定期学術集会抄録集121回SF - 1(一社)日本外科学会2021年04月
ロボット支援下肺葉切除術時の胸壁損傷を考察する
宗 淳一; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 須田 健一; 武本 智樹; 光冨 徹哉
日本外科学会定期学術集会抄録集121回SF - 5(一社)日本外科学会2021年04月
胸腺上皮性腫瘍切除例におけるFDG-PETのSUVmax値と病理学的所見の関連
下治 正樹; 須田 健一; 小原 秀太; 藤野 智大; 古賀 教将; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉
日本外科学会定期学術集会抄録集121回PS - 4(一社)日本外科学会2021年04月
EGFR野生型非小細胞肺癌における術前血清フィブリノゲン値の臨床的意義の検討
小原 秀太; 須田 健一; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉
日本外科学会定期学術集会抄録集121回PS - 6(一社)日本外科学会2021年04月
右肺S3区域切除後の残存上葉に高度鬱血をきたしたが、保存的加療で軽快した1切除例
櫻井 真倫; 武本 智樹; 神波 奈央子; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 宗 淳一; 光冨 徹哉
日本外科学会定期学術集会抄録集121回RS - 9(一社)日本外科学会2021年04月
MET exon14 skipping変異陽性肺多形癌におけるintra-およびinter-tumor heterogeneityの検討
藤野 智大; 須田 健一; 坂井 和子; 清水 重喜; 小原 秀太; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 西尾 和人
日本外科学会定期学術集会抄録集121回SF - 4(一社)日本外科学会2021年04月
Shuta Ohara; Kenichi Suda; Toshio Fujino; Akira Hamada; Takamasa Koga; Masaya Nishino; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Junichi Soh; Tetsuya Mitsudomi
Lung cancer (Amsterdam, Netherlands)15484 - 912021年04月[査読有り]
OBJECTIVE: Emergence of acquired resistance is almost inevitable during EGFR-tyrosine kinase inhibitor therapy for non-small-cell lung cancer (NSCLC) harboring EGFR mutations. Drug tolerance, a reversible state of drug insensitivity in the early phases of tyrosine kinase inhibitor therapy, is considered to serve as the basis of recurrent disease. Therefore, it is important to elucidate the molecular mechanisms of drug tolerance. MATERIALS AND METHODS: Five EGFR-mutated NSCLC cell lines were used in this study. We established drug-tolerant cells (DTCs) via 72 h treatment with osimertinib (600 nM) or afatinib (60 nM). Acquisition of drug tolerance was evaluated by growth inhibitory assay, and the molecular mechanisms of drug tolerance were analyzed by phospho-RTK array. RESULTS: DTCs were successfully induced in PC9, HCC4006, and H1975 cells against osimertinib and in PC9 cells against afatinib. We observed that a high drug concentration was required to induce DTCs, and HCC4006 cells become tolerant when a higher dose of afatinib (>180 nM) was used. In the analysis of HCC4006 DTCs against osimertinib, we observed increased receptor-like tyrosine kinase (RYK) expression, and siRNA-mediated RYK knockdown inhibited the proliferation of DTCs. CONCLUSIONS: These results suggest that induction of DTCs is dose-dependent, and increased RYK expression was the mechanism of drug tolerance in HCC4006 cells against osimertinib.
【これだけ!あんしん86ポイント 内視鏡外科手術バイブル】(第3章)呼吸器内視鏡外科手術 呼吸器 内視鏡外科手術の特徴・適応疾患
小原 秀太; 宗 淳一
オペナーシング2021春季増刊154 - 155(株)メディカ出版2021年03月
【これだけ!あんしん86ポイント 内視鏡外科手術バイブル】(第3章)呼吸器内視鏡外科手術 呼吸器 よく使用する器械やデバイス
小原 秀太; 宗 淳一
オペナーシング2021春季増刊156 - 157(株)メディカ出版2021年03月
【これだけ!あんしん86ポイント 内視鏡外科手術バイブル】(第3章)呼吸器内視鏡外科手術 呼吸器 よくある手技と介助のポイント
小原 秀太; 宗 淳一
オペナーシング2021春季増刊158 - 159(株)メディカ出版2021年03月
【これだけ!あんしん86ポイント 内視鏡外科手術バイブル】(第3章)呼吸器内視鏡外科手術 呼吸器 患者へのアプローチや外回り看護のポイント
小原 秀太; 宗 淳一
オペナーシング2021春季増刊160 - 161(株)メディカ出版2021年03月
【これだけ!あんしん86ポイント 内視鏡外科手術バイブル】(第3章)呼吸器内視鏡外科手術 呼吸器 胸腔鏡下肺がん手術ってどんな術式?
小原 秀太; 宗 淳一
オペナーシング2021春季増刊162 - 163(株)メディカ出版2021年03月
【これだけ!あんしん86ポイント 内視鏡外科手術バイブル】(第3章)呼吸器内視鏡外科手術 呼吸器 胸腔鏡下右上葉切除術 手術の流れと看護のポイント
小原 秀太; 宗 淳一
オペナーシング2021春季増刊164 - 167(株)メディカ出版2021年03月
【これだけ!あんしん86ポイント 内視鏡外科手術バイブル】(第3章)呼吸器内視鏡外科手術 呼吸器 胸腔鏡下ブラ切除術ってどんな術式?
小原 秀太; 宗 淳一
オペナーシング2021春季増刊168 - 169(株)メディカ出版2021年03月
【これだけ!あんしん86ポイント 内視鏡外科手術バイブル】(第3章)呼吸器内視鏡外科手術 呼吸器 胸腔鏡下ブラ切除術 手術の流れと看護のポイント
小原 秀太; 宗 淳一
オペナーシング2021春季増刊170 - 172(株)メディカ出版2021年03月
【これだけ!あんしん86ポイント 内視鏡外科手術バイブル】(第3章)呼吸器内視鏡外科手術 呼吸器 胸腔鏡下縦隔腫瘍手術ってどんな術式?
小原 秀太; 宗 淳一
オペナーシング2021春季増刊173 - 174(株)メディカ出版2021年03月
【これだけ!あんしん86ポイント 内視鏡外科手術バイブル】(第3章)呼吸器内視鏡外科手術 呼吸器 胸腔鏡下拡大胸腺摘出術 手術の流れと看護のポイント
小原 秀太; 宗 淳一
オペナーシング2021春季増刊175 - 177(株)メディカ出版2021年03月
Shuta Ohara; Atsushi Yasuda; Shigeki Shimizu; Kenichi Suda; Tetsuya Mitsudomi
Human Pathology: Case Reports23200481 - 2004812021年03月[査読有り]
Kenichi Suda; Kazuko Sakai; Keiko Obata; Shuta Ohara; Toshio Fujino; Takamasa Koga; Akira Hamada; Junichi Soh; Kazuto Nishio; Tetsuya Mitsudomi
Clinical lung cancer222e141-e145 2021年03月[査読有り]
BACKGROUND: Several clinical and preclinical studies suggest that non-small cell lung cancers (NSCLCs) with EGFR compound mutations were associated with lower efficacies of first-generation EGFR inhibitors than tumors with single EGFR mutation. Some researchers hypothesize that EGFR mutation status is heterogeneous in such tumors and that second-generation EGFR inhibitors may eliminate cancer cells with uncommon EGFR mutations from tumors with EGFR compound mutations. However, this hypothesis is currently unproven; therefore, we performed the current study to determine if tumor cells with EGFR compound mutations are present in heterogeneous or hom*ogeneous manners. PATIENTS AND METHODS: Multiregion analysis was performed for surgically resected primary NSCLC tumors with EGFR compound mutations to examine the intratumor heterogeneity of EGFR compound mutations. In addition, we evaluated the intertumor heterogeneity of EGFR compound mutations using 2 pleural disseminations obtained from a patient with NSCLC at exploratory thoracotomy and 9 primary or metastatic lesions obtained from 2 autopsied NSCLC patients. Digital polymerase chain reaction, target sequencing, or direct sequencing were used to detect EGFR mutations. RESULTS: This study included 5 NSCLC cases; their compound mutations were L858R+S768I, G719X+S768I, G719A+R776H, L858R+E709G, and L858R+I759M. Noncancerous pulmonary tissues from each patient did not harbor EGFR mutations, which revealed that all mutations were somatic. We did not detect any intra- or intertumor heterogeneity in these EGFR compound mutations. CONCLUSION: No intra- or intertumor heterogeneity was observed for EGFR compound mutations. Our results indicate that both EGFR mutations were truncal and selective elimination of cancer cells with uncommon EGFR mutations is unrealistic.
Toshiki Takemoto; Junichi Soh; Shuta Ohara; Toshio Fujino; Takamasa Koga; Masaya Nishino; Akira Hamada; Masato Chiba; Masaki Shimoji; Kenichi Suda; Kenji Tomizawa; Tetsuya Mitsudomi
Surgery today5191480 - 14872021年02月[査読有り]
PURPOSE: Few studies have so far focused on the preoperative presence of venous thromboembolism (VTE) in lung cancer patients undergoing surgery. In this study, we investigated the prevalence and risk factors for preoperative deep venous thrombosis (DVT) in patients scheduled to undergo lung cancer surgery. METHODS: Between June 2013 and December 2018, 948 consecutive patients underwent lung cancer surgery in Kindai University Hospital. Four patients did not undergo screening for DVT; thus, 944 patients were enrolled in this study. Preoperatively, venous ultrasonography of the lower extremities was performed in patients deemed at risk for DVT, and the prevalence and risk factors for preoperative DVT were examined. RESULTS: Ninety-one patients (9.6%) were diagnosed with preoperative DVT, and postoperative symptomatic pulmonary thromboembolism occurred in one patient (0.11%). A multivariable logistic regression analysis demonstrated that female sex, age ≥ 72years, history of VTE, a Wells score ≥ 2 points, chronic obstructive pulmonary disease (COPD), and lower hemoglobin levels were significantly associated with preoperative DVT. CONCLUSION: Female sex, age ≥ 72years, history of VTE, Wells score ≥ 2 points, COPD, and lower hemoglobin levels were identified to be independent risk factors for preoperative DVT. Monitoring for these risk factors and management considering them should help improve the outcomes after lung cancer surgery.
Shuta Ohara; Kenichi Suda; Tetsuya Mitsudomi
Cells1022021年02月[査読有り]
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are first-line drugs for lung cancers with activating EGFR mutations. Although first- and second-generation EGFR-TKIs were standard first-line treatments, acquired resistance (AR) to these drugs is almost inevitable. Cell line models have been widely used to explore the molecular mechanisms of AR to first- and second-generation EGFR-TKIs. Many research groups, including ours, have established AR cell lines that harbor the EGFR T790M secondary mutation, MET gene amplification, or epithelial-mesenchymal transition (EMT) features, which are all found in clinical specimens obtained from TKI-refractory lesions. Currently, many oncologists prescribe osimertinib, a third-generation EGFR-TKI that can overcome T790M-mediated resistance, as a first-line TKI. Although few clinical data are available about AR mechanisms that arise when osimertinib is used as a first-line therapy, many research groups have established cell lines with AR to osimertinib and have reported on their AR mechanisms. In this review, we summarize the findings on AR mechanisms against first-line osimertinib obtained from analyses of cell line models.
Shuta Ohara; Kenichi Suda; Kenji Tomizawa; Toshiki Takemoto; Toshio Fujino; Akira Hamada; Takamasa Koga; Masaya Nishino; Masato Chiba; Katsuaki Sato; Masaki Shimoji; Junichi Soh; Tetsuya Mitsudomi
Surgery today50111427 - 14332020年11月[査読有り]
PURPOSE: A high plasma level of either fibrinogen or D-dimer has been shown to correlate with a poor prognosis in patients with surgically resected non-small-cell lung cancer (NSCLC). The present study aimed to identify whether or not both markers combined had a superior prognostic value to either alone. METHODS: Of the 1344 patients who underwent surgical resection for NSCLC at our institution between January 2007 and December 2016, 1065 had preoperative plasma fibrinogen and D-dimer data available and were included in the analysis. RESULTS: The recurrence-free survival (RFS) and overall survival (OS) rates were similar for patients with high plasma levels of either or both fibrinogen (> 4.0g/L) or D-dimer (> 1.0μg/mL); therefore, these three groups were combined for a further analysis into a single group with high plasma levels of either or both proteins. The high-level group had significantly lower 5-year RFS (53% vs. 68%, p < 0.001) and 5-year OS (65% vs. 80%, p < 0.001) rates than patients with normal plasma levels of fibrinogen and D-dimer (control group). CONCLUSIONS: Our results suggest that preoperative tests for both plasma fibrinogen and D-dimer are necessary to identify patients with surgically resected NSCLC likely to have a poor RFS and OS.
古賀 教将; 須田 健一; 小原 秀太; 藤野 智大; 濱田 顕; 宗 淳一; 光冨 徹哉
肺癌606533 - 533(NPO)日本肺癌学会2020年10月
宗 淳一; 富沢 健二; 小原 秀太; 藤野 智大; 濱田 顕; 古賀 教将; 西野 将矢; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉
肺癌606611 - 611(NPO)日本肺癌学会2020年10月
宗 淳一; 千葉 眞人; 武本 智樹; 小原 秀太; 藤野 智大; 濱田 顯; 古賀 教将; 西野 将矢; 下治 正樹; 須田 健一; 光冨 徹哉
日本胸部外科学会定期学術集会73回LRS1 - 10(一社)日本胸部外科学会2020年10月
Kenichi Suda; Isao Murakami; Keiko Obata; Kazuko Sakai; Toshio Fujino; Takamasa Koga; Shuta Ohara; Akira Hamada; Junichi Soh; Kazuto Nishio; Tetsuya Mitsudomi
Lung cancer (Amsterdam, Netherlands)148100 - 1042020年10月[査読有り]
BACKGROUND: Overcoming acquired resistance against targeted therapies to improve outcomes of lung cancer patients harboring driver mutations is a critical issue. While drug therapy oriented to a resistance mechanism appears attractive, spatial heterogeneity of resistance mechanisms in each patient will diminish treatment efficacy. However, the frequency, clinical backgrounds, clinical implications, and patterns of spatial heterogeneity in resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs) are largely unknown. PATIENTS AND METHODS: This study included 128 specimens from 24 autopsied patients with lung adenocarcinoma harboring EGFR mutation. Acquired resistance mechanisms reported as relatively frequent in lung cancer, e.g., T790 M and other secondary EGFR mutations, MET and ERBB2 gene amplification, and histological transformation, were retrospectively examined. All patients had received 1st/2nd generation EGFR-TKI and showed acquired resistance to the drug before death. No patient received osimertinib. RESULTS: No resistance mechanism was identified in two patients. T790M mutation was detected in 20 patients (83 %); however, nine of these patients also had lesions without T790M mutation. Among 22 patients whose resistance mechanisms were identified, ten had spatial heterogeneity of resistance mechanisms (45 %), and these patients had significantly shorter time-to-treatment failure compared with those without heterogeneity (median 4.7 months vs. 14.7 months, p = 0.0004). CONCLUSION: We observed significant spatial heterogeneity of acquired resistance mechanisms to EGFR-TKIs in lung adenocarcinoma. Our results also indicate that the incidence of resistance mechanisms may vary based on the biopsied tumor locations.
Shuta Ohara; Kenichi Suda; Kazuko Sakai; Masaya Nishino; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Toshio Fujino; Takamasa Koga; Akira Hamada; Junichi Soh; Kazuto Nishio; Tetsuya Mitsudomi
Translational lung cancer research951915 - 19232020年10月[査読有り]
Background: Recent studies of advanced lung cancer patients have shown that circulating tumor DNA (ctDNA) analysis is useful for molecular profiling, monitoring tumor burden, and predicting therapeutic efficacies and disease progression. However, the usefulness of ctDNA analysis in surgically resected lung cancers is unclear. Methods: This study included 20 lung cancer patients with clinical stage IIA-IIIA disease. Preoperative and postoperative (3-12 days) plasma samples were collected for ctDNA analysis. Cancer personalized profiling by deep sequencing, which can detect mutations in 197 cancer-related genes, was used for ctDNA detection. The cohort consisted of 18 men and 2 women with a median age of 69 (range, 37-88) years. Sixteen patients (80%) had a history of smoking. Histologically, there were four squamous cell carcinomas, 13 adenocarcinomas, two adenosquamous cell carcinomas, and one small cell carcinoma. Results: At the time of data analysis, the 20 patients had been monitored for a median follow-up of 12 months. Eight patients (40%) were positive for preoperative ctDNA, and this was significantly correlated with tumor size (≥5 vs. <5 cm, P=0.018). Four patients (20%) were positive for postoperative ctDNA, and this was significantly correlated with histological grade (3 vs. 1 or 2, P=0.032). Postoperative positivity for ctDNA also predicted shorter recurrence-free survival (RFS) (P=0.015), while pre- and post-operative carcinoembryonic antigen levels (P=0.150 and P=0.533, respectively) and preoperative positivity for ctDNA (P=0.132) were not correlated with RFS. Conclusions: Detecting ctDNA postoperatively was a poor prognostic factor in surgically resected lung cancer patients that may suggest there is minimal residual disease (MRD).
新規低侵襲(単孔式・ロボット支援)手術におけるヒヤリハット Uniportal VATSにおけるヒヤリハット 逸脱例からの考察
千葉 眞人; 福田 祥大; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 濱田 顕; 須田 健一; 武本 智樹; 宗 淳一; 光冨 徹哉
日本呼吸器外科学会雑誌343VWS2 - 2(一社)日本呼吸器外科学会2020年08月
ロボット支援下肺葉切除術導入時のヒヤリハットを考察する 胸壁損傷とその対策
宗 淳一; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顯; 千葉 眞人; 須田 健一; 武本 智樹; 光冨 徹哉
日本呼吸器外科学会雑誌343V1 - 4(一社)日本呼吸器外科学会2020年08月
ヒト胸郭モデルと豚摘出肺を用いた研修医教育の取り組み
武本 智樹; 福田 祥太; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 宗 淳一; 光冨 徹哉
日本呼吸器外科学会雑誌343O39 - 4(一社)日本呼吸器外科学会2020年08月
切除肺に10個以上の病変を認めた多発肺腺癌の3例
古賀 教将; 須田 健一; 福田 祥大; 小原 秀太; 藤野 智大; 西野 将矢; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉
日本呼吸器外科学会雑誌343MO10 - 6(一社)日本呼吸器外科学会2020年08月
非小細胞肺癌における術前NLR高値は、腫瘍のPD-L1発現と関連する
藤野 智大; 須田 健一; 下治 正樹; 濱田 顕; 小原 秀太; 古賀 教将; 西野 将矢; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉
日本呼吸器外科学会雑誌343MO36 - 5(一社)日本呼吸器外科学会2020年08月
掻把術にて根治できなかった難治性術後膿胸に対するクリスタルバイオレットを用いた胸腔内洗浄の有用性
須田 健一; 小原 秀太; 西野 将矢; 古賀 教将; 藤野 智大; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉
日本呼吸器外科学会雑誌343MO59 - 1(一社)日本呼吸器外科学会2020年08月
異所性子宮内膜症由来が疑われた横隔膜明細胞癌の1切除例
波江野 真大; 武本 智樹; 福田 祥太; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 太田 真見子; 前西 修; 宗 淳一; 光冨 徹哉
日本呼吸器外科学会雑誌343MO29 - 1(NPO)日本呼吸器外科学会2020年08月
松本 正孝; 武本 智樹; 小原 秀太; 須田 健一; 光冨 徹哉
日本呼吸器外科学会雑誌342121 - 125(NPO)日本呼吸器外科学会2020年03月
症例は38歳男性。近医にて前縦隔腫瘍を指摘され当科紹介となった。CTで境界明瞭な4×3.5×3cmの充実性腫瘍を前縦隔に認め、PETでは同部位にSUVmax 7.04の異常集積を認めた。またPET検査において、膵鉤部にもSUVmax 3.65のFDG異常集積を認めた。高Ca血症とCTで副甲状腺腺腫が疑われること、父がMEN1型であることからMEN1型に合併した胸腺カルチノイドと診断し、胸腺全摘術を施行した。病理診断は腫瘍部位に卵円形核を持つ多角形細胞が増生し、ロゼット構造が散見、免疫染色では神経内分泌マーカーが陽性であった。核分裂像は8個/10HPFであり非定型的カルチノイドと診断された。MEN1型は胸腺カルチノイドの25%に合併するとされ、特に非定型的カルチノイドは予後不良とされている。(著者抄録)
Fujino T; Kobayashi Y; Suda K; Koga T; Nishino M; Ohara S; Chiba M; Shimoji M; Tomizawa K; Takemoto T; Mitsudomi T
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer14101753 - 17652019年10月[査読有り]
BACKGROUND: MNNG HOS transforming gene (MET) exon 14 mutations in lung cancer, including exon 14 skipping and point mutations, have been attracting the attention of thoracic oncologists as new therapeutic targets. Tumors with these mutations almost always acquire resistance, which also occurs in other oncogene-addicted lung cancers. However, the resistance mechanisms and treatment strategies are not fully understood. METHODS: We generated Ba/F3 cells expressing MET exon 14 mutations by retroviral gene transfer. The sensitivities of these cells to eight MET-tyrosine kinase inhibitors (TKIs) were determined using a colorimetric assay. In addition, using N-ethyl-N-nitrosourea mutagenesis, we generated resistant clones, searched for secondary MET mutations, and then examined the sensitivities of these resistant cells to different TKIs. RESULTS: Ba/F3 cells transfected with MET mutations grew in the absence of interleukin-3, indicating their oncogenic activity. These cells were sensitive to all MET-TKIs except tivantinib. We identified a variety of secondary mutations. D1228 and Y1230 were common sites for resistance mutations for type I TKIs, which bind the active form of MET, whereas L1195 and F1200 were common sites for type II TKIs, which bind the inactive form. In general, resistance mutations against type I were sensitive to type II, and vice versa. CONCLUSIONS: MET-TKIs inhibited the growth of cells with MET exon 14 mutations. We also identified mutation sites specific for TKI types as resistance mechanisms and complementary activities between type I and type II inhibitors against those mutations. These finding should provide relevant clinical implication for treating patients with lung cancer harboring MET exon 14 mutations.
Shuta Ohara; Kenji Tomizawa; Shigeki Shimizu; Kenichi Suda; Toshio Fujino; Akira Hamada; Takamasa Koga; Masaya Nishino; Yoshihisa Kobayashi; Katsuaki Sato; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Junichi Soh; Tetsuya Mitsudomi
Surgical case reports51105 - 1052019年06月[査読有り]
BACKGROUND: A total of 75% of patients with Sjögren's syndrome are complicated with pulmonary lesions, of which 12% are lymphoma and 6% are amyloid nodules; the coexistence of both is considered to be rare. CASE PRESENTATION: A 67-year-old female with Sjögren's syndrome presented with multiple pulmonary nodules on chest computed tomography. Since a definitive diagnosis by transbronchial biopsy was not obtained, wedge resection of the nodules was performed. Pathologic diagnosis revealed eosinophilic deposition that stained positive with Congo red. In addition, lymphoepithelial lesions and lymphocytic infiltration were observed. Lymphocytes with monoclonal proliferation predominantly had κ chain. Based on these findings, the nodules were diagnosed as mucosa-associated lymphoid tissue (MALT) lymphoma with amyloid deposition. CONCLUSIONS: The combination of these diseases is very rare, and this is the sixth resected case to the best of our knowledge.
Kenji Tomizawa; Katsuaki Sato; Shuta Ohara; Toshio Fujino; Takamasa Koga; Masaya Nishino; Yoshihisa Kobayashi; Masato Chiba; Masaki Shimoji; Kenichi Suda; Toshiki Takemoto; Tetsuya Mitsudomi
Surgery today496513 - 5202019年06月[査読有り]
PURPOSE: The morbidity and mortality associated with lung cancer surgery in patients on chronic hemodialysis (CHD) is high; however, the relationship between the severity of postoperative complications and clinicopathological features is unclear. METHODS: Among 1214 consecutive patients who underwent pulmonary resection for primary lung cancer in our institute between 2004 and 2015, we identified 21 patients on CHD, who were the subjects of this study. Life-threatening postoperative complications were defined as grade 4 and 5 per the Clavien-Dindo classification. RESULTS: Fourteen (67%) of these 21 patients suffered postoperative complications, which were life threatening in 5. There was a higher frequency of interstitial pneumonia (IP) in the patients with life-threatening postoperative complications than in those with complications that were not life threatening (p = 0.032). The rates of acute exacerbation and 90-day mortality in the patients with IP were 50% and 75%, respectively. The overall survival (OS) rate of the patients with life-threatening postoperative complications was significantly lower than that of those with complications that were not life threatening (1- and 3-year OS rates: 40% and 0% vs. 80% and 57%, respectively, p = 0.001). CONCLUSIONS: Postoperative mortality and morbidity were high in patients on CHD who underwent pulmonary resection, especially if they had coexisting IP. Although IP is not a contraindication to pulmonary resection, the surgical strategy for CHD patients with IP should be considered carefully.
Nishino Masaya; Suda Kenichi; Ohara Shuta; Fujino Toshio; Koga Takamasa; Kobayashi Yoshihisa; Chiba Masato; Shimoji Masaki; Tomizawa Kenji; Takemoto Toshiki; Mitsudomi Tetsuya
CANCER SCIENCE1091184 2018年12月[査読有り]
Masaya Nishino; Kenichi Suda; Yoshihisa Kobayashi; Shuta Ohara; Toshio Fujino; Takamasa Koga; Masato Chiba; Masaki Shimoji; Kenji Tomizawa; Toshiki Takemoto; Tetsuya Mitsudomi
Lung cancer (Amsterdam, Netherlands)126149 - 1552018年12月[査読有り]
OBJECTIVES: Non-small cell lung cancers (NSCLCs) that harbor activating mutations for epidermal growth factor receptor (EGFR) show remarkable initial response to EGFR-tyrosine kinase inhibitors (TKIs), but inevitably acquire resistance, half of which are due to a T790 M secondary mutation when first-generation (1 G) or 2 G EGFR-TKIs are used. Osimertinib, a 3 G EGFR-TKI, is a standard of care in this situation, but eventually also evokes resistance, reportedly due to some tertiary EGFR mutations. However, the FLAURA trial showed the superiority of osimertinib over 1 G EGFR-TKIs in treatment-naïve patients, thus providing an option of first-line osimertinib treatment. Resistance in this setting is also inevitable, but its mechanism is unclear. We investigated whether resistance mutations that emerged with T790 M were responsible for the osimertinib resistance in the first-line setting; i.e. without T790 M, and if so, what treatment option was available. MATERIALS AND METHODS: We used literature search to identify EGFR mutations at codons L718, G724, L792, G796, and C797 as mechanisms of osimertinib resistance in the presence of T790 M. These mutations were introduced into Ba/F3 cells in cis with activating EGFR mutations but not with T790 M; inhibitory effects of five EGFR-TKIs were evaluated. RESULTS: Only C797S conferred significant resistance against osimertinib when exon 19 deletion was the activating mutation. However, co-existence of L858R with C797S, C797 G, L718Q, or L718 V mutations all conferred resistance to osimertinib. Erlotinib showed the greatest activity for C797S-mediated resistance. However, 2 G EGFR-TKIs (afatinib or dacomitinib) were effective for other resistance mutations. CONCLUSION: After first-line osimertinib failure, 1 G or 2 G EGFR-TKIs are effective, depending on combinations of secondary and activating mutations.
Takamasa Koga; Yoshihisa Kobayashi; Kenji Tomizawa; Kenichi Suda; Takayuki Kosaka; Yuichi Sesumi; Toshio Fujino; Masaya Nishino; Shuta Ohara; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Makoto Suzuki; Pasi A Jänne; Tetsuya Mitsudomi
Lung cancer (Amsterdam, Netherlands)12672 - 792018年12月[査読有り]
OBJECTIVES: Oncogenic HER2 mutations are present in 2-4% of lung adenocarcinomas, but the relevant clinical trials are unsatisfactory. The novel HER2 inhibitor poziotinib was recently developed and clinical trials are ongoing. We compared poziotinib with nine tyrosine kinase inhibitors (TKIs), and derived poziotinib-resistant clones to investigate the resistant mechanism. MATERIALS AND METHODS: We introduced three common HER2 mutations A775_G776insYVMA (YVMA), G776delinsVC (VC) and P780_Y781insGSP (GSP), which account for 94% of HER2 exon 20 insertions in the literature, into Ba/F3 cells. We then compared the activity of poziotinib with that of nine TKIs (erlotinib, afatinib, dacomitinib, neratinib, osimertinib, AZ5104, pyrotinib, lapatinib, and irbinitinib), determined the 90% inhibitory concentration (IC90) through a growth inhibition assay, and defined a sensitivity index (SI) as IC90 divided by the trough concentration at the recommended dose as a surrogate for drug activity in humans. We also generated resistant clones by exposure to poziotinib in the presence of N-ethyl-N-nitrosourea, and HER2 secondary mutations that might serve as a resistance mechanism were searched. RESULTS: YVMA showed resistance to all tested drugs except neratinib, poziotinib and pyrotinib. Poziotinib was the only drug with an SI less than 10 for YVMA, the most common HER2 exon 20 insertion. We established 62 poziotinib-resistant clones, and among these, only C805S of HER2, which is hom*ologous to C797S of the EGFR, was identified as a secondary mutation in 19 clones. We also revealed that heat shock protein (HSP) 90 inhibitors show potent anti-growth activity to the C805S secondary mutant clone. CONCLUSIONS: Poziotinib showed the most potent activity against HER2 exon 20 mutations. We identified the secondary C805S at the covalent binding site of HER2 to poziotinib as a potential mechanism of acquired resistance. HSP90 inhibitors might be a therapeutic strategy for the C805S secondary mutation.
Yoshihisa Kobayashi; Toshio Fujino; Masaya Nishino; Takamasa Koga; Masato Chiba; Yuichi Sesumi; Shuta Ohara; Masaki Shimoji; Kenji Tomizawa; Toshiki Takemoto; Tetsuya Mitsudomi
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer135727 - 7312018年05月[査読有り]
INTRODUCTION: Dacomitinib was superior to gefitinib in terms of progression-free survival in patients with EGFR-mutant lung cancer in a recent ARCHER 1050 trial. However, despite a marked initial response, lung cancers eventually acquire resistance to these inhibitors. This study aimed to elucidate the mechanisms of acquired resistance to dacomitinib invitro. METHODS: Dacomitinib-resistant clones were established by exposure to fixed concentrations of dacomitinib by using N-ethyl-N-nitrosourea (ENU) mutagenesis or by chronic exposure to increasing concentrations of dacomitinib without ENU. EGFR secondary mutations were analyzed by Sanger sequencing. Time to resistance in each clone was compared according to the mutational status. EGFR Del19, L858R, and G719A mutations were introduced into Ba/F3 cells by using retroviral vectors. RESULTS: Chronic exposure to dacomitinib without ENU induced T790M in Ba/F3 cells expressing Del19. ENU mutagenesis resulted in 171 dacomitinib-resistant clones. Among these clones, 90% acquired T790M. However, C797S occurred in 11% of L858R-mutant clones (four of 35) and in 24% of G719A-mutant clones (12 of 38) established by using low-dose dacomitinib. Time to resistance was not significantly different between T790M- and C797S-mutant clones in both of L858R clones (p= 0.93) and G719A clones (p= 0.86). Cells expressing Del19 that acquired T790M were sensitive to osimertinib, whereas cells with L858R plus C797S mutations were sensitive to gefitinib or erlotinib. CONCLUSIONS: These invitro data demonstrate that dacomitinib can directly induce T790M or C797S secondary mutations. Our data suggest the importance of analyzing these secondary mutations because appropriate selection of EGFR inhibitors could overcome acquired resistance to dacomitinib in a subset of lung cancers.
小原 秀太; 武本 智樹; 小林 祥久; 佐藤 克明; 富沢 健二; 光冨 徹哉
日本呼吸器外科学会雑誌322136 - 140(NPO)日本呼吸器外科学会2018年03月[査読有り]
67歳・男性。左右対称性の手・肘関節痛と両手の浮腫を自覚し近医を受診した。リウマチ疑いで紹介された病院でRemitting Seronegative Symmetrical Synovitis with Pitting Edema Syndrome(RS3PE症候群)と診断された。この症候群は悪性腫瘍の合併が多いことが知られており、全身検索の結果、肺癌が診断され、手術目的で当院に紹介された。CTで右肺上葉に1.3cmの充実性結節を認め、経気管支肺生検で腺癌と診断した。リンパ節や他臓器に転移を認めなかったため、胸腔鏡下右肺上葉切除術を施行した。術後、関節痛、浮腫の改善を認めた。RS3PE症候群は腫瘍随伴性症候群の一つとして知られているが、肺癌に合併した報告は稀である。(著者抄録)
Kenji Tomizawa; Shigeki Shimizu; Shuta Ohara; Toshio Fujino; Masaya Nishino; Yuichi Sesumi; Yoshihisa Kobayashi; Katsuaki Sato; Masato Chiba; Masaki Shimoji; Kenichi Suda; Toshiki Takemoto; Tetsuya Mitsudomi
Lung cancer (Amsterdam, Netherlands)11257 - 612017年10月[査読有り]
OBJECTIVES: The prognostic impact of tumor cavitation is unclear in patients with early-stage primary lung cancer. The aim of the present study was to examine the clinicopathological features and prognoses of patients with pathological stage I-IIA (p-stage I-IIA) primary lung cancers harboring tumor cavitation. This study was conducted according to the eighth edition of the TNM classification for lung cancer. MATERIALS AND METHODS: We examined 602 patients with p-stage I-IIA primary lung cancer out of 890 patients who underwent pulmonary resection from January 2007 through March 2014 and searched for the presence of tumor cavitation, which is defined as the presence of air space within the primary tumor. RESULTS: A total of 59 out of the 602 patients had tumor cavitation (10%). Compared with patients without tumor cavitation, those with tumor cavitation had a significantly higher frequency of the following characteristics: high serum carcinoembryonic antigen (CEA) level (≥5ng/ml, p=0.027), interstitial pneumonia (p=0.0001), high SUVmax value on FDG-PET scan (≥4.2, p=0.023), tumors located in the lower lobe (p=0.024), large tumor size (>3cm, p=0.002), vascular invasion (66% vs 17%, p<0.0001) and non-adenocarcinoma histology (p=0.025). The overall survival period of patients with tumor cavitation was significantly shorter than that of patients without tumor cavitation (log-rank test: p<0.0001, 5-year OS rate: 56% vs 81%). Tumor cavitation was found to be an independent and significant factor associated with poor prognosis in the multivariate analysis (hazard ratio: 1.76, 95% confidence interval: 1.02-3.10, p=0.042). CONCLUSIONS: Tumor cavitation is an independent factor for poor prognosis in patients with resected p-stage I-IIA primary lung cancer. Based on our analyses, patients with tumor cavitation should be regarded as a separate cohort that requires more intensive follow-up.
