Noninvasive diagnoses for malignant neuroendocrine neoplasms

• Project/Area Number: 19K09041
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Kudo Atsushi 東京医科歯科大学, 東京医科歯科大学病院, 准教授 (20376734)
• Co-Investigator(Kenkyū-buntansha): 田中 真二 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30253420) ; 田邉 稔 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (50197513)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 転移能 / イメージングバイオマーカー / 網羅的遺伝子解析 / 分子標的

Outline of Research at the Start

膵神経内分泌腫瘍は我が国の10万人に2.7人が発症するとされているが近年増加傾向にあり、剖検では日本人の1.6-10％に発症している可能性が示唆される.我々は2016年に肉眼型分類を世界で初めて創設し、網羅的遺伝子解析で肝転移の指標としてPAX6を同定した.本研究はこれらについて全国集計でvalidationを行うと共に、新しい画像診断学的指標を開発し、分子生物学的特徴を調べる。

Outline of Final Research Achievements

Comprehensive gene analysis was performed as a test study in 10 non-simple nodule type cases and 10 simple nodule type cases, and gene set enrichment analysis (GSEA) was performed. The protein expression of the obtained target gene was immunostained. Currently, 50 samples have been collected and are being reanalyzed. The pathophysiological significance of sugar chain marker expression was examined. The number of PAX6 test cases was increased to about 200. Accumulation of data for new non-invasive indicators. The validation study for macroscopic classification, along with the prospective data accumulated at the TRI Medical Innovation Center, is investigating the impact of macroscopic classification on prognosis.

Academic Significance and Societal Importance of the Research Achievements

膵神経内分泌腫瘍には病理学的、あるいは画像診断学的に予後の悪い腫瘍の肉眼分類がある。非単純結節型と単純結節型の分子学的特徴を導くことで、一時独立に行った糖鎖マーカー発現のメカニズムとの関係が明らかにできる可能性がある。糖鎖マーカーの解析では予後を決定するメカニズムが新たに発見できた。分子生物学的な特徴と病理学的肉眼所見、画像診断学的所見をつなぐことができ、新しい非侵襲的指標の作成が可能になった。

Research Products

• [Journal Article] Somatostatin Receptor 2 Expression Profiles and Their Correlation with the Efficacy of Somatostatin Analogues in Gastrointestinal Neuroendocrine Tumors (2022)
  • Author(s): Watanabe Hirofumi、Fujishima Fumiyoshi、Komoto Izumi、Imamura Masayuki、Hijioka Susumu、Hara Kazuo、Yatabe Yasushi、Kudo Atsushi、Masui Toshihiko、Tsuchikawa Takahiro、Sakamoto Kazuhiro、Shiga Hisashi、Nakamura Tomohiro、Nakaya Naoki、Motoi Fuyuhiko、Unno Michiaki、Sasano Hironobu
  • Journal Title: Cancers Volume: 14 Issue: 5 Pages: 775-775
  • DOI: 10.1002/ags3.12458
  • Peer Reviewed / Open Access
• [Journal Article] Surgery after sunitinib administration to improve survival of patients with advanced pancreatic neuroendocrine neoplasms (2021)
  • Author(s): Murase Yoshiki、Kudo Atsushi、Akahoshi Keiichi、Maekawa Aya、Ishikawa Yoshiya、Ueda Hiroki、Ogawa Kosuke、Ono Hiroaki、Tanaka Shinji、Tanabe Minoru
  • Journal Title: Annals of Gastroenterological Surgery Volume: 5 Issue: 11 Pages: 692-700
  • DOI: 10.1111/cas.15134
  • Peer Reviewed
• [Journal Article] Inhibitor library screening identifies ispinesib as a new potential chemotherapeutic agent for pancreatic cancers (2021)
  • Author(s): Murase Yoshiki、Ono Hiroaki、Ogawa Kosuke、Yoshioka Risa、Ishikawa Yoshiya、Ueda Hiroki、Akahoshi Keiichi、Ban Daisuke、Kudo Atsushi、Tanaka Shinji、Tanabe Minoru
  • Journal Title: Cancer Science Volume: 112 Issue: 6 Pages: 4641-4654
  • DOI: 10.1371/journal.pone.0252917
  • Peer Reviewed / Open Access
• [Journal Article] Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells (2021)
  • Author(s): Kato Tomotaka、Ono Hiroaki、Fujii Mikiya、Akahoshi Keiichi、Ogura Toshiro、Ogawa Kosuke、Ban Daisuke、Kudo Atsushi、Tanaka Shinji、Tanabe Minoru
  • Journal Title: PLOS ONE Volume: 16 Issue: 4 Pages: 0252917-0252917
  • DOI: 10.1007/s00432-021-03660-0
  • Peer Reviewed
• [Journal Article] Hormonal tumor mapping for liver metastases of gastroenteropancreatic neuroendocrine neoplasms: a novel therapeutic strategy. (2021)
  • Author(s): Maekawa A, Kudo A, Kishino Mitsuhiro, Murase Y, Watanabe S, Ishikawa Y, Ueda Hiroki, Akahoshi K, Ogawa K, Ono H, Tanaka S, Kinowaki Y, Tanabe M.
  • Journal Title: Journal of Cancer Research and Clinical Oncology, in press Volume: - Issue: 3 Pages: 931-941
  • DOI: 10.1007/s00432-021-03650-2
  • Peer Reviewed
• [Journal Article] A Pilot Study Analyzing the Clinical Utility of Comprehensive Genomic Profiling Using Plasma Cell-Free DNA for Solid Tumor Patients in Japan (PROFILE Study) (2021)
  • Author(s): Matsudera S、Kano Y、Aoyagi Y、Tohyama K、Takahashi K、Kumaki Y、Mitsumura T、Kimura K、Onishi I、Takemoto A、Ban D、Ono H、Kudo Atsushi、et.al.
  • Journal Title: Annals of Surgical Oncology Volume: - Issue: 13 Pages: 697-706
  • DOI: 10.1245/s10434-021-09856-5
  • Peer Reviewed
• [Journal Article] Importance of Intestinal Environment and Cellular Plasticity of Islets in the Development of Postpancreatectomy Diabetes. (2021)
  • Author(s): Fukuda T, Bouchi R, Takeuchi T, Amo-Shiinoki K, Kudo A, Tanaka S, Tanabe M, Akashi T, Hirayama K, Odamaki T, Igarashi M, Kimura I, Tanabe K, Tanizawa Y, Yamada T, Ogawa Y
  • Journal Title: Diabetes Care Volume: 44(4) Issue: 4 Pages: 1002-1011
  • DOI: 10.2337/dc20-0864
  • Peer Reviewed / Open Access
• [Journal Article] Survey of Surgical Resections for Neuroendocrine Liver Metastases: A Project Study of the Japan Neuroendocrine Tumor Society (JNETS) (2021)
  • Author(s): Aoki Taku、Kubota Keiichi、Kiritani Sho、Arita Junichi、Morizane Chigusa、Masui Toshihiko、Kudo Atsushi、Komoto Izumi、Hatano Etsuro、Ito Tetsuhide、Osamura Robert Y、Unno Michiaki、Uemoto Shinji、Kokudo Norihiro、The Japanese Neuroendocrine Tumor Society (JNETS)
  • Journal Title: Journal of Hepato-Biliary-Pancreatic Sciences Volume: - Issue: 6 Pages: 489-497
  • DOI: 10.1002/jhbp.956
  • Peer Reviewed
• [Journal Article] Extraordinary first jejunal arterial variation associated with annular pancreas undergoing pancreaticoduodenectomy for pancreatic cancer: a case report (2021)
  • Author(s): Iwao Yasuhito、Ban Daisuke、Muro Satoru、Kudo Atsushi、Tanaka Shinji、Menon Krishna、Tanabe Minoru
  • Journal Title: Surgical and Radiologic Anatomy Volume: - Issue: 5 Pages: 805-810
  • DOI: 10.1007/s00276-020-02671-9
  • Peer Reviewed
• [Journal Article] Islet cell dedifferentiation is a pathologic mechanism of long-standing progression of type 2 diabetes. (2021)
  • Author(s): Amo-Shiinoki K, Tanabe K, Hoshii Y, Matsui H, Harano R, Fukuda T, Takeuchi T, Bouchi R, Takagi T, Hatanaka M, Takeda K, Okuya S, Nishimura W, Kudo A, Tanaka S, Tanabe M, Akashi T, Yamada T, Ogawa Y, Ikeda E, Nagano H, Tanizawa Y.
  • Journal Title: JCI Insight Volume: 6 Issue: 1 Pages: 143791-143791
  • DOI: 10.1172/jci.insight.143791
  • Peer Reviewed / Open Access
• [Journal Article] O6-methylguanine DNA methyltransferase and glucose transporter 2 in foregut and hindgut gastrointestinal neuroendocrine neoplasms (2020)
  • Author(s): Watanabe Hirofumi、Yamazaki Yuto、Fujishima Fumiyoshi、Izumi Komoto、Imamura Masayuki、Hijioka Susumu、Toriyama Kazuhiro、Yatabe Yasushi、Kudo Atsushi、Motoi Fuyuhiko、Unno Michiaki、Sasano Hironobu
  • Journal Title: BMC Cancer Volume: 20 Issue: 1 Pages: 1195-1195
  • DOI: 10.1186/s12885-020-07579-6
  • Peer Reviewed / Open Access
• [Journal Article] Dynamic Enhancement Pattern on CT for Predicting Pancreatic Neuroendocrine Neoplasms with Low PAX6 Expression: A Retrospective Observational Study (2020)
  • Author(s): Kimura Koichiro、Tsuchiya Junichi、Kitazume Yoshio、Kishino Mitsuhiro、Akahoshi Keiichi、Kudo Atsushi、Tanaka Shinji、Tanabe Minoru、Tateishi Ukihide
  • Journal Title: Diagnostics Volume: 10 Issue: 11 Pages: 919-919
  • DOI: 10.3390/diagnostics10110919
  • Peer Reviewed
• [Journal Article] An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping (2020)
  • Author(s): Kawasaki K、Toshimitsu K、Matano M、Fujita M、Kudo Atsushi、Kitagawa Y、Kanai T、Nakagawa H、Sato T, et.al.
  • Journal Title: Cell Volume: 183 Issue: 5 Pages: 1420-1435
  • DOI: 10.1016/j.cell.2020.10.023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Curative Surgery and Ki-67 Value Rather than Tumor Differentiation Predict the Survival of Patients with High-grade Neuroendocrine Neoplasms (2020)
  • Author(s): Asano Daisuke、Kudo Atsushi、Akahoshi Keiichi、Maekawa Aya、Murase Yoshiki、Ogawa Kosuke、Ono Hiroaki、Ban Daisuke、Tanaka Shinji、Tanabe Minoru
  • Journal Title: Annals of Surgery Volume: Publish Ahead of Print Issue: 2 Pages: e108-e113
  • DOI: 10.1097/sla.0000000000004495
  • Peer Reviewed
• [Journal Article] Long‐term safety and efficacy of lanreotide autogel in Japanese patients with neuroendocrine tumors: Final results of a phase II open‐label extension study (2020)
  • Author(s): Ito Tetsuhide、Fujimori Nao、Honma Yoshitaka、Kudo Atsushi、Hijioka Susumu、Katsushima Shinji、Kimura Yasutoshi、Fukutomi Akira、Hisamatsu Seiichi、Nakajima Akihiro、Shimatsu Akira
  • Journal Title: Asia-Pacific Journal of Clinical Oncology Volume: - Issue: 5
  • DOI: 10.1111/ajco.13371
  • Peer Reviewed / Open Access
• [Journal Article] Des-gamma-carboxy prothrombin affects the survival of HCC patients with marginal liver function and curative treatment: ACRoS1402 (2020)
  • Author(s): Kudo Atsushi、Association for Clinical Research on Surgery Group、Shinoda Masahiro、Ariizumi Shunichi、Kumamoto Takafumi、Katayama Masafumi、Otsubo Takehito、Endo Itaru、Kitagawa Yuko、Tanabe Minoru、Yamamoto Masakazu
  • Journal Title: Journal of Cancer Research and Clinical Oncology Volume: 146 Issue: 11 Pages: 2949-2956
  • DOI: 10.1007/s00432-020-03270-2
• [Journal Article] Diagnostic accuracy of selective arterial calcium injection test for localization of gastrinoma (2020)
  • Author(s): Hayashi R, Minami I, Sasahara Y, Izumiyama H, Yoshimoto T, Kishino M, Kudo A, Tateishi U, Tanabe M, Yamada T.
  • Journal Title: Endocrine Journal Volume: 67 Issue: 3 Pages: 305-315
  • DOI: 10.1507/endocrj.EJ19-0413
  • NAID: 130007821362
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed
• [Presentation] Cross-sectional study of genomic sequencing in HBP malignancies (2021)
  • Author(s): Hiroaki Ono,Sadakatsu Ikeda,Yoshiya Ishikawa,Shuichi Watanabe,Keiichi Akahoshi,Kosuke Ogawa,Daisuke Ban,Atsushi Kudo,Satoshi Miyake,Minoru Tanabe
  • Organizer: 第75回日本消化器外科学会総会
  • Int'l Joint Research
• [Presentation] Evaluation of laparoscopic distal pancreatectomy for pancreatic neuroecdocrine tumors (2021)
  • Author(s): Kohei Yagi,Atsushi Kudo, Aya Maekawa, Yoshiki Murase, Takeshi Ishii, Tomotaka Kato, Masafumi Sugawara, Yoshiya Ishikawa, Shuichi Watanabe, Keiichi Akahoshi, Kosuke Ogawa, Hiroaki Ono, Daisuke Ban, Shinji Tanaka, Minoru Tanabe
  • Organizer: The 32nd Meeting of Japanese Society of Hepato-Biliary-Pancreatic Surgery
  • Int'l Joint Research
• [Presentation] Iver resection after systemic chemotherapy improved overallsuvival of metastatic neuroendocrine neoplasms (2021)
  • Author(s): Keiichi Akahoshi, Yoshiya Ishikawa, Hiroki Ueda, Kosuke Ogawa, Hiroaki Ono, Atsushi Kudo, Shinji Tanaka, Minoru Tanabe
  • Organizer: The 32nd Meeting of Japanese Society of Hepato-Biliary-Pancreatic Surgery
  • Int'l Joint Research
• [Presentation] Combination of Weekly Streptozocin and Oral S-1 Treatment is e ective treatment for unresectable or metastatic pancreatic NET-G1 and NET-G2 patients (2021)
  • Author(s): Hiroaki Ono, Atsushi Kudo, Yoshiya Ishikawa, Hiroki Ueda, Keiichi Akahoshi, Kosuke Ogawa, Shinji Tanaka, Minoru Tanabe
  • Organizer: The 33rd Meeting of Japanese Society of Hepato-Biliary-Pancreatic Surgery
  • Int'l Joint Research
• [Presentation] The management of GEP-NET with MEN type 1 in our department (2021)
  • Author(s): Takeshi Ishii, Atsushi Kudo, Yoshiki Murase, Aya Maekawa, Toshitaka Sugawara, Yoshiya Ishikawa, Shuichi Watanabe, Hiroki Ueda, Keiichi Akahoshi, Kousuke Ogawa, Hiroaki Ono, Shinji Tanaka, Minoru Tanabe
  • Organizer: The 33rd Meeting of Japanese Society of Hepato-Biliary-Pancreatic Surgery
  • Int'l Joint Research