網羅的ctDNA変異解析モニタリングによる膵癌個別化集学的治療の開発

• Project/Area Number: 21K08803
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Hyogo Medical University
• Principal Investigator: 廣野 誠子 兵庫医科大学, 医学部, 教授 (60468288)
• Co-Investigator(Kenkyū-buntansha): 北畑 裕司 和歌山県立医科大学, 医学部, 講師 (00535338) ; 山上 裕機 和歌山県立医科大学, 医学部, 学長特命教員(特別顧問) (20191190) ; 川井 学 和歌山県立医科大学, 医学部, 教授 (40398459) ; 岡田 健一 和歌山県立医科大学, 医学部, 講師 (50407988) ; 宮澤 基樹 和歌山県立医科大学, 医学部, 博士研究員 (90549734)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 膵癌 / ctDNA変異解析

Outline of Research at the Start

膵癌患者の生存期間延長には、術前治療・外科的切除・術後補助療法による集学的治療が必須であり、術前治療の効果判定と切除後再発の早期診断が重要である。本研究は、膵癌患者を対象に、原発・転移巣から血中に循環するctDNA変異解析をモニタリングすることにより、①術前治療としてのGEM・nab-PTX併用療法の効果予測と効果判定、②外科的切除後再発の早期診断を行うことを目的とする。本研究では、膵癌患者の血漿から抽出したcell-free DNAを用いて、癌特異的に変異を認める197遺伝子の標的領域の変異を高感度に検出できるCAPP-Seqにより、ctDNA変異頻度を定量化する革新的な独自の方法で行う。

Outline of Annual Research Achievements

1)膵癌に対するgemcitabine (GEM)・nab-paclitaxel (nab-PTX)併用療法による術前化学療法の安全性と有効性の検討：われわれは、多施設共同前向き第Ⅱ相試験(NAC-GA trial)により、切除可能な膵癌に対する術前治療としてGEM・nab-PTX併用療法が安全で有効であることを証明した(AGSurg 2023)。
2)術前治療ならびに外科的切除の前後におけるcirculating cell-free tumor DNA (ctDNA)と生存期間の関係：GEM・nab-PTX併用療法による術前化学療法後に外科的切除を行った膵癌症例28例を対象に、術前治療前、術前治療後、手術後に血液を採取し、ctDNA変異解析のモニタリングを行った結果、術前治療前と術前治療後にctDNAを検出した症例と検出しなかった症例で生存期間に差は認めなかったが、手術後にctDNAを検出した症例は検出しなかった症例よりも有意に生存期間は不良であった。本結果から、膵癌患者の予後を規定する因子として術後ctDNA変異の評価が最も有用であることがわかった(Ann Surg Oncol 2022)。
3)外科的切除を受けた膵癌患者に対するCAPP-Seqによる術後ctDNA変異解析のモニタリグ：GEM・nab-PTX併用療法による術前化学療法後、外科的切除術を受けた膵癌症例28例を対象に、術後3ヶ月毎に採血を行い、ctDNA変異解析のモニタリングが術後再発の早期診断に有用であるかを現在検討中であるが、術後再発症例13例中8例において画像所見ならびに血清腫瘍マーカーCEAおよびCA19-9の上昇よりも早期にctDNA変異を検出しており、ctDNA変異解析のモニタリングが術後再発の早期診断に有用である可能性が高い。最終登録患者の術後2年の観察期間を経た2024年6月に解析し論文化する。

Research Products

• [Journal Article] Is multidisciplinary treatment effective for invasive intraductal papillary mucinous carcinoma? (2024)
  • Author(s): Hirono S, Higuchi R, Honda G, Nara S, Esaki M, Gotohda N, Takami H, Unno M, Sugiura T, Ohtsuka M, Shimizu Y, et al.
  • Journal Title: Ann Gastroenterol Surg Volume: - Issue: 5 Pages: 845-859
  • DOI: 10.1002/ags3.12790
  • Peer Reviewed / Open Access
• [Journal Article] Surgical Intervention After Lenvatinib Treatment in Patients With Advanced Hepatocellular Carcinoma (2024)
  • Author(s): OKUNO MASAYUKI、HATANO ETSURO、TADA MASAHARU、NISHIMURA TAKASHI、OKAMOTO TOMOHIRO、SUEOKA HIDEAKI、IIDA KENJIRO、NAKAMURA IKUO、IIJIMA HIROKO、HIRONO SEIKO
  • Journal Title: Anticancer Research Volume: 44 Issue: 4 Pages: 1727-1737
  • DOI: 10.21873/anticanres.16972
  • Peer Reviewed
• [Journal Article] A multi-institutional randomized phase III study comparing minimally invasive distal pancreatectomy versus open distal pancreatectomy for pancreatic cancer; Japan Clinical Oncology Group study JCOG2202 (LAPAN study) (2024)
  • Author(s): Ikenaga N, Hashimoto T, Mizusawa J, Kitabayashi R, Sano Y, Fukuda H, Nakata K, Shibuya K, Kitahata Y, Takada M, Kamei K, Kurahara H, Ban D, Kobayashi S, Nagano H, Imamura H, Unno M, Takahashi A, Yagi S, Wada H, Shirakawa H, Yamamoto N, Hirono S, et al.
  • Journal Title: BMC Cancer Volume: 24(1) Issue: 1 Pages: 231-231
  • DOI: 10.1186/s12885-024-11957-9
  • Peer Reviewed / Open Access
• [Journal Article] Subcutaneous emphysema associated with laparoscopic or robotic abdominal surgery: a retrospective single-center study (2024)
  • Author(s): Ito K, Kataoka K, Takenaka Y, Beppu N, Tsukasaki Y, Kohno K, Tsubamoto H, Shinohara H, Hirono S, Yamamoto S, Ikeuchi H, Ikeda M.
  • Journal Title: Surg Endosc Volume: 38(4) Issue: 4 Pages: 1969-1975
  • DOI: 10.1007/s00464-024-10701-5
  • Peer Reviewed
• [Journal Article] Radiographic duodenal invasion is associated with poor prognosis and early recurrence in patients with pancreatic ductal adenocarcinoma (2023)
  • Author(s): Miyazawa Motoki、Hirono Seiko、Kawai Manabu、Okada Ken-ichi、Kitahata Yuji、Motobayashi Hideki、Sato Masatoshi、Yoshimura Tomohiro、Ueno Masaki、Hayami Shinya、Miyamoto Atsushi、Shimizu Atsushi、Yamaue Hiroki
  • Journal Title: European Journal of Surgical Oncology Volume: 49 Issue: 10 Pages: 106960-106960
  • DOI: 10.1016/j.ejso.2023.06.012
  • Peer Reviewed
• [Journal Article] A comparative study between computed tomography and endoscopic ultrasound in the detection of a mural nodule in intraductal papillary mucinous neoplasm -Multicenter observational study in Japan (2023)
  • Author(s): Kin T, Shimizu Y, Hijioka S, Hara K, Katanuma A, Nakamura M, Yamada R, Itoi T, Ueki T, Masamune A, Hirono S, Koshita S, Hanada K, Kamata K, Yanagisawa A, Takeyama Y.
  • Journal Title: Pancreatology Volume: 23(5) Issue: 5 Pages: 550-555
  • DOI: 10.1016/j.pan.2023.05.010
  • Peer Reviewed
• [Journal Article] Autophagy Inhibition Increased Sensitivity of Pancreatic Cancer Cells to Carbon Ion Radiotherapy (2023)
  • Author(s): Sudo M, Tsutsui H, Hayashi S, Yasuda K, Mitani K, Iwami N, Anzai M, Tsubouchi T, Ishida M, Satoi S, Kanai T, Hirono S, Hatano E, Fujimoto J.
  • Journal Title: Cell Physiol Biochem Volume: 57(4) Issue: 4 Pages: 212-225
  • DOI: 10.33594/000000639
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of neoadjuvant nab-paclitaxel plus gemcitabine therapy in patients with borderline resectable pancreatic cancer: A multicenter single-arm phase II study (NAC-GA trial). (2023)
  • Author(s): Okada Ken‐ichi、Hirono Seiko、Kawai Manabu、Yamaue Hiroki、et al.
  • Journal Title: Annals of Gastroenterological Surgery Volume: 7 Issue: 6 Pages: 997-1008
  • DOI: 10.1002/ags3.12712
  • Peer Reviewed / Open Access
• [Journal Article] Is preoperative pancreatic juice cytology useful for determining therapeutic strategies for patients with intraductal papillary mucinous neoplasm of the pancreas? (2023)
  • Author(s): Nagayama Rintaro,Ueki Toshiharu,Shimizu Yasuhiro,Hijioka Susumu,Nakamura Masafumi、Kitano Masayuki、Hara Kazuo、Masamune Atsushi、Kin Toshifumi、Hanada Keiji、Koshita Shinsuke、Yamada Reiko、Takenaka Mamoru、Itoi Takao、Yanagisawa Akio、Otuka Takao、Hirono Seiko、Kanno Atsushi、Ideno Noboru、Kuwahara Takamichi、et al.
  • Journal Title: Journal of Hepato-Biliary-Pancreatic Sciences Volume: 31 Issue: 3 Pages: 183-192
  • DOI: 10.1002/jhbp.1394
  • Peer Reviewed
• [Journal Article] Protocol of the RACB study: a multicenter, single-arm, prospective study to evaluate the efficacy of resection of initially unresectable hepatocellular carcinoma with atezolizumab combined with bevacizumab (2023)
  • Author(s): Okuno M, Ishii T, Ichida A, Soyama A, Takemura N, Hirono S, Eguchi S, Hasegawa K, Sasaki Y, Uemura K, Kokudo N, Hatano E.
  • Journal Title: BMC Cancer Volume: 23(1) Issue: 1 Pages: 780-780
  • DOI: 10.1186/s12885-023-11302-6
  • Peer Reviewed / Open Access
• [Journal Article] Detection of Abdominal Lymph Node Metastasis from Pancreatic Neuroendocrine Tumor by Somatostatin Receptor Scintigraphy: Comparison with Somatostatin Receptor Type 2 Immunostaining (2023)
  • Author(s): Kitajima K, Shiomi H, Kihara T, Hirono S, Nakano R, Okamoto T, Yagi C, Eda H, Matsuda K, Hatano M, Yoshida M, Kono H, Hirota S, Minami T, Yamakado K.
  • Journal Title: Case Rep Oncol Volume: 16(1) Pages: 537-543
  • DOI: 10.1159/000531572
  • Peer Reviewed / Open Access
• [Journal Article] Features of T1 pancreatic cancer and validation of the eighth edition AJCC staging system definition using a Korean-Japanese joint cohort and the SEER database (2023)
  • Author(s): Kwon W, Heo JS, Han IW, Kang CM, Hwang HK, Kim SC, Park SJ, Yoon YS, Kim YH, Lim CS, Lee SY, Park T, Takami H, Watanabe N, Shimizu Y, Okuno M, Yamaue H, Kawai M, Hirono S, Nagakawa Y, Osakabe H, Sugiura T, Toyama H, Ohtsuka M, Unno M, Endo I, Kitago M, Jang JY.
  • Journal Title: J Hepatobiliary Pancreat Sci Volume: - Issue: 9 Pages: 1129-1140
  • DOI: 10.1002/jhbp.1316
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Radiological Shape of the Tumor Predicts Progression and Survival in Resected Extrahepatic Cholangiocarcinoma. (2023)
  • Author(s): Okada KI, Kawai M, Hirono S, Miyazawa M, Kitahata Y, Ueno M, Hayami S, Ikoma A, Sonomura T, Wan K, Shimokawa T, Yamaue H.
  • Journal Title: J Gastrointest Surg Volume: - Issue: 6 Pages: 1113-1121
  • DOI: 10.1007/s11605-023-05614-y
  • Peer Reviewed
• [Journal Article] Supervised Exercise Therapy and Adjuvant Chemotherapy for Pancreatic Cancer: A Prospective, Single-Arm, Phase II Open-Label, Nonrandomized, Historically Controlled Study. (2022)
  • Author(s): Okada KI, Kouda K, Kawai M, Hirono, S, Miyazawa M, Kitahata Y, Kawanishi M, Natsume Y, Wan K, Yamaue, H.
  • Journal Title: Journal of the American College of Surgeons Volume: 235 Issue: 6 Pages: 848-858
  • DOI: 10.1097/xcs.0000000000000408
  • Peer Reviewed
• [Journal Article] Positive drain fluid culture on postoperative day 1 predicts clinically relevant pancreatic fistula in early drain removal with higher drain fluid amylase after pancreaticoduodenectomy (2022)
  • Author(s): Kawai M, Okada KI, Miyazawa M, Kitahata Y, Motobayashi H, Ueno M, Hayami S, Miyamoto A, Hirono S, Yamaue H
  • Journal Title: Surgery Volume: 173 Issue: 2 Pages: 511-520
  • DOI: 10.1016/j.surg.2022.10.008
  • Peer Reviewed
• [Journal Article] Pancreatectomy With Artery En-bloc Resection for Pancreatic Neck/Body Cancer: A Single-arm Pilot Study. (2022)
  • Author(s): Okada KI, Kawai M, Hirono S, Hayami S, Miyazawa M, Kitahata Y, Ueno M, Kobayashi R, Miyamoto A, Wada Y, Asamura S, Yamaue H.
  • Journal Title: Anticancer Res. Volume: 42 Issue: 1 Pages: 217-227
  • DOI: 10.21873/anticanres.15476
  • Peer Reviewed
• [Journal Article] Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System (2022)
  • Author(s): Yachida Shinichi、Totoki Yasushi、Noe Michael 、Nakatani Yoichiro、Horie Masafumi、Kawasaki Kenta、Nakamura Hiromi、Saito-Adachi Mihoko、Suzuki Masami、Takai Erina、Hama Natsuko、Higuchi Ryota、Hirono Seiko、Shiba Satoshi、Sato Toshiro、Kiyono Tohru、Shibata Tatsuhiro、他25名
  • Journal Title: Cancer Discovery Volume: 12 Issue: 3 Pages: 692-711
  • DOI: 10.1158/2159-8290.cd-21-0669
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Circulating Tumor DNA as a Potential Prognostic Marker in Patients with Borderline-Resectable Pancreatic Cancer Undergoing Neoadjuvant Chemotherapy Followed by Pancreatectomy. (2022)
  • Author(s): Kitahata Y, Kawai M, Hirono S, Okada KI, Miyazawa M, Motobayashi H, Ueno M, Hayami S, Miyamoto A, Yamaue H.
  • Journal Title: Ann Surg Oncol. Volume: 29 Issue: 3 Pages: 1596-1605
  • DOI: 10.1245/s10434-021-10985-0
  • Peer Reviewed
• [Journal Article] Liquid biopsyが解き明かす膵癌における至適術式． (2022)
  • Author(s): 廣野誠子，山上裕機．
  • Journal Title: 胆と膵 Volume: 43 Pages: 67-70
• [Journal Article] Complete circumferential lymphadenectomy around the superior mesenteric artery with preservation of nerve plexus reduces locoregional recurrence after pancreatoduodenectomy for resectable pancreatic ductal adenocarcinoma. (2021)
  • Author(s): Hirono S, Kawai M, Okada KI, Miyazawa M, Kitahata Y, Kobayashi R, Hayami S, Ueno M, Yamaue H.
  • Journal Title: Eur J Surg Oncol. Volume: 47 Issue: 10 Pages: 2586-2594
  • DOI: 10.1016/j.ejso.2021.06.005
  • Peer Reviewed
• [Journal Article] Radiographic Splenic Artery Involvement Is a Poor Prognostic Factor in Upfront Surgery for Patients with Resectable Pancreatic Body and Tail Cancer. (2021)
  • Author(s): Kawai M, Hirono S, Okada KI, Miyazawa M, Kitahata Y, Kobayashi R, Ueno M, Hayami S, Yamaue H.
  • Journal Title: Ann Surg Oncol. Volume: 28 Issue: 3 Pages: 1521-1532
  • DOI: 10.1245/s10434-020-08922-8
  • Peer Reviewed
• [Journal Article] Advances in immunotherapy for pancreatic ductal adenocarcinoma. (2021)
  • Author(s): Miyazawa M, Katsuda M, Kawai M, Hirono S, Okada KI, Kitahata Y, Yamaue H
  • Journal Title: J Hepatobiliary Pancreat Sci Volume: 28 Issue: 5 Pages: 419-430
  • DOI: 10.1002/jhbp.944
  • Peer Reviewed
• [Journal Article] Malignant potential and specific characteristics of pure main duct type intraductal papillary mucinous neoplasm. (2021)
  • Author(s): Fujita Y, Hirono S, Kawai M, Okada KI, Miyazawa M, Kitahata Y, Ueno M, Hayami S, Kobayashi R, Yanagisawa A, Yamaue H
  • Journal Title: Eur J Surg Oncol Volume: 48 Issue: 5 Pages: 1054-1061
  • DOI: 10.1016/j.ejso.2021.11.137
  • Peer Reviewed
• [Presentation] Pancreas Surgery in Octogenarians (2024)
  • Author(s): Seiko Hirono
  • Organizer: HBP Surgery week 2024
  • Int'l Joint Research / Invited
• [Presentation] 膵癌術式に関する臨床試験 ーmesenteric approach vs. conventional approachー (2023)
  • Author(s): 廣野誠子
  • Organizer: 第54回日本膵臓学会
  • Invited
• [Presentation] Invasive IPMCに対する術後補助療法の 有用性に関する後ろ向き観察研究 (2023)
  • Author(s): 廣野誠子
  • Organizer: 第54回日本膵臓学会大会
  • Invited
• [Presentation] 手術先行切除可能膵癌の再発危険因子からみた切除可能膵癌の治療戦略 (2022)
  • Author(s): 廣野誠子、川井 学、岡田健一、宮澤基樹、北畑裕司、小林良平、速水晋也、宮本 篤、尾島敏康、勝田将裕、上野昌樹、山上裕機
  • Organizer: 第122回日本外科学会総会
• [Presentation] Surgical indication and optimal postoperative surveillance for IPMN. (2021)
  • Author(s): Hirono S., and Yamaue H
  • Organizer: The Asian-Pacific Hepato-Pancreato-Biliary Association (A-PHPBA) 2021 Bali Virtual Congress
  • Int'l Joint Research / Invited
• [Presentation] Risk factors of recurrence after up-front pancreatoduodenectomy for resectable pancreatic ductal adenocarcinoma. (2021)
  • Author(s): Hirono S., Kawai M., Okada KI., Miyazawa M., Kitahata Y., Kobayashi R., Hayami S., Ueno M., and Yamaue H
  • Organizer: International Association of Surgeons, Gastroenterologists, and Oncologists (IASGO) 2021
  • Int'l Joint Research / Invited
• [Presentation] Total mesopancreas excision with artery first approach for the treatment of pancreatic head cancer. (2021)
  • Author(s): Hirono S., and Yamaue H
  • Organizer: The 4th International Advanced Liver & Pancreas Surgery Symposium
  • Int'l Joint Research / Invited
• [Presentation] 再発危険因子からみた切除可能膵癌の治療戦略． (2021)
  • Author(s): 廣野誠子，川井 学，岡田健一，宮澤基樹，北畑裕司，上野昌樹，速水晋也，小林良平，宮本 篤，尾島敏康，勝田将裕，山上裕機．
  • Organizer: 第59回日本癌治療学会学術集会
• [Presentation] Pancreatic division at neck reduces pancreatic fistula after laparoscopic distal pancreatectomy compared to at body. (2021)
  • Author(s): 廣野誠子，川井 学，岡田健一，宮澤基樹，北畑裕司，小林良平，早田啓治，速水晋也，上野昌樹，山上裕機．
  • Organizer: Japanese Digestive Disease Week (JDDW) 2021
• [Presentation] 手術先行切除可能膵癌の再発危険因子からみた切除可能膵癌の治療戦略 (2021)
  • Author(s): 廣野誠子，川井 学，岡田健一，宮澤基樹，北畑裕司，上野昌樹，速水晋也，宮本 篤，小林良平，尾島敏康，勝田将裕，山上裕機
  • Organizer: 第83回日本臨床外科学会総会
• [Presentation] Invasive IPMCに対する術後補助療法の有用性に関する後ろ向き観察研究 (2021)
  • Author(s): 廣野誠子
  • Organizer: 第52回日本膵臓学会大会．東京（web参加），2021. 9
  • Invited
• [Presentation] 手術先行切除可能膵頭癌の再発危険因子からみた切除可能膵癌の治療戦略． (2021)
  • Author(s): 廣野誠子，川井 学，岡田健一，宮澤基樹，北畑裕司，小林良平，速水晋也，宮本 篤，上野昌樹，山上裕機．
  • Organizer: 第52回日本膵臓学会大会