肝胆膵外科学分野｜群馬大学大学院医学系研究科総合外科学講座

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研究

|　研究の背景

　肝胆膵領域の癌には難治性の癌腫が多く、疫学的にも増加傾向です。平成26年度の厚生統計要覧によれば、日本における年間死亡者数は肝臓癌約3万人、胆道癌約1万8千人、膵臓癌約3万人と報告されています。これらの癌腫の死亡率は発生率とほぼ同じであり、他の癌腫と比較して予後不良です。2016年1月に国立がん研究センターにより集計されたがんの部位別10年生存率は、肝臓癌15.3%、胆道癌19.7%、膵臓癌4.9%と、すべてのがんの全臨床病期の10年相対生存率58.2%と比べても極めて低い状況です。

|　主な研究テーマ

• 肝切除適応の確立　－肝機能評価の確立と肝切除の適応拡大－
• 系統的肝切除の確立　－安全で出血の少ない肝切除－
• 腹腔鏡下肝切除をより安全に行う工夫
• 全身合併症の評価と手術の安全性の確立
• 周術期におけるサルコペニアの意義
• 生体肝移植治療成績の向上
• IPMNの悪性度について
• 腹腔鏡下胆嚢摘出術の工夫
• 大腸癌肝転移の切除適応
• 肝切除におけるFunctional liver volumetryの検証：EOB-MRI法と99mTc-GSA scintigraphy-fusion analysis法の比較
• 肝悪性腫瘍の予後と血液凝固との関係

基礎的な研究のテーマとしては、癌関連線維芽細胞（CAF）やユビキチンリガーゼの一種でがん抑制因子と考えられているFBXW7、細胞房室-核輸送タンパクとしてがんの悪性度に関わるとされるKPNA2、細胞内シグナル伝達において重要とされるRAB5等に注目し、肝胆膵癌における新規バイオマーカーや治療戦略の開発を目指し、基礎研究に取り組んでいます。

• 肝癌・膵癌に対する肝・膵星細胞に注目した新しい治療戦略
• 肝再生とオートファジー
• 膵癌に対する新規免疫療法の開発－新規エピトープペプチドの同定－
• 膵発癌血清マーカーの開発
• 細胞質－核輸送タンパクに注目した新しい治療戦略と抗癌剤感受性の制御
• がん幹細胞に対する新たな治療戦略の確立

肝癌関連線維芽細胞を標的とした新規治療の開発

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膵癌進展におけるエンドソーム関連タンパクRAB5発現の意義

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胆管癌におけるNK細胞活性化型リガンド発現の意義

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細胞周期調節因子FBXW7の胆管癌、膵癌における意義

業績

|　和文論文・著書

1. 新木　健一郎、調　憲、齊藤　文良、桑野　博行. 外傷性胆汁漏の治療. 臨床外科71(7)821-825,2016
2. 新木　健一郎、調　憲、久保　憲生、渡辺　亮、五十嵐　隆通、塚越　真梨子、桑野　博行.　GIST肝転移. 臨床外科. 71(12)1366-1371, 2016
3. 調　憲、新木　健一郎、平井　圭太郎、久保　憲生、渡辺　亮、星野　弘毅、桑野　博行. 肝臓外科における周術期栄養管理の実際. 臨床栄養128(7)912-916, 2016
4. 調　憲、新木　健一郎、久保　憲生、播本　憲史、池上　徹、吉住　朋晴、伊藤　心二、桑野　博行、前原　喜彦. サルコペニアと外科. 臨床外科71(6)748-753, 2016
5. 齊藤　文良、新木　健一郎、石井　範洋、塚越　真梨子、渡辺　亮、久保　憲生、伊古田　勇人、調　憲、桑野　博行.IgG4関連硬化性胆管炎の組織所見を伴った下部胆管癌の1切除例.胆道30(5)864-869,2016
6. 調　憲、新木　健一郎、塚越　真梨子．肝疾患におけるサルコペニア研究の現状と今後の展開．日消誌 114:826-33, 2017.
7. 新木　健一郎、調　憲、塚越　真梨子、桑野　博行．肝胆膵がん患者における特有の栄養異常とサルコペニアを背景においた術前栄養管理の意義．栄養経営エキスパート2017:7:31-34.
8. 山中　崇弘、新木　健一郎、石井　範洋、塚越　真梨子、五十嵐　隆通、渡辺　亮、久保　憲生、大島　清宏、桑野　博行、調　憲．侵襲性クエブシエラ感染症の1救命例。日本腹部救急医学会雑誌37：931-4、2017．
9. 新木　健一郎、調　憲、久保　憲生、渡辺　亮、桑野　博行
   手術ステップごとに理解する標準術式アトラス：中央二区域切除. 臨床外科 72(7); 11:202-207. 2017
10. 五十嵐　隆通、新木　健一郎、山中　崇弘、萩原　慶、石井　範洋、塚越　真梨子、渡辺　亮、久保　憲生、播本　憲史、調　憲、桑野　博行、柴　慎太郎、入江　大介、岡本　雅彦、加藤　弘之、清原　浩樹、大野　達也、中野　隆史．局所進行膵癌に対するGemcitabine併用重粒子線治療．癌の臨床63(5)455-459, 2017
11. 調　憲、塚越　真梨子、播本　憲史．NASH/NAFLDにおけるサルコペニアの関与．肝胆膵　76(4)；576-581; 2018
12. 山中　崇弘、新木　健一郎、石井　範洋、塚越　真梨子、五十嵐　隆通、渡辺　亮、久保　憲生、播本　憲史、渋谷　圭、大島　清宏、桑野　博行、調　憲．集学的治療で救命し得た、肝膿瘍による門脈血栓症の1例。日本腹部救急医学会雑誌38(7)：1189-93． 2018．

|　英文論文・著書

1. Ishii N, Araki K, Yokobori T, Tsukagoshi M, Igarashi T, Watanabe A, Kubo N, Hirai K, Shirabe K, Kuwano H. Presence of Cytokeratin 19-Expressing Cholangiocarcinoma-Like Tumour in a Liver Metastatic Lesion of Rectal Neuroendocrine Tumour. Case Rep Gastroenterol. 2016 Aug 12;10(2):431-439.
2. Tsukagoshi M, Satoshi Wada, Takehiko Yokobori, Bolag Altan, Norihiro Ishii, Akira Watanabe, Norio Kubo, Fumiyoshi Saito, Kenichiro Araki, Hideki Suzuki, Yasuo Hosouchi, and Hiroyuki Kuwano. Overexpression of natural killer group 2 member D ligands Predicts favorable prognosis in cholangiocarcinoma. Cancer Science.107:116-122,2016
3. Tsukagoshi M, Hosouchi Y, Araki K, Mochida Y, Aihara R, Shirabe K, Kuwano H. Neuroendocrine tumor of the ampulla of Vater with distant cystic lymph node metastasis: a case report. Surg Case Rep. 2016 Dec;2(1):73.
4. Kubo N, Araki K, Kuwano H, Shirabe K. Cancer-associated fibroblasts in hepatocellular carcinoma. World J Gastroenterol. 2016 Aug 14;22(30):6841-50.
5. Watanabe A, Araki K, Hirai K, Kubo N, Igarashi T, Tsukagoshi M, Ishii N, Hoshino K, Kuwano H, Shirabe K. A Novel Clinical Factor, D-Dimer Platelet Multiplication, May Predict Postoperative Recurrence and Prognosis for Patients with Cholangiocarcinoma. Ann Surg Oncol. 2016 Dec;23(Suppl 5):886-891.
6. Araki K, Fuks D, Nomi T, Ogiso S, Lozano RR, Kuwano H, Gayet B. Feasibility of laparoscopic liver resection for caudate lobe: technical strategy and comparative analysis with anteroinferior and posterosuperior segments. Surg Endosc. 2016 Oct;30(10).
7. Saito F, Araki K, Yokobori T, Ishii N, Tsukagoshi M, Watanabe A, Kubo N, Altan B, Shirabe K, Kuwano H. High expression of karyopherin-α2 and stathmin 1 is associated with proliferation potency and transformation in the bile duct and gall bladder epithelia in the cases of pancreaticobiliary maljunction. J Surg Oncol. 2016 Sep;114(4):462-8.
8. Igarashi T, Araki K, Yokobori T, Altan B, Yamanaka T, Ishii N, Tsukagoshi M, Watanabe A, Kubo N, Handa T, Hosouchi Y, Nishiyama M, Oyama T, Shirabe K, Kuwano H. Association of RAB5 overexpression in pancreatic cancer with cancer progression and poor prognosis via E-cadherin suppression. Oncotarget. 2017 Jan 17. doi: 10.18632/oncotarget.14703. [Epub ahead of print]
9. Tsukagoshi M, Araki K, Yokobori T, Altan B, Suzuki H, Kubo N, Watanabe A, Ishii N, Hosouchi Y, Nishiyama M, Shirabe K, Kuwano H. Overexpression of karyopherin-a2 in cholangiocarcinoma correlates with poor prognosis and gemcitabine sensitivity via nuclear translocation of DNA repair proteins. Oncotarget. 2017 Feb 2. doi: 10.18632/oncotarget.15020. [Epub ahead of print]
10. Kubo N, Araki K, Yamanaka T, Hoshino K, Ishii N, Tsukagoshi M, Igarashi T, Watanabe A, Hirai K, Saitoh F, Kuwano H, Shirabe K. Perioperative management of hepatectomy in patients with interstitial pneumonia: a report of three cases and a literature review. Surg Today. 2017 Mar 1. doi: 10.1007/s00595-017-1489-7. [Epub ahead of print] Review.
11. Muranushi R, Suzuki M, Araki K, Kubo N, Otake S, Nishida Y, Ishige T, Arakawa H, Kuwano H, Shirabe K.Successful hepatectomy for hepatic abscess with chronic granulomatous disease: a case report.　Surg Case Rep. 2017 Dec;3(1):57. doi: 10.1186/s40792-017-0333-z. Epub 2017 Apr 26.　PMID:28447322.
12. Kubo N, Araki K, Altan B, Hoshino K, Ishii N, Tsukagoshi M, Igarashi T, Watanabe A, Kato T, Hirai K, Yokobori T, Saito F, Suzuki H, Kuwano H, Shirabe K.　Enhanced karyopherin-α2 expression is associated with carcinogenesis in patients with intraductal papillary mucinous neoplasms.　Pancreatology. 2017 Apr 23. pii: S1424-3903(17)30077-7. doi: 10.1016/j.pan.2017.04.011. [Epub ahead of print]
13. Watanabe A, Araki K, Yokobori T, Altan B, Ishii N, Tsukagoshi M, Kubo N, Saito F, Suzuki H, Kuwano H.　Stathmin 1 promotes the proliferation and malignant transformation of pancreatic intraductal papillary mucinous neoplasms.　Oncol Lett. 2017 Mar;13(3):1783-1788. doi: 10.3892/ol.2017.5603. Epub 2017 Jan 17
14. Ishii N, Araki K, Yokobori T, Watanabe A, Tsukagoshi M, Kubo N, Suzuki H, Saito F, Altan B, Hosouchi Y, Shirabe K, Kuwano H. Poor prognosis in cholangiocarcinoma patients with low FBXW7 expression is improved by chemotherapy. Oncol Lett. 2017 May;13(5):3653-3661.
15. Uchiyama H, Shirabe K, Araki K, Sugimachi K, Morita K, Takenaka K, Maehara Y. Left hepatectomy with simultaneous hepatic artery and portal vein reconstructions in the operation for cholangiocarcinoma: the surgical techniques comprised of step-by-step established procedures. Transl Gastroenterol Hepatol. 2017 Apr 28;2:34. doi: 10.21037/tgh.2017.03.16. eCollection 2017.
16. Yamanaka T, Araki K, Ishii N, Tsukagoshi M, Igarashi T, Watanabe A, Kubo N, Kuwano H, Shirabe K. Carcinoma of the Papilla of Vater after Diversion Operation for Pancreaticobiliary Maljunction. Case Rep Gastroenterol. 2017 May 17;11(2):265-270. doi: 10.1159/000462967. eCollection 2017 May-Aug.
17. Tsukagoshi M, Araki K, Saito F, Kubo N, Watanabe A, Igarashi T, Ishii N, Yamanaka T, Shirabe K, Kuwano H.　Evaluation of the International Consensus Guidelines for the Surgical Resection of Intraductal Papillary Mucinous Neoplasms. Dig Dis Sci. 2017 Jun 30. doi: 10.1007/s10620-017-4667-y. [Epub ahead of print]
18. Ishii N, Araki K, Yamanaka T, Handa T, Tsukagoshi M, Igarashi T, Watanabe A, Kubo N, Aishima S, Kuwano H, Shirabe K. Small cholangiolocellular carcinoma that was difficult to distinguish from cholangiocellular carcinoma: a case report. Surg Case Rep. 2017 Sep 15;3(1):103. doi: 10.1186/s40792-017-0377-0.
19. Araki K, Shirabe K, Watanabe A, Kubo N, Sasaki S, Suzuki H, Asao T, Kuwano H. Risk factors for an additional port in single-incision laparoscopic cholecystectomy in patients with cholecystitis. J Med Invest. 2017;64(3.4):245-249.
20. Yazawa T, Watanabe A, Araki K, Segawa A, Hirai K, Norio Kubo N, Igarashi T, Tsukagoshi M, Ishii N, Hoshino K, Kuwano H, Shirabe K. Complete resection of a huge pancreatic undifferentiated carcinoma with osteoclast-like giant cells.　International Cancer Conference Journal October 2017, Volume 6, Issue 4, pp 193–196.
21. Araki K, Kubo N, Watanabe A, Kuwano H, Shirabe K. Systematic review of the feasibility and future of laparoscopic liver resection for difficult lesions.
    Surg Today. 2017 Nov 13. doi: 10.1007/s00595-017-1607-6. Review.
22. Kenichiro Araki, Claudius Conrad.
    Section 2-15: Intraoperative laparoscopic ultrasound for laparoscopic hepatopancreatobiliary surgery. Laparoscopic Liver, Pancreas, and Biliary Surgery, Claudius Conrad, Brice Gayet, eds.
    John Wiley & Sons Ltd, Hoboken(NJ), p231-237, 2017
23. Yamanaka T, Araki K, Hagiwara K, Ishii N, Tsukagoshi M, Igarashi T, Watanabe A, Kubo N, Kuwano H, Shirabe K. Internal Hernia into the Treitz Fossa after Pancreaticoduodenectomy.
    Case Rep Gastroenterol. 2017 Oct 30;11(3):643-646.
24. Ishii N, Araki K, Yokobori T, Gantumur D, Yamanaka T, Altan B, Tsukagoshi M, Igarashi T, Watanabe A, Kubo N, Hosouchi Y, Kuwano H, Shirabe K.　Reduced FBXW7 expression in pancreatic cancer correlates with poor prognosis and chemotherapeutic resistance via accumulation of MCL1.　Oncotarget. 2017 Nov 6;8(68):112636-112646.
25. Shirabe K, Bekki Y, Gantumur D, Araki K, Ishii N, Kuno A, Narimatsu H, Mizokami M.　Mac-2 binding protein glycan isomer (M2BPGi) is a new serum biomarker for assessing liver fibrosis: more than a biomarker of liver fibrosis.　J Gastroenterol. 2018 Jan 9. doi: 10.1007/s00535-017-1425-z. [Epub ahead of print] Review
26. Shirabe K, Eguchi S, Okajima H, Hasegawa K, Marubashi S, Umeshita K, Kawasaki S, Yanaga K, Shimada M, Kaido T, Kawagishi N, Taketomi A, Mizuta K, Kokudo N, Uemoto S, Maehara Y; Japanese Liver Transplantation Society.　Current status of surgical incisions used in donors during living related liver transplantation - a nationwide survey in Japan.　Transplantation. 2018 Feb 9. doi: 10.1097/TP.0000000000002126. [Epub ahead of print]
27. Araki K, Kubo N, Ishii N, Tsukagoshi M, Igarashi T, Watanabe A, Kuwano H, Shirabe K.　Left Lobe Mobilization Strategy of Right-Sided Major Hepatectomy for Treatment of a Tumor Causing Severe Inferior Vena Cava Compression: A Novel Strategy Using the Modified Liver-Hanging Maneuver.　Ann Surg Oncol. 2018 Feb 14. doi: 10.1245/s10434-018-6362-4. [Epub ahead of print]
28. Watanabe A, Araki K, Harimoto N, Kubo N, Igarashi T, Ishii N, Yamanaka T, Hagiwara K, Kuwano H, Shirabe K.D-dimer predicts postoperative recurrence and prognosis in patients with liver metastasis of colorectal cancer.　Int J Clin Oncol. 2018 Mar 24. doi: 10.1007/s10147-018-1271-x. [Epub ahead of print]
29. Watanabe T, Araki K, Ishii N, Igarashi T, Watanabe A, Kubo N, Kuwano H, Shirabe K.　A Surgically Resected Pancreatic Schwannoma with Obstructive Jaundice with Special Reference to Differential Diagnosis from Other Cystic Lesions in the Pancreas. Case Rep Gastroenterol. 2018 Feb 21;12(1):85-91.
30. Hagiwara K, Araki K, Yamanaka T, Ishii N, Igarashi T, Watanabe A, Kubo N, Harimoto N, Kuwano H, Nobusawa S, Aishima S, Shirabe K.　Resected primary mucinous cholangiocarcinoma of the liver.　Surg Case Rep. 2018 May 2;4(1):41. doi: 10.1186/s40792-018-0450-3.
31. Kubo N, Harimoto N, Shibuya K, Ishii N, Tsukagoshi M, Igarashi T, Watanabe A, Araki K, Miyazaki M, Kuwano H, Shirabe K. Successful treatment of isolated bile leakage after hepatectomy combination therapy with percutaneous transhepatic portal embolization and bile duct ablation with ethanol: a case report.　Surg Case Rep. 2018 Jun 19;4(1):61. doi: 10.1186/s40792-018-0463-y.
32. Harimoto N, Yoshizumi T, Inokuchi S, Itoh S, Adachi E, Ikeda Y, Uchiyama H, Utsunomiya T, Kajiyama K, Kimura K, Kishihara F, Sugimachi K, Tsujita E, Ninomiya M, Fukuzawa K, Maeda T, Shirabe K, Maehara Y.　Prognostic Significance of Preoperative Controlling Nutritional Status (CONUT) Score in Patients Undergoing Hepatic Resection for Hepatocellular Carcinoma: A Multi-institutional Study.　Ann Surg Oncol. 2018 Jul 26. doi: 10.1245/s10434-018-6672-6. [Epub ahead of print]
33. Harimoto N, Hoshino H, Muranushi R, Hagiwara K, Yamanaka T, Ishii N, Tsukagoshi M, Igarashi T, Watanabe A, Kubo N, Araki K, Shirabe K. Skeletal Muscle Volume and Intramuscular Adipose Tissue Are Prognostic Predictors of Postoperative Complications After Hepatic Resection. Anticancer Res. 2018 Aug;38(8):4933-39.
34. Harimoto N, Hagiwara K, Yamanaka T, Ishii N, Igarashi T, Watanabe A, Kubo N, Araki K, Ikota H, Suyama M, Maki T, Aishima S, Kuwano H, Shirabe K.　Fairly rare clear cell adenocarcinoma mimicking liver cancer: a case report.　Surg Case Rep. 2018 Aug 16;4(1):97. doi: 10.1186/s40792-018-0500-x.
35. Tsukagoshi M, Wada S, Hirono S, Yoshida S, Yada E, Sasada T, Shirabe K, Kuwano H, Yamaue H.Identification of a novel HLA-A24-restricted cytotoxic T lymphocyte epitope peptide derived from mesothelin in pancreatic cancer. Oncotarget. 2018 Jul 31;9(59):31448-31458. doi: 10.18632/oncotarget.25837. eCollection 2018 Jul 31.
36. Kubo N, Harimoto N, Araki K, Hagiwara K, Yamanaka T, Ishii N, Tsukagoshi M, Igarashi T, Watanabe A, Miyazaki M, Yokoo H, Kuwano H, Shirabe K.　The Feature of Solitary Small Nodular Type of Hepatic Epithelioid Hemangioendothelioma.　Case Rep Gastroenterol. 2018 Aug 21;12(2):402-410.
37. Watanabe A, Harimoto N, Araki K, Yoshizumi T, Arima K, Yamashita Y, Baba H, Tetsuya H, Kuwano H, Shirabe K. A new strategy based on fluorodeoxyglucose-positron emission tomography for managing liver metastasis from colorectal cancer. J Surg Oncol. 2018 Sep 27. doi: 10.1002/jso.25250.
38. Ishii N, Araki K, Yokobori T, Hagiwara K, Dorgormaa G, Yamanaka T, Handa T, Tsukagoshi M, Igarashi T, Watanabe A, Kubo N, Harimoto N, Masamune A, Umezawa K, Kuwano H, Shirabe K.
    Conophylline suppresses pancreatic cancer desmoplasia and cancer-promoting cytokines produced by cancer-associated fibroblasts.
    Cancer Sci. 2018 Oct 24. doi: 10.1111/cas.13847.
39. Watanabe A, Harimoto N, Araki K, Kubo N, Igarashi T, Tsukagoshi M, Ishii N, Yamanaka T, Yoshizumi T, Shirabe K.
    Absolute Neutrophil Count Predicts Postoperative Prognosis in Mass-forming Intrahepatic Cholangiocarcinoma.
    Anticancer Res. 2019 Feb;39(2):941-947. doi: 10.21873
40. Harimoto N, Hoshino K, Muranushi R, Hagiwara K, Yamanaka T, Ishii N, Tsukagoshi M, Igarashi T, Tanaka H, Watanabe A, Kubo N, Araki K, Tomonaga H, Higuchi T, Tsushima Y, Shirabe K.
    Impact of Metabolic Parameters of 18F-Fluorodeoxyglucose Positron-emission Tomography After Hepatic Resection in Patients With Intrahepatic Cholangiocarcinoma.
    Anticancer Res. 2019 Feb;39(2):971-977. doi: 10.21873