血漿マイクロRNAを用いた大腸癌肝転移Precision Medicineの構築

2017 Fiscal Year Research-status Report

• Project/Area Number: 16K10573
• Research Institution: Okayama University
• Principal Investigator: 楳田 祐三 岡山大学, 大学病院, 講師 (10573735)
• Co-Investigator(Kenkyū-buntansha): 藤原 俊義 岡山大学, 医歯薬学総合研究科, 教授 (00304303) ; 八木 孝仁 岡山大学, 大学病院, 教授 (00304353) ; 永坂 岳司 川崎医科大学, 医学部, 准教授 (30452569)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 大腸癌肝転移

Outline of Annual Research Achievements

1. 大腸癌原発巣・肝転移サンプル解析、およびGenetic/Epigenetic解析：これまで岡山大学病院 消化管外科・肝胆膵外科にて手術された進行大腸癌・転移性肝癌の切除標本より収集された組織サンプルからのDNA抽出を全て完了しGenetic/Epigenetic解析を行った。

2. 循環miRNAの産生形態を証明するための実験アッセイ確立：能動的に活性腫瘍細胞より放出されたExtracellular vesicle 膜小胞パッケージ（EV-miRNA）と、抗癌剤により細胞死から受動放出されたあるアルゴネイチャーファミリーと結合したAGO2-miRNAの産生形態を証明する実験として、大腸がん細胞株を用いた抗癌剤投与下でのcell viability評価、LDH assay,miRNA測定の実験系を確立した。

3. Liquid biopsy：大腸癌集学的治療の経過中における採血サンプルを用いてEV-miRNA/AGO2-miRNAを測定し、臨床Eventと併せ評価することで、精緻な腫瘍病勢評価が可能であることを証明し、臨床応用への道筋をつけた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

前年度から継続してきたサンプル集積と実験結果は蓄積されてきており、解析と考察も順調に進んでいる。
論文投稿に向けて、総括を行っている段階であり、最終年度内の論文受領を目標に、順調に研究は進んでいる。

Strategy for Future Research Activity

前年度から継続してきたサンプル集積と実験結果は蓄積されてきており、解析と考察も順調に進んでいる。
研究総括を踏まえ設立したPrecision medicineを臨床現場に応用すべく、学術論文に投稿し、情報発信を企図している。
論文投稿については、査読後の追加実験に備え、予備実験も適宜進めていく予定である（具体例：抗ヒトAgo2抗体を用いて、血漿からAgo2蛋白を抽出し、Western blottingによるAgo2蛋白同定を予定）。

Causes of Carryover

大腸癌原発巣・肝転移サンプル収集・及びGenetic/Epigenetic解析を行う中で、リアルタイムPCR, 細胞培養に用いる試薬・抗体購入を予定していたが、予定していたよりも少ない量で順調に実験結果が得られたために、次年度繰り越し金を生じた。
（使用計画）
今後、論文査読の中で生じる追加実験（基礎実験、in vivo実験）の実施にあたり費用がかかるために、繰り越し研究費を充てる予定である。

Research Products

• [Journal Article] BRAF V600E mutation is a predictive indicator of upfront chemotherapy for stage IV colorectal cancer. (2018)
  • Author(s): Morikawa T, Inada R, Nagasaka T, Mori Y, Kishimoto H, Kawai T, Umeda Y, Mishima H, Goel A, Fujiwara T.
  • Journal Title: Oncol Lett. Volume: 15(2) Pages: 2195-2201
  • DOI: 10.18926/AMO/56374
  • Peer Reviewed / Open Access
• [Journal Article] Clinical outcomes of women with ovarian metastases of colorectal cancer treated with oophorectomy with respect to their somatic mutation profiles. (2018)
  • Author(s): Mori Y, Nyuya A, Yasui K, Toshima T, Kawai T, Taniguchi F, Kimura K, Inada R, Nishizaki M, Haraga J, Nakamura K, Umeda Y, Kishimoto H, Fujiwara T, Katata Y, Yamaguchi Y, Nagasaka T.
  • Journal Title: Oncotarget Volume: 27;9(23) Pages: 16477-16488
  • DOI: 10.18632/oncotarget.24735
  • Peer Reviewed / Open Access
• [Journal Article] Effect of an enhanced recovery after surgery protocol in patients undergoing pancreaticoduodenectomy: A randomized controlled trial. (2018)
  • Author(s): Takagi K, Yoshida R, Yagi T, Umeda Y, Nobuoka D, Kuise T, Hinotsu S, Matsusaki T, Morimatsu H, Eguchi J, Wada J, Senda M, Fujiwara T.
  • Journal Title: Clinical Nutrition Volume: in press Pages: in press
  • DOI: 10.1016/j.clnu.2018.01.002.
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of outcomes between symptomatic and asymptomatic patients with colorectal cancer: a propensity score-matched analysis of surgical invasiveness, medical costs and oncological outcomes. (2018)
  • Author(s): Inada R, Nagasaka T, Watanabe A, Yagi T, Mori Y, Kondo Y, Kishimoto H, Umeda Y, Fujiwara T.
  • Journal Title: BMJ Open Gastroenterol. Volume: 3;4(1) Pages: e000146.
  • DOI: 10.1136/bmjgast-2017-000146.
  • Peer Reviewed / Open Access
• [Journal Article] Living Donor Liver Transplantation for Acute Liver Failure : Comparing Guidelines on the Prediction of Liver Transplantation. (2017)
  • Author(s): Yoshida K, Umeda Y, Takaki A, Nagasaka T, Yoshida R, Nobuoka D, Kuise T, Takagi K, Yasunaka T, Okada H, Yagi T, Fujiwara T.
  • Journal Title: Acta Med Okayama Volume: 71(5) Pages: 381-390
  • DOI: 10.3892/ol.2017.7553.
  • Peer Reviewed / Open Access
• [Journal Article] A novel intestinal rotation method for digestive reconstruction after combined pancreaticoduodenectomy and extended right hemicolectomy: A case report and surgical technique. (2017)
  • Author(s): Takagi K, Yagi T, Umeda Y, Yoshida R, Nobuoka D, Kuise T, Kumano K, Kojima T, Fushimi T, Fujiwara T.
  • Journal Title: Int J Surg Case Rep Volume: 39 Pages: 51-55
  • DOI: 10.1016/j.ijscr.2017.07.063.
  • Peer Reviewed / Open Access
• [Journal Article] Primary pancreatic-type acinar cell carcinoma of the jejunum with tumor thrombus extending into the mesenteric venous system: a case report and literature review. (2017)
  • Author(s): Takagi K, Yagi T, Tanaka T, Umeda Y, Yoshida R, Nobuoka D, Kuise T, Fujiwara T.
  • Journal Title: BMC Surg Volume: 17(1): Pages: 75.
  • DOI: 10.1186/s12893-017-0273-3.
  • Peer Reviewed / Open Access
• [Journal Article] Radiographic sarcopenia predicts postoperative infectious complications in patients undergoing pancreaticoduodenectomy. (2017)
  • Author(s): Takagi K, Yoshida R, Yagi T, Umeda Y, Nobuoka D, Kuise T, Fujiwara T.
  • Journal Title: BMC Surg Volume: 26;17(1) Pages: 64.
  • DOI: 10.1186/s12893-017-0261-7.
  • Peer Reviewed / Open Access
• [Journal Article] Preoperative Controlling Nutritional Status (CONUT) Score for Assessment of Prognosis Following Hepatectomy for Hepatocellular Carcinoma. (2017)
  • Author(s): Takagi K, Yagi T, Umeda Y, Shinoura S, Yoshida R, Nobuoka D, Kuise T, Araki H, Fujiwara T.
  • Journal Title: World J Surg. Volume: 41(9) Pages: 2353-2360
  • DOI: 10.1007/s00268-017-3985-8.
  • Peer Reviewed / Open Access
• [Journal Article] Early Chimerism After Liver Transplantation Reflects the Clinical Course of Recurrent Hepatitis C. (2017)
  • Author(s): Utsumi M, Takaki A, Umeda Y, Koike K, Napier SC, Watanabe N, Shinoura S, Yoshida R, Nobuoka D, Yasunaka T, Oto T, Araki M, Yamamoto K, Fujiwara T, Yagi T.
  • Journal Title: Annals of Transplantation. Volume: 24;22 Pages: 156-165
  • Peer Reviewed / Open Access
• [Journal Article] Predictive biomarkers for the efficacy of peptide vaccine treatment: based on the results of a phase II study on advanced pancreatic cancer. (2017)
  • Author(s): Shindo Y, Hazama S, Suzuki N, Iguchi H, Uesugi K, Tanaka H, Aruga A, Hatori T, Ishizaki H, Umeda Y, Fujiwara T, Ikemoto T, Shimada M, Yoshimatsu K, Takenouchi H, Matsui H, Kanekiyo S, Iida M, Koki Y, Arima H, Furukawa H, Ueno T, Yoshino S, Fujita T, Kawakami Y, Nakamura Y, Oka M, Nagano H.
  • Journal Title: J Exp Clin Cancer Res. Volume: 28;36(1) Pages: 36.
  • DOI: 10.1186/s13046-017-0509-1.
  • Peer Reviewed / Open Access
• [Journal Article] Safety and Efficacy of Small Bowel Examination by Capsule Endoscopy for Patients before Liver Transplantation. (2017)
  • Author(s): Seiji K, Akinobu T, Masaya I, Tetsuya Y, Yoshiyasu K, Kou M, Toshihiro I, Yoshiro K, Yuzo U, Takahito Y, Hiroyuki O.
  • Journal Title: Biomed Res Int. Volume: 2017: Pages: 8193821
  • DOI: 10.1155/2017/8193821.
  • Peer Reviewed
• [Journal Article] Syndrome of Inappropriate Antidiuretic Hormone Secretion Following Liver Transplantation. (2017)
  • Author(s): Takagi K, Yagi T, Shinoura S, Umeda Y, Yoshida R, Nobuoka D, Watanabe N, Kuise T, Fuji T, Araki H, Fujiwara T.
  • Journal Title: Acta Med Okayama. Volume: 71(1) Pages: 85-89
  • DOI: 10.18926/AMO/54830
  • Peer Reviewed
• [Journal Article] Phase II clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS-PC study. (2017)
  • Author(s): Suzuki N, Hazama S, Iguchi H, Uesugi K, Tanaka H, Hirakawa K, Aruga A, Hatori T, Ishizaki H, Umeda Y, Fujiwara T, Ikemoto T, Shimada M, Yoshimatsu K, Shimizu R, Hayashi H, Sakata K, Takenouchi H, Matsui H, Shindo Y, Iida M, Koki Y, Arima H, Furukawa H, Ueno T, Yoshino S, Nakamura Y, Oka M, Nagano H.
  • Journal Title: Cancer Sci. Volume: 108(1) Pages: 73-80
  • DOI: 10.1111/cas.13113.
  • Peer Reviewed / Open Access
• [Presentation] Gene expression profiles in BRAF V600E mutant colorectal cancer and association with SFRP2 methylation status (2017)
  • Author(s): Yasui K, Nagasaka T, ToshimaT, Kawai T, Shigeyasu K, Mori Y, Haraga J, Nakamura K, Umeda Y, Tazawa H, Goel A, Fujiwara T
  • Organizer: AACR Annual Meeting 2017, Washington, D.C.
  • Int'l Joint Research
• [Presentation] 遺伝子変異情報に基づいた大腸癌肝転移の治療戦略―原発巣の左右局在とRAS/RAF 変異の意義― (2017)
  • Author(s): 楳田祐三, 永坂岳司, 母里淑子, 吉田龍一, 信岡大輔, 杭瀬 崇, 藤 智和, 河合 毅, 荒木宏之, 八木孝仁, 藤原俊義
  • Organizer: 第117回日本外科学会定期学術集会, 横浜
• [Presentation] StageIV大腸癌に対するPrecision Medicineの構築 (2017)
  • Author(s): 河合 毅, 永坂岳司, 母里淑子, 楳田祐三, 稲田 涼, 谷口文崇, 安井和也, 戸嶋俊明, 岸本浩行, 藤原俊義
  • Organizer: 第117回日本外科学会定期学術集会, 横浜
• [Presentation] Radical distal pancreatectomy with en block celiac axis resection and retroperitoneal dissection for advanced pancreatic cancer (2017)
  • Author(s): Umeda Y, Yagi T, Yoshida R, Nobuoka D, Kuise T, Koujima T, Kumano K, Takagi K, Araki H, Kajioka H, Fujiwara T
  • Organizer: Joint Congress of The 6th Biennial Congress of the Asian-Pacific Hepato-Pancreato-Biliary Association & The 29th Meeting of Japanese Society of Hepato-Biliary-Pancreatic Surgery, Yokohama
  • Int'l Joint Research
• [Presentation] Clinical significance of radical lymphadenectomy for intrahepatic cholangiocarcinoma - analysis based on tumor location and recurrence pattern - (2017)
  • Author(s): Kuise T, Umeda Y, Yoshida R, Nobuoka D, Kumano K, Koujima T, Takagi K, Araki H, Kajioka H, Fujiwara T, Yagi T
  • Organizer: Joint Congress of The 6th Biennial Congress of the Asian-Pacific Hepato-Pancreato-Biliary Association & The 29th Meeting of Japanese Society of Hepato-Biliary-Pancreatic Surgery, Yokohama
  • Int'l Joint Research
• [Presentation] Hepatectomy for multiple colorectal liver metastasis - precise tumor removal and parenchymal sparing - (2017)
  • Author(s): Kajioka H, Umeda Y, Yoshida R, Nagasaka T, Nobuoka D, Kuise T, Koujima T, Kumano K, Araki H, Fujiwara T, Yagi T
  • Organizer: Joint Congress of The 6th Biennial Congress of the Asian-Pacific Hepato-Pancreato-Biliary Association & The 29th Meeting of Japanese Society of Hepato-Biliary-Pancreatic Surgery, Yokohama
  • Int'l Joint Research
• [Presentation] Surgical approach to cirrhotic patients with hepatocellular carcinoma: splenectomy ameliorates liver function which could expand the chance of hepatectomy (2017)
  • Author(s): Koujima T, Umeda Y, Watanabe N, Yoshida R, Nobuoka D, Kuise T, Kumano K, Takagi K, Araki H, Fujiwara T, Yagi T
  • Organizer: Joint Congress of The 6th Biennial Congress of the Asian-Pacific Hepato-Pancreato-Biliary Association & The 29th Meeting of Japanese Society of Hepato-Biliary-Pancreatic Surgery, Yokohama
  • Int'l Joint Research
• [Presentation] Ovarian metastasectomy in colorectal cancer may improve the clinical outcomes of patients with metastatic colorectal cancer regardless of BRAF or KRAS mutational profiles (2017)
  • Author(s): Mori Y, Nagasaka T, Tanioka H, Nyuya A, Kawai T, Toshima T, Yasui K, Shigeyasu K, Kishimoto H, Umeda Y, Fujiwara T
  • Organizer: ESMO 19th World Congress on Gastrointestinal Cancer, Barcelona, Spain
  • Int'l Joint Research
• [Presentation] 大腸癌多発肝転移におけるRAS/RAF変異の意義～生物学的悪性度から術前化学療法適応を見極める～ (2017)
  • Author(s): 楳田祐三, 八木孝仁, 永坂岳司, 吉田龍一, 信岡大輔, 母里淑子, 杭瀬 崇, 高木弘誠, 河合 毅, 藤原俊義
  • Organizer: 第72回日本消化器外科学会総会, 金沢
• [Presentation] 局所進行直腸癌に対する術前化学療法の有用性 (2017)
  • Author(s): 母里淑子, 永坂岳司, 河合 毅, 重安邦俊, 矢野修也, 近藤喜太, 楳田祐三, 岸本浩行, 藤原俊義
  • Organizer: 第72回日本消化器外科学会総会, 金沢
• [Presentation] Gene expression signatures in BRAF V600E mutant colorectal cancer in relation to WNT signaling cascade (2017)
  • Author(s): Yasui K, Nagasaka T, Nyuya A, Toshima T, Kawai T, Shigeyasu K, Yano S, Mori Y, Haraga J, Nakamura K, Umeda Y, Goel A, Fujiwara T
  • Organizer: ESMO 2017 Congress, Madrid
  • Int'l Joint Research
• [Presentation] Heterogenity of epigenetic and EMT marks observed in hepatocellular carcinoma with keratin 19 proficiency (2017)
  • Author(s): Nagasaka T, Okada T, Yokomichi N, Taniguchi F, Toshima T, Yasui K, Fuji T, Mori Y, Kawai T, Umeda Y, Yagi T, Fujiwara T, Goel A
  • Organizer: ESMO 2017 Congress, Madrid
  • Int'l Joint Research
• [Presentation] A novel circulating cell free DNA-based assay can predict tumor response to systematic chemotherapy (2017)
  • Author(s): Toshima T, Nagasaka T, Mori Y, Kawai T, Yasui K, Fuji T, Taniguchi F, Kimura K, Kishimoto H, Umeda Y, Goel A, Fujiwara T
  • Organizer: ESMO 2017 Congress, Madrid
  • Int'l Joint Research
• [Presentation] Prediction of salvage liver transplantation for hcc recurrence: when and which patient should we decide transplant? (2017)
  • Author(s): Umeda Y, Yagi T, Yoshida R, Nobuoka D, Kuise T, Kumano K, Koujima T, Takagi K, Nagasaka T, Fujiwara T
  • Organizer: 18th Congress of the European Society for Organ Transplantation, Barcelona
  • Int'l Joint Research
• [Presentation] Is poor outcome of living donor liver transplantation for primary sclerosing cholangitis the nature of the disease itself or insufficient immunosuppression? (2017)
  • Author(s): Yagi T, Nobuoka D, Umeda Y, Yoshida R, Kuise T, Takagi K, Kumano K, Fujiwara T
  • Organizer: 18th Congress of the European Society for Organ Transplantation, Barcelona
  • Int'l Joint Research
• [Presentation] Surgical outcomes of living donor liver surgery: technical knack for zero morbidity (2017)
  • Author(s): Kuise T, Umeda Y, Yoshida R, Nobuoka D, Kumano K, Koujima T, Takagi K, Fujiwara T, Yagi T
  • Organizer: 18th Congress of the European Society for Organ Transplantation, Barcelona
  • Int'l Joint Research
• [Presentation] 切除不能進行再発大腸がんの２次治療以降における Ramcirumab + FOLFIRI 療法の治療成績 (2017)
  • Author(s): 永坂岳司, 母里淑子, 重安邦俊, 河合 毅, 矢野修也, 岸本浩行, 楳田祐三, 山口佳之, 藤原俊義
  • Organizer: 第55回日本癌治療学会学術集会, 横浜
• [Presentation] 安全で正確な系統的肝切除の実践に向けて：Knack & Pitfalls (2017)
  • Author(s): 楳田祐三, 八木孝仁, 吉田龍一, 信岡大輔, 杭瀬 崇, 國府島 健, 伏見卓郎, 香川俊輔, 白川靖博, 藤原俊義
  • Organizer: 第79回日本臨床外科学会総会, 東京
  • Invited
• [Presentation] Preoperative proximal splenic artery embolization: alternative portal modulation for prophylaxis of small-for-size syndrome (2017)
  • Author(s): Umeda Y, Yagi T, Yoshida R, Nobuoka D, Kuise T, Kumano K, Koujima T, Takagi K, Nagasaka T, Fujiwara T
  • Organizer: Asian Transplantation Week 2017 (ATW 2017), Incheon
  • Int'l Joint Research
• [Presentation] Prediction of salvage liver transplantation for hepatocellular carcinoma recurrence: when and for which patient should we decide transplant? (2017)
  • Author(s): Fushimi T, Umeda Y, Yoshida R, Nobuoka D, Kuise T, Takagi K, Yasunaka T, Takaki A, Fujiwara T, Yagi T
  • Organizer: Asian Transplantation Week 2017 (ATW 2017), Incheon
  • Int'l Joint Research
• [Presentation] Efficacious use of Tolvaptan for refractory ascites and hyponatremia in perioperative management in liver transplantation (2017)
  • Author(s): Kuise T, Umeda Y, Yoshida R, Nobuoka D, Kumano K, Koujima T, Takagi K, Fujiwara T, Yagi T
  • Organizer: Asian Transplantation Week 2017 (ATW 2017), Incheon
  • Int'l Joint Research
• [Presentation] テロメラーゼ標的蛍光発現ウィルスを用いた腹腔内遊離膵癌細胞診断技術の開発 (2017)
  • Author(s): 吉田龍一, 桒田和也, 楳田祐三, 信岡大輔, 杭瀬 崇, 國府島 健, 熊野健二郎, 伏見卓郎, 香川俊輔, 八木孝仁, 藤原俊義
  • Organizer: 第44回日本膵切研究会