Development of new technologies for liver surgery by using fluorescent imaging

• Project/Area Number: 17H04279
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Kokudo Norihiro 国立研究開発法人国立国際医療研究センター, その他部局等, 理事長 (00205361)
• Co-Investigator(Kenkyū-buntansha): 石沢 武彰 東京大学, 医学部附属病院, 講師 (10422312) ; 浦野 泰照 東京大学, 大学院薬学系研究科(薬学部), 教授 (20292956) ; 秋光 信佳 東京大学, アイソトープ総合センター, 教授 (40294962) ; 金子 順一 東京大学, 医学部附属病院, 講師 (50328118)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2020: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2019: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2017: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
• Keywords: 肝癌 / 蛍光ナビゲーション / 蛍光プローブ

Outline of Final Research Achievements

This study aimed to develop basic technologies of fluorescent navigation to support liver surgery. The accumulated indocyanine green (ICG) in hepatocellular carcinoma (HCC) was effective for the detection of new region of HCC. The novel gamma-glutamyltranspeptidase reactive fluorescent probe was available for the sensitive detection of various hepatic tumor tissues. Near-infrared irradiation to the ICG-accumulated HCC tissue had anti-cancer effect by inducing apoptosis and oxidative stress in cancer cells. These results suggest that those fluorescent technologies are effective for supporting the liver surgery.

Academic Significance and Societal Importance of the Research Achievements

本研究では、ICGや新規蛍光プローブといった種々のマテリアルを使用して、肝癌組織を高感度に検出する技術や蛍光発光した癌組織に対する特異性の高い光線力学療法を開発した。これらの技術は、外科的治療技術が発達した現在においても依然として術後生存率が低い肝癌患者の予後の向上に貢献すると考えられる。また、肝臓外科手術の手技は高難度であると共に、その手術の正確性や時間が患者の術後予後に大きく影響する。本研究で確立された蛍光ナビゲーションに基づく種々の支援技術が、肝臓外科手術の質的向上に需要な役割を果たすと期待される。

Research Products

• [Journal Article] Identification of liver lesions using fluorescence imaging: comparison of methods for administering indocyanine green (2021)
  • Author(s): Kobayashi Kosuke、Kawaguchi Yoshikuni、Kobayashi Yuta、Matsumura Masaru、Ishizawa Takeaki、Akamatsu Nobuhisa、Kaneko Junichi、Arita Junichi、Sakamoto Yoshihiro、Kokudo Norihiro、Hasegawa Kiyoshi
  • Journal Title: HPB Volume: 23 Issue: 2 Pages: 262-269
  • DOI: 10.1016/j.hpb.2020.06.006
  • Peer Reviewed / Open Access
• [Journal Article] Indocyanine green administration a day before surgery may increase bile duct detectability on fluorescence cholangiography during laparoscopic cholecystectomy (2020)
  • Author(s): Matsumura Masaru、Kawaguchi Yoshikuni、Kobayashi Yuta、Kobayashi Kosuke、Ishizawa Takeaki、Akamatsu Nobuhisa、Kaneko Junichi、Arita Junichi、Kokudo Norihiro、Hasegawa Kiyoshi
  • Journal Title: Journal of Hepato-Biliary-Pancreatic Sciences Volume: 28 Issue: 2 Pages: 202-210
  • DOI: 10.1002/jhbp.855
  • Peer Reviewed / Open Access
• [Journal Article] Consensus Guidelines for the Use of Fluorescence Imaging in Hepatobiliary Surgery (2020)
  • Author(s): Wang Xiaoying、Teh Catherine S. C.、Ishizawa Takeaki、Aoki Takeshi、Cavallucci David、Lee Ser-Yee、Panganiban Katherine M.、Perini Marcos V.、Shah Sudeep R.、Wang Hongguang、Xu Yinzhe、Suh Kyung-Suk、Kokudo Norihiro
  • Journal Title: Annals of Surgery Volume: Publish Ahead of Print Issue: 1 Pages: 97-106
  • DOI: 10.1097/sla.0000000000004718
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] On-Site Monitoring of Postoperative Bile Leakage Using Bilirubin-Inducible Fluorescent Protein (2020)
  • Author(s): Kono Yoshiharu、Ishizawa Takeaki、Kokudo Norihiro、Kuriki Yugo、Iwatate Ryu J.、Kamiya Mako、Urano Yasuteru、Kumagai Akiko、Kurokawa Hiroshi、Miyawaki Atsushi、Hasegawa Kiyoshi
  • Journal Title: World Journal of Surgery Volume: 44 Issue: 12 Pages: 4245-4253
  • DOI: 10.1007/s00268-020-05774-x
  • Peer Reviewed / Open Access
• [Journal Article] Late-Evening Carbohydrate and Branched-Chain Amino Acid Snacks Improve the Nutritional Status of Patients Undergoing Hepatectomy Based on Bioelectrical Impedance Analysis of Body Composition (2019)
  • Author(s): Kobayashi Kosuke、Kaneko Junichi、Yamaguchi Takamune、Kawaguchi Yoshikuni、Arita Junichi、Akamatsu Nobuhisa、Ishizawa Takeaki、Sekine Rie、Ijichi Hideaki、Kubota Naoto、Fukatsu Kazuhiko、Kokudo Norihiro、Hasegawa Kiyoshi
  • Journal Title: Gastrointestinal Tumors Volume: 6 Issue: 3-4 Pages: 81-91
  • DOI: 10.1159/000501452
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of Preoperative Liver Function for Surgical Decision Making in Patients with Hepatocellular Carcinoma (2019)
  • Author(s): Kokudo Takashi、Hasegawa Kiyoshi、Shirata Chikara、Tanimoto Meguri、Ishizawa Takeaki、Kaneko Junichi、Akamatsu Nobuhisa、Arita Junichi、Demartines Nicolas、Uldry Emilie、Kokudo Norihiro、Halkic Nermin
  • Journal Title: Liver Cancer Volume: 8 Issue: 6 Pages: 447-456
  • DOI: 10.1159/000501368
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Albumin?Indocyanine Green Evaluation (ALICE) grade combined with portal hypertension to predict post‐hepatectomy liver failure (2019)
  • Author(s): Shirata Chikara、Kokudo Takashi、Arita Junichi、Akamatsu Nobuhisa、Kaneko Junichi、Sakamoto Yoshihiro、Kokudo Norihiro、Hasegawa Kiyoshi
  • Journal Title: Hepatology Research Volume: 印刷中 Issue: 8 Pages: 942-949
  • DOI: 10.1111/hepr.13327
  • Peer Reviewed / Open Access
• [Journal Article] Randomized Trial of Near-infrared Incisionless Fluorescent Cholangiography (2019)
  • Author(s): Dip Fernando、LoMenzo Emanuelle、Sarotto Luis、Phillips Edward、Todeschini Hernan、Nahmod Mario、Alle Lisandro、Schneider Sylke、Kaja Ludwig、Boni Luigi、Ferraina Pedro、Carus Thomas、Kokudo Norihiro、Ishizawa Takeaki、Walsh Mathew、Simpfendorfer Conrad、Mayank Roy、White Kevin、Rosenthal Raul J.
  • Journal Title: Annals of Surgery Volume: 印刷中 Issue: 6 Pages: 1-1
  • DOI: 10.1097/sla.0000000000003178
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel liver-specific fluorescent anti-cancer drug delivery system using indocyanine green (2019)
  • Author(s): Inagaki Yoshinori、Kokudo Takashi、Kamiya Mako、Uno Shin-nosuke、Sato Masumitsu、Kaneko Junichi、Kokudo Norihiro、Urano Yasuteru、Hasegawa Kiyoshi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 3044-3044
  • DOI: 10.1038/s41598-019-39269-0
  • Peer Reviewed / Open Access
• [Journal Article] Usefulness of indocyanine green-fluorescence imaging for real-time visualization of pancreas neuroendocrine tumor and cystic neoplasm (2018)
  • Author(s): Shirata Chikara、Kawaguchi Yoshikuni、Kobayashi Kosuke、Kobayashi Yuta、Arita Junichi、Akamatsu Nobuhisa、Kaneko Junichi、Sakamoto Yoshihiro、Kokudo Norihiro、Hasegawa Kiyoshi
  • Journal Title: Journal of Surgical Oncology Volume: 118 Issue: 6 Pages: 1012-1020
  • DOI: 10.1002/jso.25231
  • Peer Reviewed
• [Journal Article] Establishment of Molecular Design Strategy To Obtain Activatable Fluorescent Probes for Carboxypeptidases (2018)
  • Author(s): Kuriki Yugo、Kamiya Mako、Kubo Hidemasa、Komatsu Toru、Ueno Tasuku、Tachibana Ryo、Hayashi Kento、Hanaoka Kenjiro、Yamashita Suguru、Ishizawa Takeaki、Kokudo Norihiro、Urano Yasuteru
  • Journal Title: Journal of the American Chemical Society Volume: 140 Issue: 5 Pages: 1767-1773
  • DOI: 10.1021/jacs.7b11014
  • Peer Reviewed
• [Journal Article] Near-infrared photothermal/photodynamic therapy with indocyanine green induces apoptosis of hepatocellular carcinoma cells through oxidative stress (2017)
  • Author(s): Shirata Chikara、Kaneko Junichi、Inagaki Yoshinori、Kokudo Takashi、Sato Masumitsu、Kiritani Sho、Akamatsu Nobuhisa、Arita Junichi、Sakamoto Yoshihiro、Hasegawa Kiyoshi、Kokudo Norihiro
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 13958-13958
  • DOI: 10.1038/s41598-017-14401-0
  • Peer Reviewed / Open Access
• [Journal Article] Portal vein territory identification using indocyanine green fluorescence imaging: Technical details and short-term outcomes (2017)
  • Author(s): Kobayashi Yuta、Kawaguchi Yoshikuni、Kobayashi Kosuke、Mori Kazuhiro、Arita Junichi、Sakamoto Yoshihiro、Hasegawa Kiyoshi、Kokudo Norihiro
  • Journal Title: Journal of Surgical Oncology Volume: 116 Issue: 7 Pages: 921-931
  • DOI: 10.1002/jso.24752
  • Peer Reviewed / Open Access
• [Journal Article] Intraoperative imaging of hepatic cancers using γ-glutamyltranspeptidase-specific fluorophore enabling real-time identification and estimation of recurrence (2017)
  • Author(s): Miyata Yoichi、Ishizawa Takeaki、Kamiya Mako、Yamashita Suguru、Hasegawa Kiyoshi、Ushiku Aya、Shibahara Junji、Fukayama Masashi、Urano Yasuteru、Kokudo Norihiro
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 3542-3542
  • DOI: 10.1038/s41598-017-03760-3
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic accuracy of indocyanine green fluorescence imaging and multidetector row computed tomography for identifying hepatocellular carcinoma with liver explant correlation (2017)
  • Author(s): Masuda, K. Kaneko, J. Kawaguchi, Y. Togashi, J. Arita, J. Akamatsu, N. Sakamoto, Y. Hasegawa, K. Sumihito, T. Kokudo, N.
  • Journal Title: Hepatol Res. Volume: Epub ahead of print Issue: 12 Pages: 1-9
  • DOI: 10.1111/hepr.12870
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Induction of apoptosis of hepatocellular carcinoma cells by near-infrared photodynamic treatment with indocyanine green (2020)
  • Author(s): 稲垣善則、白田力、金子順一、桐谷翔、佐藤祐充、國土貴嗣、赤松延久、有田淳一、國土典宏、長谷川潔
  • Organizer: 第93回日本生化学会大会
• [Presentation] 外科手術における新しい術中診断modality：共焦点レーザー顕微内視鏡による胆管腫瘍・肝腫瘍の存在と範囲診断 (2020)
  • Author(s): 河口義邦、松村優、高尾幹也、風見由祐、谷本芽弘理、真木治文、田中麻理子、牛久哲男、石沢武彰、赤松 延久、金子順一、有田淳一、國土典宏、長谷川潔
  • Organizer: 第120回日本外科学会定期学術集会
• [Presentation] 肝細胞がんに対する肝切除時の肝離断方法と早期再発率についての検討 (2020)
  • Author(s): 伊藤橋司、竹村信行、稲垣冬樹、三原史規、徳原真、清松知充、多田敬一郎、山田和彦、國土典宏
  • Organizer: 第120回日本外科学会定期学術集会
• [Presentation] ICG蛍光法による術中観察を行なった肝細胞癌リンパ節転移の一切除例 (2019)
  • Author(s): 小澤貴臣 黒川敏昭 伊藤橋司 稲垣冬樹 三原史規 清松知充 山田和彦 竹村信行 國土典宏
  • Organizer: 第853回外科集談会
• [Presentation] 肝細胞癌に対する新規抗癌剤としてのインドシアニングリーン－ゲムシタビン結合体の創出 (2019)
  • Author(s): 稲垣善則、國土貴嗣、神谷真子、宇野 真之介、佐藤祐充、金子順一、國土典宏、浦野泰照、長谷川潔
  • Organizer: 第92回日本生化学会大会
• [Presentation] ICG 蛍光法およびRT-PCR 法を用いたラット肝における肝静脈閉塞領域の肝機能評価 (2018)
  • Author(s): 伊藤大介、河口義邦、稲垣善則、有田淳一、赤松延久、金子順一、阪本良弘、國土典宏、長谷川潔
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] テイラーメイド手術の実現に向けた術中蛍光イメージングの開発：10年の軌跡と将来展望 (2018)
  • Author(s): 石沢武彰、齋浦明夫、大庭篤志、三瀬祥弘、井上陽介、伊藤寛倫、高橋祐、栗木優五、神谷真子、浦野泰照、森一洋、宮田陽一、山下俊、阪本良弘、長谷川潔、國土典宏
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] 肝細胞がんに対するインドシアニングリーン蛍光法による肝区域同定、エネルギーデバイスを用いた系統的肝切除 (2018)
  • Author(s): 金子順一、千代田武大、河口義邦、有田淳一、赤松延久、阪本良弘、長谷川潔、國土典宏
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] Tumor Identification Using Fluorescence Imaging: Comparison of Timing and Dosage of Indocyanine Green (2018)
  • Author(s): Kobayashi K, Kawaguchi Y, Kobayashi Y, Matsumura M, Arita J, Akamatsu N, Kaneko J, Sakamoto Y, Kokudo N, Hasegawa K
  • Organizer: 13th IHPBA World Congress
  • Int'l Joint Research
• [Presentation] Diagnostic Accuracy of Indocyanine Green Fluorescence Imaging and Multidetector Row Computed Tomography for Identifying Hepatocellular Carcinoma with Liver Explant correlation (2018)
  • Author(s): Kaneko J, Kouichi M, Arita J, Akamatsu N, Sakamoto Y, Kokudo N, Hasegawa K
  • Organizer: 13th IHPBA World Congress
  • Int'l Joint Research
• [Presentation] ICG蛍光法を用いた系統的肝切除-個別処置、グリソン一括、門脈穿刺法- (2018)
  • Author(s): 竹村信行、伊藤橋司、稲垣冬樹、三原史規、黒川敏昭、清松知充、德原真、多田敬一郎、山田和彦、國土典宏
  • Organizer: 第80回日本臨床外科学会総会
• [Presentation] ICG蛍光法が有用であった肝細胞癌リンパ節転移の一切除例 (2018)
  • Author(s): 稲垣 冬樹、竹村 信行、三原 史規、黒川 敏昭、國土 典宏
  • Organizer: 第1回蛍光ガイド手術研究会
• [Presentation] ICG蛍光法が切除範囲の決定に有用であった肝細胞癌リンパ節転移の一例 (2018)
  • Author(s): 稲垣 冬樹、竹村 信行、片岡 温子、三原 史規、黒川 敏昭、清松 知充、山田 和彦、矢野 秀朗、國土 典宏
  • Organizer: 第77回東京地区国立病院外科研究会