Challenging for the management of HCC using novel liquid biopsy test

• Project/Area Number: 19K17463
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Yamaguchi University
• Principal Investigator: Saeki Issei 山口大学, 医学部附属病院, 講師 (60634756)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 肝細胞癌 / リキッドバイオプシー / 腫瘍マーカー / 進行肝細胞癌

Outline of Research at the Start

進行肝細胞癌の治療薬の第一選択肢は分子標的薬であり非常に高価なチロシンキナーゼ阻害薬が中心である．しかしながら，本薬剤の治療効果を早期に判定できる血清バイオマーカーは存在せず，無効な薬剤の漫然とした投与による副作用出現や医療費の高騰をもたらしている．各種治療の効果判定を早期に可能とする血清バイオマーカーとしてリキッドバイオプシーに注目した．本研究では極少量のDNAからでも任意の遺伝子のメチル化レベルを1コピーでも測定可能としており，候補遺伝子の肝癌の治療効果判定としての有用性を検証する．これにより，不必要な薬剤投与の抑制による医療コスト削減や副作用減少につながることが期待される．

Outline of Final Research Achievements

We reported the utility of a liquid biopsy test targeting methylated SEPT9 (mSEPT9) as a biomarker for the diagnosis of HCC (Hepatol Commun. 2020). In this study, we investigated the usefulness of mSEPT9 as a prognostic biomarker for molecular targeted therapy for unresectable HCC. As a result, we found that "AFP" and "mSEPT9" were important prognostic factors, in addition to "performance status". Furthermore, we developed a prognostic score using these three factors, and validated the usefulness of this score in a multicenter study (Hepatol Int. 2023).

Academic Significance and Societal Importance of the Research Achievements

肝癌に対して多数の治療選択肢が登場し,適切に逐次選択していくことが予後の延長に寄与すると報告されている.しかしながら,どのように逐次していくのか治療効果予測マーカーが存在しない現状がある.本研究成果によりmSEPT9を初めとした各バイオマーカーによる治療の効率化が可能となった. さらに,我々は肝癌患者でエネルギー障害の代替マーカーとして,ALBI score<-2.18が有用であることを見出しており（Clinical Nutrition 2020）, エネルギー障害を反映した肝予備能と肝癌の治療効果・予後予測バイオマーカーを組み合わせた包括的マネージメントが可能となった.

Research Products

• [Journal Article] Impact of skeletal muscle volume on patients with BCLC stage-B hepatocellular carcinoma undergoing sorafenib therapy (2023)
  • Author(s): Saeki I, Yamasaki T, Yamauchi Y, Kawaoka T, Uchikawa S, Hiramatsu A, Aikata H, Kobayashi K, Kondo T, Ogasawara S, Chiba T, Kawano R, Chayama K, Kato N, Takami T.
  • Journal Title: Cancer Med. Volume: - Issue: 9 Pages: 10625-10635
  • DOI: 10.1002/cam4.5810
  • Peer Reviewed / Open Access
• [Journal Article] Double cancer of primary hepatic angiosarcoma and hepatocellular carcinoma treated with atezolizumab plus bevacizumab. Hepatol Res. 2023 Feb 24. (2023)
  • Author(s): Yamauchi Y, Saeki I, Yamasaki T, Egusa M, Nishiyama N, Fujioka T, Kawamoto D, Nishimura T, Tanabe N, Oono T, Matsumoto T, Ishikawa T, Marumoto Y, Matsukuma S, Shindo Y, Tokumitsu Y, Yoshimine S, Murakami J, Tanaka T, Kimura S, Hoshii Y, Hamano K, Nagano H, Takami T.
  • Journal Title: Hepatol Res. Volume: - Issue: 7 Pages: 681-686
  • DOI: 10.1111/hepr.13894
  • Peer Reviewed
• [Journal Article] A combination of liver stiffness and international normalized ratio is an ideal prognostic predictor of portosystemic shunt occlusion in patients with portal hypertension (2022)
  • Author(s): Ishikawa Tsuyoshi、Egusa Maho、Fujioka Tsuyoshi、Nishiyama Natsuko、Kawamoto Daiki、Sasaki Ryo、Nishimura Tatsuro、Tanabe Norikazu、Oono Takashi、Saeki Issei、Takami Taro
  • Journal Title: Journal of Gastroenterology Volume: 58 Issue: 3 Pages: 246-256
  • DOI: 10.1007/s00535-022-01947-8
  • Peer Reviewed
• [Journal Article] Screening for portopulmonary hypertension using computed tomography-based measurements of the main pulmonary artery and ascending aorta diameters in patients with portal hypertension. (2022)
  • Author(s): Ishikawa T, Egusa M, Kawamoto D, Nishimura T, Sasaki R, Saeki I, Sakaida I, Takami T.
  • Journal Title: Hepatol Res. Volume: 52(3) Issue: 3 Pages: 255-268
  • DOI: 10.1111/hepr.13735
  • Peer Reviewed / Open Access
• [Journal Article] Short-term Effects of Hepatic Arterial Buffer Responses Induced by Partial Splenic Embolization on the Hepatic Function of Patients with Cirrhosis According to the Child-Pugh Classification (2021)
  • Author(s): Ishikawa Tsuyoshi、Sasaki Ryo、Nishimura Tatsuro、Matsuda Takashi、Iwamoto Takuya、Saeki Issei、Hidaka Isao、Takami Taro、Sakaida Isao
  • Journal Title: Internal Medicine Volume: 60 Issue: 9 Pages: 1331-1342
  • DOI: 10.2169/internalmedicine.6267-20
  • NAID: 130008033267
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-05-01
  • Peer Reviewed / Open Access
• [Journal Article] Skeletal Muscle Volume Is an Independent Predictor of Survival after Sorafenib Treatment Failure for Hepatocellular Carcinoma (2021)
  • Author(s): Saeki Issei、Yamasaki Takahiro、Yamauchi Yurika、Takami Taro、Kawaoka Tomokazu、Uchikawa Shinsuke、Hiramatsu Akira、Aikata Hiroshi、Kawano Reo、Kobayashi Kazufumi、Kondo Takayuki、Ogasawara Sadahisa、Chiba Tetsuhiro、Chayama Kazuaki、Kato Naoya、Sakaida Isao
  • Journal Title: Cancers Volume: 13 Issue: 9 Pages: 2247-2247
  • DOI: 10.3390/cancers13092247
  • Peer Reviewed / Open Access
• [Journal Article] Successful Management With Dual Therapy of Lenvatinib and Macitentan for HCC With Portopulmonary Hypertension (2021)
  • Author(s): Ishikawa Tsuyoshi、Sasaki Ryo、Matsuda Takashi、Saeki Issei、Takami Taro、Wada Yasuaki、Yano Masafumi、Sakaida Isao
  • Journal Title: Hepatology Volume: 74 Issue: 4 Pages: 2300-2303
  • DOI: 10.1002/hep.31865
  • Peer Reviewed / Open Access
• [Journal Article] Splenic non-infarction volume determines a clinically significant hepatic venous pressure gradient response to partial splenic embolization in patients with cirrhosis and hypersplenism (2021)
  • Author(s): Ishikawa Tsuyoshi、Sasaki Ryo、Nishimura Tatsuro、Matsuda Takashi、Iwamoto Takuya、Saeki Issei、Hidaka Isao、Takami Taro、Sakaida Isao
  • Journal Title: Journal of Gastroenterology Volume: 56 Issue: 4 Pages: 382-394
  • DOI: 10.1007/s00535-021-01762-7
  • Peer Reviewed / Open Access
• [Journal Article] Albumin-bilirubin score as a useful predictor of energy malnutrition in patients with hepatocellular carcinoma (2020)
  • Author(s): Kotoh Yurika、Saeki Issei、Yamasaki Takahiro、Sasaki Ryo、Tanabe Norikazu、Oono Takashi、Maeda Masaki、Hidaka Isao、Ishikawa Tsuyoshi、Takami Taro、Sakaida Isao
  • Journal Title: Clinical Nutrition Volume: - Issue: 5 Pages: 3585-3591
  • DOI: 10.1016/j.clnu.2020.12.023
  • Peer Reviewed / Open Access
• [Journal Article] Effect of Handgrip Strength on Clinical Outcomes of Patients with Hepatocellular Carcinoma Treated with Lenvatinib (2020)
  • Author(s): Yurika Kotoh, Issei Saeki, Takahiro Yamasaki, Ryo Sasaki, Norikazu Tanabe, Takashi Oono, Takashi Matsuda, Takuro Hisanaga, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Taro Takami, Isao Sakaida
  • Journal Title: applied sciences Volume: 10 Issue: 16 Pages: 5403-5403
  • DOI: 10.3390/app10165403
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Benefits of Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma (2020)
  • Author(s): Takahiro Yamasaki, Issei Saeki, Yurika Kotoh-Yamauchi, Ryo Sasaki, Norikazu Tanabe, Takashi Oono, Takashi Matsuda, Takuro Hisanaga, Toshihiko Matsumoto, Isao Hidaka, Tsuyoshi Ishikawa, Taro Takami, Yutaka Suehiro, Isao Sakaida
  • Journal Title: applied sciences Volume: 11 Issue: 4 Pages: 1882-1882
  • DOI: 10.3390/app11041882
  • Peer Reviewed / Open Access
• [Journal Article] Early Predictors of Objective Response in Patients with Hepatocellular Carcinoma Undergoing Lenvatinib Treatment (2020)
  • Author(s): Saeki Issei、Yamasaki Takahiro、et al.
  • Journal Title: Cancers Volume: 12 Issue: 4 Pages: 779-779
  • DOI: 10.3390/cancers12040779
  • Peer Reviewed / Open Access
• [Journal Article] Novel Liquid Biopsy Test Based on a Sensitive Methylated SEPT9 Assay for Diagnosing Hepatocellular Carcinoma. Hepatol Commun (2020)
  • Author(s): Kotoh Y, Suehiro Y, Saeki I, Hoshida T, Maeda M, Iwamoto T, Matsumoto T, Hidaka I, Ishikawa T, Takami T, Higaki S, Fujii I, Suzuki C, Shindo Y, Tokumitsu Y, Nagano H, Sakaida I, Yamasaki T
  • Journal Title: Hepatol Commun Volume: 4(3) Issue: 3 Pages: 461-470
  • DOI: 10.1002/hep4.1469
  • Peer Reviewed / Open Access
• [Journal Article] Blood Free-Circulating DNA Testing of Methylated RUNX3 Is Useful for Diagnosing Early Gastric Cancer (2020)
  • Author(s): Hideura Eizaburou、Suehiro Yutaka、Nishikawa Jun、Shuto Takuya、Fujimura Hiroyuki、Ito Shunsuke、Goto Atsushi、Hamabe Kouichi、Saeki Issei、Okamoto Takeshi、Higaki Shingo、Fujii Ikuei、Suzuki Chieko、Hoshida Tomomi、Matsumoto Toshihiko、Takami Taro、Sakaida Isao、Yamasaki Takahiro
  • Journal Title: Cancers Volume: 12 Issue: 4 Pages: 789-789
  • DOI: 10.3390/cancers12040789
  • Peer Reviewed / Open Access
• [Journal Article] Complications after Radiofrequency Ablation for Hepatocellular Carcinoma: A Multicenter Study Involving 9,411 Japanese Patients (2019)
  • Author(s): Maeda Masaki、Saeki Issei、et al.
  • Journal Title: Liver Cancer Volume: 9 Issue: 1 Pages: 50-62
  • DOI: 10.1159/000502744
  • Peer Reviewed / Open Access
• [Journal Article] A novel therapeutic strategy for esophageal varices using endoscopic treatment combined with splenic artery embolization according to the Child-Pugh classification (2019)
  • Author(s): Ishikawa Tsuyoshi、Sasaki Ryo、Nishimura Tatsuro、Aibe Yuki、Saeki Issei、Iwamoto Takuya、Hidaka Isao、Takami Taro、Sakaida Isao
  • Journal Title: PLOS ONE Volume: 14 Issue: 9 Pages: e0223153-e0223153
  • DOI: 10.1371/journal.pone.0223153
  • Peer Reviewed / Open Access
• [Presentation] メチル化SEPT9は肝細胞癌治療に対する分子標的治療薬の予後予測バイオマーカーとなる (2022)
  • Author(s): 佐伯一成, 山﨑隆弘, 高見 太郎
  • Organizer: 第58回日本肝臓学会総会
• [Presentation] Prognostic prediction by methylated-SEPT9 assay in patients with intermediate-stage hepatocellular carcinoma receiving molecular targeted agents (2022)
  • Author(s): Issei Saeki, Takahiro Yamasaki, Taro Takami
  • Organizer: APASL Oncology
  • Int'l Joint Research / Invited
• [Presentation] Liquid biopsy test based on methylated-SEPT9 for surveillance of nonBnonC hepatocellular carcinoma. (2022)
  • Author(s): Issei Saeki, Takahiro Yamasaki, Taro Takami
  • Organizer: APASL Oncology
  • Int'l Joint Research
• [Presentation] Liquid biopsy test based on methylated-SEPT9 for diagnosis of hepatocellular carcinoma (2022)
  • Author(s): Issei Saeki, Takahiro Yamasaki, Taro Takami
  • Organizer: JDDW 2022
• [Presentation] Usefulness of liquid biopsy based on a methylated SEPT9 assay in hepatocellular carcinoma patients treated with molecular targeted agents (2022)
  • Author(s): Issei Saeki, Yurika Yamauchi, Yutaka Suehiro, Hiroaki Nagano, Mototsugu Shimokawa, Taro Takami, Takahiro Yamasaki
  • Organizer: AASLD 2022
  • Int'l Joint Research
• [Presentation] Lenvatinib治療における握力と骨格筋量の関連 (2021)
  • Author(s): 山内 由里佳、佐伯 一成、坂井田 功
  • Organizer: 第107回日本消化器病学会総会
• [Presentation] 肝内脂肪沈着は腹囲により推定可能である (2021)
  • Author(s): 山内 由里佳、佐伯 一成、中島 小百合、松尾 亜矢、西川 寛子、田邉 規和、日髙 勲、高見 太郎、山﨑 隆弘、坂井田 功
  • Organizer: 第94回日本超音波医学会
• [Presentation] Transcatheter Arterial Chemoembolization Therapy in Combination Strategy with Lenvatinib in Patients with Unresectable Hepatocellular Carcinoma (TACTICS-L) in Japan: Interim analysis. (2021)
  • Author(s): Issei Saeki, Toru Ishikawa, Kazuomi Ueshima, et al.
  • Organizer: APPLE Meeting 2021
  • Int'l Joint Research
• [Presentation] Analysis of skeletal muscle changes during sorafenib or lenvatinib therapy for hepatocellular carcinoma. (2021)
  • Author(s): Yurika Yamauchi, Issei Saeki, Takahiro Yamasaki, Norikazu Tanabe, Taro Takami.
  • Organizer: JSH International Liver Conference 2021
  • Int'l Joint Research
• [Presentation] Liquid biopsy based on sensitive methylated SEPT9 as a prognostic marker in hepatocellular carcinoma patients treated with molecular targeted agents. (2021)
  • Author(s): Issei Saeki, Yurika Yamauchi, Yutaka Suehiro, Hiroaki Nagano, Mototsugu Shimokawa, Taro Takami, Takahiro Yamasaki.
  • Organizer: JSH International Liver Conference 2021
  • Int'l Joint Research
• [Presentation] Potential application of a liquid biopsy based on sensitive methylated SEPT9 as a prognostic marker in hepatocellular carcinoma patients treated with molecular targeted agents. (2021)
  • Author(s): Issei Saeki, Yurika Yamauchi, Yutaka Suehiro, Hiroaki Nagano, Mototsugu Shimokawa, Taro Takami, Takahiro Yamasaki.
  • Organizer: The Liver Meeting 2021, AASLD
  • Int'l Joint Research
• [Presentation] 肝癌分子標的治療薬に対するメチル化 SEPT9 によるリキッドバイオプシー検査の予後予測マーカーとしての可能性 (2021)
  • Author(s): 佐伯一成、山﨑隆弘、高見太郎
  • Organizer: 第44回日本肝臓学会西部会
• [Presentation] SorafenibおよびLenvatinib治療中の骨格筋量の変化 (2021)
  • Author(s): 内 由里佳、佐伯 一成、川本 大樹、西村 達朗、田邉 規和、大野 高嗣、石川 剛、山﨑 隆弘、高見 太郎
  • Organizer: 第44回日本肝臓学会西部会
• [Presentation] 肝細胞癌に対する 3次治療以上の逐次治療可能予測因子 (2021)
  • Author(s): 田邉規和、佐伯一成、川本大樹、山内由里佳、西村達朗、大野高嗣、石川 剛、山﨑隆弘、高見太郎
  • Organizer: 第44回日本肝臓学会西部会
• [Presentation] Impact of skeletal muscle volume in patients with intermediate-stage hepatocellular carcinoma (HCC) receiving sorafenib: A comparison with advanced HCC patients. (2021)
  • Author(s): Issei Saeki, Takahiro Yamasaki, Yurika Yamauchi, Tomokazu Kawaoka, Shinsuke Uchikawa, Akira Hiramatsu, Hiroshi Aikata, Kazufumi Kobayashi, Takayuki Kondo, Sadahisa Ogasawara, Tetsuhiro Chiba, Kazuaki Chayama, Naoya Kato, Isao Sakaida, Taro Takami.
  • Organizer: APASL Oncology 2021
  • Int'l Joint Research / Invited
• [Presentation] 肝硬度はレンバチニブの奏効因子である (2020)
  • Author(s): 佐伯 一成，藤井 彩乃，松尾 亜矢，西川 寛子， 日高 勲，高見 太郎，山﨑 隆弘，坂井田 功
  • Organizer: 日本超音波医学会第93回学術集会
• [Presentation] 骨格筋量は肝細胞癌に対するSorafenibの個別化医療のひとつのファクターである (2020)
  • Author(s): 佐伯 一成、山﨑 隆弘、厚東 由里佳、河岡 友和、相方 浩、小笠原 定久、近藤 孝行、加藤 直也、茶山 一彰、坂井田 功
  • Organizer: 第56回 日本肝癌研究会
• [Presentation] 高感度SEPT9メチル化解析法による肝癌診断の有用性 (2019)
  • Author(s): 佐伯一成，山﨑隆弘，坂井田功
  • Organizer: 第43回日本肝臓学会西部会
• [Presentation] Treatment strategy using body composition for advanced hepatocellular carcinoma: hepatic arterial infusion chemotherapy (2019)
  • Author(s): Issei Saeki, Takahiro Yamasaki, Yurika Kotoh, Taro Takami, Isao Sakaida
  • Organizer: 13th Annual Conference of the International Liver Cancer Association
  • Int'l Joint Research
• [Presentation] レンバチニブの初期使用経験―山口県多施設共同研究 (2019)
  • Author(s): 佐伯 一成、前田 雅喜、山崎 隆弘、坂井田 功
  • Organizer: 第19回肝がん分子標的治療研究会
• [Presentation] レンバチニブ導入後の腫瘍マーカーの推移と画像評価―山口県多施設共同研究 (2019)
  • Author(s): 佐伯 一成，厚東 由里佳, 山﨑 隆弘，坂井田 功
  • Organizer: 第20回肝がん分子標的治療研究会
• [Presentation] 体組成評価は進行肝癌治療ストラテジーのバイオマーカーである ：動注化学療法 vs. ソラフェニブ (2019)
  • Author(s): 佐伯 一成，山﨑 隆弘，坂井田 功
  • Organizer: 第55回日本肝がん研究会