2022 Fiscal Year Research-status Report
Development of AI for the drug therapy of hepatocellular carcinoma using medical image and immunogenomics
Project/Area Number |
21K07184
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Research Institution | Kindai University |
Principal Investigator |
西田 直生志 近畿大学, 医学部, 教授 (60281755)
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Co-Investigator(Kenkyū-buntansha) |
目加田 慶人 中京大学, 工学部, 教授 (00282377)
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Project Period (FY) |
2021-04-01 – 2024-03-31
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Keywords | 肝細胞癌 / 分子標的薬 / バイオマーカー / 画像診断 / ニューラルネットワーク / Radiomics / 治療効果予測 |
Outline of Annual Research Achievements |
本研究では、肝癌治療前の画像情報と遺伝子変異、腫瘍免疫環境を情報として肝癌薬物療法の効果を予測する人工知能(AI)を開発することを目的としている。2年目の課題として、治療前画像情報から治療効果を予測するAIに、遺伝子変異情報、腫瘍免疫情報を加えて学習させるための基礎的検討を行った。154例の肝癌組織にて、免疫チェックポイント分子の発現を免疫染色にて検討した。また、deep sequenceによる癌関連遺伝子変異、およびmRNA発現より肝癌をTMEの面から分類し、TCGAから得た377例の肝癌のexome, transcriptomeデータにて結果を確認した。加えて、肝癌症例でPD-1抗体を投与された34例の治療前生検を用い、TMEとPD-1抗体治療効果との関連を解析した。さらに画像所見よりTMEを反映する特徴を抽出した。PD-L1陽性肝癌はCD8+リンパ球(TIL)が有意に多く、PI3K-Akt経路に活性型変異を持つ傾向にあった(p = 0.0206)、TILには複数の抑制型受容体が発現していた。一方、b-カテニン経路の活性型変異を持つ肝癌はPD-L1陰性 (p = 0.0302)。TCGAコホートにおいても、同様の関連を示した。腫瘍の b-カテニン経路活性化, CD8+ TIL量, PD-L1発現にて抗PD-1抗体の無増悪生存期間を層別化できた(p < 0.0001)。造影MRIによる肝細胞相でのrelative enhance ratio (RER)はPD-1抗体治療の有効性と関連した。すなわち"immune hot-type"では、TILには複数の抑制型受容体が発現し、PI3K-Akt変異例が多い。"immune clod-type"ではb-カテニン経路活性型変異を持つ。TMEや腫瘍画像所見の解析より、抗PD-1抗体有効例を推定可能であった。
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Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
2年目に課題として、肝癌化学療法の効果を予測する人工知能開発のため、肝癌標本を用い、遺伝子変異の網羅的解析、transcriptome解析と免疫染色による肝癌の腫瘍免疫環境の分類を行った。また、腫瘍免疫環境を反映する遺伝子変異プロファイルの特徴、特にimmune cold phenotypeとb-カテニン経路活性化変異の関連を見出し、さらにb-カテニン経路活性化を持つ肝癌の画像的特徴を明らかにした。これは腫瘍のPD-1抗体治療への反応性と関連した。すなわち、画像的特徴と遺伝子変異プロファイル、transcriptome解析と免疫染色に基づく腫瘍免疫環境による人口知能の学習は、肝癌薬物療法の効果を推定する有効な情報であることを明らかにしたため、2年目の目標はおおよそ達成できたと考える。
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Strategy for Future Research Activity |
2年目の成果で明らかにした、次世代シークエンサーによるゲノム変異、免疫関連遺伝子のトランスクリプトーム解析の結果を学習データに加え、人工知能の再学習を行う。教師データとして、腫瘍の反応性に加え、治療開始後の腫瘍進行までの期間(Time To Progression: TTP)を付与する。画像に加え、genomics/immunogenomicsの情報を学習したAIモデルにより、症例毎に、最適治療を提示させ、治療計画の個人適応(オーダーメイド医療)を目指した人工知能モデルを検討する。さらに、肝癌で肝細胞癌に次いで多い肝内胆管細胞癌の画像情報、次世代シークエンサーによるゲノム変異、免疫関連遺伝子のトランスクリプトーム解析を行い、治療計画の個人適応を目的とした人工知能開発の可能性を探る。
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Causes of Carryover |
ほぼ予定通り支出しており、標本作成数が予定より少なかったため、若干の残高が生じた。次年度4月に追加の標本作成費用として支出予定である。
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[Journal Article] Impact of body mass index in patients receiving atezolizumab plus bevacizumab for hepatocellular carcinoma.2023
Author(s)
Vithayathil M, D'Alessio A, Fulgenzi CAM, Nishida N, Schonlein M, von Felden J, Schulze K, Wege H, Saeed A, Wietharn B, Hildebrand H, Wu L, Ang C, Marron TU, Weinmann A, Galle PR, Bettinger D, Bengsch B, Vogel A, Balcar L, et al.
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Journal Title
Hepatology international
Volume: ー
Pages: ー
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Role of the prognostic nutritional index in predicting survival in advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab.2023
Author(s)
Persano M, Rimini M, Tada T, Suda G, Shimose S, Kudo M, Cheon J, Finkelmeier F, Lim HY, Presa Ramos J, Masi G, Yoo C, Lonardi S, Stefanini B, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Chon HJ, Himmelsbach V, Montes M, Vivaldi C, Solda C, Hiraoka A, Sho T, Niizeki T, Nishida N, et al.
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Journal Title
Oncology
Volume: ー
Pages: ー
DOI
Peer Reviewed / Int'l Joint Research
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[Journal Article] Outcomes of beta blocker use in advanced hepatocellular carcinoma treated with immune checkpoint inhibitors.2023
Author(s)
Wu YL, van Hyfte G, Ozbek U, Reincke M, Gampa A, Mohamed YI, Nishida N, Wietharn B, Amara S, Lee PC, Scheiner B, Balcar L, Pinter M, Vogel A, Weinmann A, Saeed A, Pillai A, Rimassa L, Naqash AR, Muzaffar M, Huang YH, Kaseb AO, Kudo M, Pinato DJ, Ang C.
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Journal Title
Frontiers in oncology
Volume: 13
Pages: 128569-1128569
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Successful initial tofacitinib treatment for acute severe ulcerative colitis with steroid resistance: a case series.2023
Author(s)
Komeda Y, Kono M, Kashida H, Tribonias G, Masaki S, Takada R, Nagai T, Hagiwara S, Nishida N, Takenaka M, Honjo H, Matsui S, Tsuji N, Kudo M.
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Journal Title
Annals of gastroenterology
Volume: 35 (1)
Pages: 97-102
DOI
Peer Reviewed / Int'l Joint Research
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[Journal Article] Progression patterns and therapeutic sequencing following immune checkpoint inhibition for hepatocellular carcinoma: An international observational study.2022
Author(s)
Talbot T, D'Alessio A, Pinter M, Balcar L, Scheiner B, Marron TU, Jun T, Dharmapuri S, Ang C, Saeed A, Hildebrand H, Muzaffar M, Fulgenzi CAM, Amara S, Naqash AR, Gampa A, Pillai A, Wang Y, Khan U, Lee PC, Huang YH, Bengsch B, Bettinger D, Mohamed YI, Kaseb A, Pressiani T, Nishida N, Kudo M, et al.
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Journal Title
Liver international
Volume: 43(3)
Pages: 695-707
DOI
Peer Reviewed / Int'l Joint Research
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[Journal Article] Clinical outcomes with atezolizumab plus bevacizumab or lenvatinib in patients with hepatocellular carcinoma: a multicenter real-world study.2022
Author(s)
Persano M, Rimini M, Tada T, Suda G, Shimose S, Kudo M, Cheon J, Finkelmeier F, Lim HY, Rimassa L, Presa J, Masi G, Yoo C, Lonardi S, Tovoli F, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Chon HJ, Himmelsbach V, Pressiani T, Kawaguchi T, Montes M, Vivaldi C, Solda C, Piscaglia F, Hiraoka A, Sho T, Nishida N, et al.
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Journal Title
Journal of cancer research and clinical oncology
Volume: ー
Pages: ー
DOI
Peer Reviewed / Int'l Joint Research
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[Journal Article] Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as Prognostic Biomarkers in Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab.2022
Author(s)
Wu YL, Fulgenzi CAM, D'Alessio A, Cheon J, Nishida N, Saeed A, Wietharn B, Cammarota A, Pressiani T, Personeni N, Pinter M, Scheiner B, Balcar L, Huang YH, Phen S, Naqash AR, Vivaldi C, Salani F, Masi G, Bettinger D, Vogel A, Schonlein M, von Felden J, Schulze K, Wege H, Galle PR, Kudo M, et al
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Journal Title
Cancers
Volume: 14(23)
Pages: 5834
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population.2022
Author(s)
Casadei-Gardini A, Rimini M, Tada T, Suda G, Shimose S, Kudo M, Cheon J, Finkelmeier F, Lim HY, Rimassa L, Presa J, Masi G, Yoo C, Lonardi S, Tovoli F, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Chon HJ, Himmelsbach V, Pressiani T, Montes M, Vivaldi C, Solda C, Piscaglia F, Hiraoka A, Nishida N, et al.
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Journal Title
European journal of cancer
Volume: 180
Pages: 9-20
DOI
Peer Reviewed / Int'l Joint Research
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[Journal Article] Reproducible safety and efficacy of atezolizumab plus bevacizumab for HCC in clinical practice: Results of the AB-real study2022
Author(s)
Fulgenzi CAM, Cheon J, D'Alessio A, Nishida N, Ang C, Marron TU, Wu L, Saeed A, Wietharn B, Cammarota A, Pressiani T, Personeni N, Pinter M, Scheiner B, Balcar L, Napolitano A, Huang YH, Phen S, Naqash AR, Vivaldi C, Salani F, Masi G, Bettinger D, Vogel A, Schonlein M, von Felden J, Schulze K, Kudo M, et al.
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Journal Title
European journal of cancer
Volume: 175
Pages: 204-213
DOI
Peer Reviewed / Int'l Joint Research
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[Journal Article] Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma.2022
Author(s)
Vithayathil M, D'Alessio A, Fulgenzi CAM, Nishida N, Schonlein M, von Felden J, Schulze K, Wege H, Saeed A, Wietharn B, Hildebrand H, Wu L, Ang C, Marron TU, Weinmann A, Galle PR, Bettinger D, Bengsch B, Vogel A, Balcar L, Scheiner B, Lee PC, Huang YH, Amara S, Muzaffar M, Naqash AR, Cammarota A, Kudo M, et al.
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Journal Title
Liver international
Volume: 42(11)
Pages: 2538-2547
DOI
Peer Reviewed / Int'l Joint Research
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[Journal Article] Progression from early to advanced stage of immune-related cholangitis.2022
Author(s)
Hagiwara S, Yoshida T, Nishida N, Ida H, Ueshima K, Minami Y, Takita M, Aoki T, Morita M, Cishina H, Komeda Y, Yoshida A, Hayashi H, Nakagawa K, Kudo M.
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Journal Title
Hepatology research
Volume: 52(10)
Pages: 888-892
DOI
Peer Reviewed
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[Journal Article] Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: A real-world study.2022
Author(s)
Gaillard VE, Saeed A, Wietharn B, Hildebrand H, Wu L, Ang C, Marron TU, Weinmann A, Galle PR, Bettinger D, Bengsch B, Vogel A, Balcar L, Scheiner B, Lee PC, Huang YH, Amara S, Muzaffar M, Naqash AR, Cammarota A, Personeni N, Pressiani T, Sharma R, Pinter M, Cortellini A, Kudo M, et al.
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Journal Title
Hepatology
Volume: 76(4)
Pages: 1000-1012
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Clinical implication of immune checkpoint inhibitor on the chronic hepatitis B virus infection2022
Author(s)
Hagiwara S, Nishida N, Ida H, Ueshima K, Minami Y, Takita M, Aoki T, Morita M, Chishina H, Komeda Y, Yoshida A, Hayashi H, Nakagawa K, Kudo M.
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Journal Title
Hepatology research
Volume: 52(9)
Pages: 754-761
DOI
Peer Reviewed
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[Journal Article] Validation of the easy-to-use lenvatinib prognostic index to predict prognosis in advanced hepatocellular carcinoma patients treated with lenvatinib.2022
Author(s)
Rimini M, Kang W, Burgio V, Persano M, Aoki T, Shimose S, Tada T, Kumada T, Sho T, Lai E, Celsa C, Campani C, Tonnini M, Tamburini E, Hiraoka A, Takaguchi K, Nishida N, Iwamoto H, Itobayashi E, Tsuji K, Sakamoto N, Ishikawa T, Toyoda H, Kudo M, et al.
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Journal Title
Hepatology research
Volume: 52(12)
Pages: 1050-1059
DOI
Peer Reviewed / Int'l Joint Research
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[Journal Article] Patterns and outcomes of subsequent therapy after immune checkpoint inhibitor discontinuation in HCC2022
Author(s)
Sharma R, Pillai A, Marron TU, Fessas P, Saeed A, Jun T, Dharmapuri S, Szafron D, Naqash AR, Gampa A, Wang Y, Khan U, Muzaffar M, Lee CJ, Lee PC, Bulumulle A, Paul S, Bettinger D, Hildebrand H, Yehia M, Pressiani T, Kaseb A, Huang YH, Ang C, Kudo M, Nishida N, Personeni N, Rimassa L, Pinato DJ.
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Journal Title
Hepatology communications
Volume: 6(7)
Pages: 1776-1785
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Integrated use of PD-1 inhibition and transarterial chemoembolization for hepatocellular carcinoma: evaluation of safety and efficacy in a retrospective, propensity score-matched study.2022
Author(s)
Marinelli B, Kim E, D'Alessio A, Cedillo M, Sinha I, Debnath N, Kudo M, Nishida N, Saeed A, Hildebrand H, Kaseb AO, Abugabal YI, Pillai A, Huang YH, Khan U, Muzaffar M, Naqash AR, Patel R, Fischman A, Bishay V, Bettinger D, Sung M, Ang C, Schwartz M, Pinato DJ, Marron T.
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Journal Title
Journal for immunotherapy of cancer
Volume: 10(6)
Pages: e004205
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] .Value of artificial intelligence with novel tumor tracking technology in the diagnosis of gastric submucosal tumors by contrast-enhanced harmonic endoscopic ultrasonography.2022
Author(s)
Tanaka H, Kamata K, Ishihara R, Handa H, Otsuka Y, Yoshida A, Yoshikawa T, Ishikawa R, Okamoto A, Yamazaki T, Nakai A, Omoto S, Minaga K, Yamao K, Takenaka M, Watanabe T, Nishida N, Kudo M.
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Journal Title
Journal of gastroenterology and hepatology
Volume: 37(5)
Pages: 841-846
DOI
Peer Reviewed
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[Journal Article] Role of phlebotomy in the treatment of liver damage related to erythropoietic porphyria.2022
Author(s)
Hagiwara S, Nishida N, Ida H, Ueshima K, Minami Y, Takita M, Aoki T, Morita M, Chishina H, Komeda Y, Yoshida A, Park AM, Sato M, Kawada A, Nakano H, Nakagawa H, Kudo M.
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Journal Title
Scientific reports
Volume: 12(1)
Pages: 6100-6100
DOI
Peer Reviewed / Open Access
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[Journal Article] Artificial intelligence (AI) models for the ultrasonographic diagnosis of liver tumors and comparison of diagnostic accuracies between AI and human experts.2022
Author(s)
Nishida N, Yamakawa M, Shiina T, Mekada Y, Nishida M, Sakamoto N, Nishimura T, Iijima H, Hirai T, Takahashi K, Sato M, Tateishi R, Ogawa M, Mori H, Kitano M, Toyoda H, Ogawa C, Kudo M; JSUM A. I. investigators.
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Journal Title
J Gastroenterol
Volume: 57(4)
Pages: 309-321
DOI
Peer Reviewed / Open Access
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[Presentation] 複合免疫療法時代におけるイメージングバイオマーカーとしてのEOB-MRIの役割2022
Author(s)
青木智子, 西田直生志, 上嶋一臣, 盛田真弘, 千品寛和, 田北雅弘, 南康範, 依田広, 祖父江慶太郎, 鶴崎正勝, 工藤正俊
Organizer
第58回日本肝癌研究会; パネルディスカッション8
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[Presentation] 複合免疫療法時代におけるhyper progressive disease (HPD)2022
Author(s)
青木智子, 西田直生志, 上嶋一臣, 盛田真弘, 千品寛和, 田北雅弘, 南康範, 萩原智, 依田広, 鶴崎正勝, 工藤正俊
Organizer
第58回日本肝癌研究会 パネルディスカッション5
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