Pub Date : 2026-01-15DOI: 10.1097/hep.0000000000001625
Prowpanga Udompap
{"title":"Metabolic syndrome and cholangiocarcinoma: A signal too strong to ignore","authors":"Prowpanga Udompap","doi":"10.1097/hep.0000000000001625","DOIUrl":"https://doi.org/10.1097/hep.0000000000001625","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"18 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1097/hep.0000000000001626
Vinay Jahagirdar, Juan Pablo Arab
{"title":"From intuition to index: Combining frailty and comorbidities to stratify liver transplant risk","authors":"Vinay Jahagirdar, Juan Pablo Arab","doi":"10.1097/hep.0000000000001626","DOIUrl":"https://doi.org/10.1097/hep.0000000000001626","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"29 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1097/hep.0000000000001624
Hanna Erickson
{"title":"Fueling fibrosis: The PBX1–IL7R axis and its role in hepatic stellate cell activation","authors":"Hanna Erickson","doi":"10.1097/hep.0000000000001624","DOIUrl":"https://doi.org/10.1097/hep.0000000000001624","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"41 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background & Aims: Atezolizumab plus bevacizumab (Atez/Bev) is the first-line immunotherapy for advanced hepatocellular carcinoma (HCC), yet many patients show primary or acquired resistance. We aimed to identify tumor-intrinsic mechanisms driving immune cold tumor microenvironments (TMEs) and Atez/Bev resistance. Approach & Results: We used a genetically heterogeneous immunocompetent HCC mouse model generated by hydrodynamic injection of a barcoded oncogene library, integrating single-cell RNA sequencing, spatial transcriptomics, and bulk RNA sequencing of human HCC tissues. Retrospective analyses included a multi-institutional registry of 549 Atez/Bev-treated patients and 199 surgically-resected HCC patients. External validation used RNA-seq data from 247 patients registered in the IMbrave150 and GO30140 trials. In mice, Atez/Bev eliminated hot tumors, while pre-existing cold tumors with exhausted effector T cells and Tregs predominated later. Barcode analysis revealed enrichment of NFE2L2 (NRF2) in resistant tumors. NRF2 overexpression suppressed immune infiltration and conferred resistance, which was reversed by NRF2 or COX2 inhibition. In human cohorts, both non-responders and patients with acquired resistance exhibited high NRF2/COX2 expression and immune exclusion, confirmed by spatial profiling. High NRF2 activity predicted shorter progression-free survival (PFS), whereas concomitant COX2 inhibitor use correlated with longer PFS. Plasma prostaglandin E2 (PGE₂) independently predicted poor response and survival. In IMbrave150/GO30140, NRF2 and prostaglandin pathway activation correlated with Atez/Bev resistance but not sorafenib response, validating a treatment-specific mechanism. Conclusions: Tumor-intrinsic activation of the NRF2–COX2–PGE₂ axis drives immune cold TMEs and mediates Atez/Bev resistance in HCC. Targeting this pathway may enhance efficacy, and plasma PGE₂ represents a non-invasive biomarker for stratification.
{"title":"NRF2–COX2–PGE2 axis drives immune cold tumors and predicts resistance to combination immunotherapy in hepatocellular carcinoma","authors":"Shuhei Yamamoto, Takahiro Kodama, Akifumi Kuwano, Kazuki Maesaka, Tomomi Yoshida-Hashidate, Hideo Shindou, Haruhiko Takeda, Kumiko Shirai, Yuta Myojin, Kazuhiro Murai, Yuki Makino, Yuki Tahata, Yoshinobu Saito, Atsushi Hosui, Yasutoshi Nozaki, Tasuku Nakabori, Kazuyoshi Ohkawa, Satoshi Tanaka, Akira Nishio, Masanori Miyazaki, Hayato Hikita, Kenta Motomura, Amaia Lujambio, Akinobu Taketomi, Hidetoshi Eguchi, Tetsuo Takehara","doi":"10.1097/hep.0000000000001677","DOIUrl":"https://doi.org/10.1097/hep.0000000000001677","url":null,"abstract":"Background & Aims: Atezolizumab plus bevacizumab (Atez/Bev) is the first-line immunotherapy for advanced hepatocellular carcinoma (HCC), yet many patients show primary or acquired resistance. We aimed to identify tumor-intrinsic mechanisms driving immune cold tumor microenvironments (TMEs) and Atez/Bev resistance. Approach & Results: We used a genetically heterogeneous immunocompetent HCC mouse model generated by hydrodynamic injection of a barcoded oncogene library, integrating single-cell RNA sequencing, spatial transcriptomics, and bulk RNA sequencing of human HCC tissues. Retrospective analyses included a multi-institutional registry of 549 Atez/Bev-treated patients and 199 surgically-resected HCC patients. External validation used RNA-seq data from 247 patients registered in the IMbrave150 and GO30140 trials. In mice, Atez/Bev eliminated hot tumors, while pre-existing cold tumors with exhausted effector T cells and Tregs predominated later. Barcode analysis revealed enrichment of NFE2L2 (NRF2) in resistant tumors. NRF2 overexpression suppressed immune infiltration and conferred resistance, which was reversed by NRF2 or COX2 inhibition. In human cohorts, both non-responders and patients with acquired resistance exhibited high NRF2/COX2 expression and immune exclusion, confirmed by spatial profiling. High NRF2 activity predicted shorter progression-free survival (PFS), whereas concomitant COX2 inhibitor use correlated with longer PFS. Plasma prostaglandin E2 (PGE₂) independently predicted poor response and survival. In IMbrave150/GO30140, NRF2 and prostaglandin pathway activation correlated with Atez/Bev resistance but not sorafenib response, validating a treatment-specific mechanism. Conclusions: Tumor-intrinsic activation of the NRF2–COX2–PGE₂ axis drives immune cold TMEs and mediates Atez/Bev resistance in HCC. Targeting this pathway may enhance efficacy, and plasma PGE₂ represents a non-invasive biomarker for stratification.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"19 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1097/hep.0000000000001627
Jack W. Sample, Sumera I. Ilyas
{"title":"MASLD: To screen or not to screen—That is the question","authors":"Jack W. Sample, Sumera I. Ilyas","doi":"10.1097/hep.0000000000001627","DOIUrl":"https://doi.org/10.1097/hep.0000000000001627","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"30 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose: Local tumor progression (LTP) of hepatocellular carcinoma (HCC) after thermal ablation (TA) is related to tumor invasiveness and threaten the health. We aim to build a multimodal model to explicable tumor invasiveness and reduce LTP. Methods: Contrast-enhanced ultrasound (CEUS), magnetic resonance imaging (MRI), biological, clinical and prognostic information were collected to build the model. Long short-term memory network and radiomics were used to extract image features. Logistic regression was used to combined image and clinical information. Pathological, immunohistochemical and RNA sequencing analyses were used to explicable tumor invasiveness. Moderation analysis was used to provide suitable minimum ablation margin (MAM) for high-invasiveness tumors in safe location (not adjacent to vessel or capsule) to reduce LTP. Results: 1208 HCCs were collected as training (n=502), validation (n=180), internal test (n=250) and external test (n=276) sets. AUC of model was 0.809 and 0.811 in internal and external test sets. High-invasiveness group showed higher microvascular invasion proportion, higher macrotrabecular-massive HCC proportion, lower differentiation, higher CK-7 and GPC-3 positive rate and higher VEGFA, MMP-9, HSPA1A expression ( p <0.05). KEGG and GSEA analysis revealed the upregulation of pathways related to angiogenesis, tolerance to stress response, and tumor metastasis in high-invasiveness group. The 8 mm MAM ablation strategy can effectively decrease the LTP incidence of high-invasiveness group (from 42.4% to 10.5%, p =0.027) to the level comparable to low-invasiveness group (10.5% vs. 6.1%, p =0.613) in external test set. Conclusion: Multimodal model achieved satisfactory performance on classifying tumor invasiveness, and provided effective strategy for high-invasiveness tumor to reduce LTP occurrence.
目的：肝细胞癌（HCC）热消融（TA）后的局部肿瘤进展（LTP）与肿瘤侵袭性有关，威胁健康。我们的目标是建立一个多模态模型来解释肿瘤的侵袭性和降低LTP。方法：收集超声造影（CEUS）、磁共振成像（MRI）、生物学、临床及预后资料建立模型。利用长短期记忆网络和放射组学提取图像特征。采用Logistic回归将图像与临床信息相结合。病理，免疫组织化学和RNA测序分析用于解释肿瘤的侵袭性。采用适度分析，为安全位置（不靠近血管或包膜）的高侵袭性肿瘤提供合适的最小消融边界（MAM），以降低LTP。结果：共收集到1208组hcc，分别作为训练组（n=502）、验证组（n=180）、内部测试组（n=250）和外部测试组（n=276）。模型内部和外部测试集的AUC分别为0.809和0.811。高侵袭组微血管侵袭比例高，大小梁-块状HCC比例高，分化程度低，CK-7、GPC-3阳性率高，VEGFA、MMP-9、HSPA1A表达高（p <0.05）。KEGG和GSEA分析显示，高侵袭性组血管生成、应激反应耐受和肿瘤转移相关通路上调。8 mm MAM消融策略可有效降低高创组（42.4% ~ 10.5%,p =0.027）与低创组（10.5% ~ 6.1%,p =0.613）外测组LTP发生率。结论：多模态模型在肿瘤侵袭性分类上取得了满意的效果，为高侵袭性肿瘤减少LTP的发生提供了有效的策略。
{"title":"Biologically explicable multimodal model predicting local tumor progression and tumor invasiveness of hepatocellular carcinoma","authors":"Wenzhen Ding, Jiapeng Wu, Jianping Dou, Fangyi Liu, Zhiyu Han, Jie Yu, Ping Liang","doi":"10.1097/hep.0000000000001678","DOIUrl":"https://doi.org/10.1097/hep.0000000000001678","url":null,"abstract":"Purpose: Local tumor progression (LTP) of hepatocellular carcinoma (HCC) after thermal ablation (TA) is related to tumor invasiveness and threaten the health. We aim to build a multimodal model to explicable tumor invasiveness and reduce LTP. Methods: Contrast-enhanced ultrasound (CEUS), magnetic resonance imaging (MRI), biological, clinical and prognostic information were collected to build the model. Long short-term memory network and radiomics were used to extract image features. Logistic regression was used to combined image and clinical information. Pathological, immunohistochemical and RNA sequencing analyses were used to explicable tumor invasiveness. Moderation analysis was used to provide suitable minimum ablation margin (MAM) for high-invasiveness tumors in safe location (not adjacent to vessel or capsule) to reduce LTP. Results: 1208 HCCs were collected as training (n=502), validation (n=180), internal test (n=250) and external test (n=276) sets. AUC of model was 0.809 and 0.811 in internal and external test sets. High-invasiveness group showed higher microvascular invasion proportion, higher macrotrabecular-massive HCC proportion, lower differentiation, higher CK-7 and GPC-3 positive rate and higher VEGFA, MMP-9, HSPA1A expression ( <jats:italic toggle=\"yes\">p</jats:italic> <0.05). KEGG and GSEA analysis revealed the upregulation of pathways related to angiogenesis, tolerance to stress response, and tumor metastasis in high-invasiveness group. The 8 mm MAM ablation strategy can effectively decrease the LTP incidence of high-invasiveness group (from 42.4% to 10.5%, <jats:italic toggle=\"yes\">p</jats:italic> =0.027) to the level comparable to low-invasiveness group (10.5% vs. 6.1%, <jats:italic toggle=\"yes\">p</jats:italic> =0.613) in external test set. Conclusion: Multimodal model achieved satisfactory performance on classifying tumor invasiveness, and provided effective strategy for high-invasiveness tumor to reduce LTP occurrence.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"5 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-14DOI: 10.1097/hep.0000000000001676
Jasmine J Wang,Yi-Te Lee,Amy K Kim,Augusto Villauneva,Amit G Singal,Ju Dong Yang
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death globally. HCCs are often diagnosed in advanced stages, and most patients are not eligible for curative treatments. Semiannual abdominal ultrasound with serum alpha-fetoprotein is the current recommended surveillance strategy; however, it has suboptimal sensitivity and implementation, thereby lowering its effectiveness for early-stage HCC detection. Further, post-treatment monitoring of HCC recurrence or progression is not tailored to tumor aggressiveness. These failures highlight critical unmet needs, which can be addressed by novel biomarkers that enable early detection and guide individualized surveillance and post-treatment follow-up for HCC, ultimately leading to improved outcomes in this disease. Cell-free DNA (cfDNA), consisting of small fragments of DNA released from tumor and normal cells into the bloodstream, reflects tumor-specific molecular alterations and has emerged as a promising non-invasive biomarker. This review summarizes recent advances in cfDNA applications in HCC, including risk stratification, early detection, prognostication, and minimal residual disease assessment. Among them, cfDNA has made the most progress in early detection. cfDNA assays, combined with clinical and serum parameters, demonstrate sensitivity non-inferior or superior to ultrasound for detecting early HCC, with larger phase 3 validation studies ongoing. In contrast, the use of cfDNA for risk stratification, prognostication, and minimal residual disease detection remains in the early stages of clinical development. Future multicenter studies with standardized methodologies and rigorous validation will be essential to translate cfDNA into routine clinical practice for the management of HCC.
{"title":"Clinical utilization of testing for cell-free DNA in hepatocellular cancer.","authors":"Jasmine J Wang,Yi-Te Lee,Amy K Kim,Augusto Villauneva,Amit G Singal,Ju Dong Yang","doi":"10.1097/hep.0000000000001676","DOIUrl":"https://doi.org/10.1097/hep.0000000000001676","url":null,"abstract":"Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death globally. HCCs are often diagnosed in advanced stages, and most patients are not eligible for curative treatments. Semiannual abdominal ultrasound with serum alpha-fetoprotein is the current recommended surveillance strategy; however, it has suboptimal sensitivity and implementation, thereby lowering its effectiveness for early-stage HCC detection. Further, post-treatment monitoring of HCC recurrence or progression is not tailored to tumor aggressiveness. These failures highlight critical unmet needs, which can be addressed by novel biomarkers that enable early detection and guide individualized surveillance and post-treatment follow-up for HCC, ultimately leading to improved outcomes in this disease. Cell-free DNA (cfDNA), consisting of small fragments of DNA released from tumor and normal cells into the bloodstream, reflects tumor-specific molecular alterations and has emerged as a promising non-invasive biomarker. This review summarizes recent advances in cfDNA applications in HCC, including risk stratification, early detection, prognostication, and minimal residual disease assessment. Among them, cfDNA has made the most progress in early detection. cfDNA assays, combined with clinical and serum parameters, demonstrate sensitivity non-inferior or superior to ultrasound for detecting early HCC, with larger phase 3 validation studies ongoing. In contrast, the use of cfDNA for risk stratification, prognostication, and minimal residual disease detection remains in the early stages of clinical development. Future multicenter studies with standardized methodologies and rigorous validation will be essential to translate cfDNA into routine clinical practice for the management of HCC.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"82 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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