JHEP Reports最新文献

{"title":"Self-supervised learning to predict intrahepatic cholangiocarcinoma transcriptomic classes on routine histology","authors":"Aurélie Beaufrère ,&nbsp;Tristan Lazard ,&nbsp;Rémy Nicolle ,&nbsp;Gwladys Lubuela ,&nbsp;Jérémy Augustin ,&nbsp;Miguel Albuquerque ,&nbsp;Baptiste Pichon ,&nbsp;Camille Pignolet ,&nbsp;Victoria Priori ,&nbsp;Nathalie Théou-Anton ,&nbsp;Mickael Lesurtel ,&nbsp;Mohamed Bouattour ,&nbsp;Kévin Mondet ,&nbsp;Jérôme Cros ,&nbsp;Julien Calderaro ,&nbsp;Thomas Walter ,&nbsp;Valérie Paradis","doi":"10.1016/j.jhepr.2025.101675","DOIUrl":"10.1016/j.jhepr.2025.101675","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The transcriptomic classification of intrahepatic cholangiocarcinoma (iCCA) has recently been refined from two to five classes, each associated with pathological features, targetable genetic alterations, and survival outcomes. Despite its potential prognostic and therapeutic value, the transcriptomic classification is not routinely used in practice because of technical limitations, including insufficient tissue material and the high cost of molecular analyses. Here, we assessed a self-supervised learning (SSL) model for predicting iCCA transcriptomic classes on digitised whole-slide images (WSIs)</div></div><div><h3>Methods</h3><div>Transcriptomic classes defined from RNA sequencing data were available for all samples. The SSL method (Giga-SSL) was used to train our model on a discovery set of 766 WSIs from 137 biopsies and 109 surgical specimens obtained from 246 patients, using a five-fold cross-validation scheme. The model was validated in The Cancer Genome Atlas (TCGA) cohort (n = 29) and a French external validation set (n = 32), both using WSIs from surgical samples.</div></div><div><h3>Results</h3><div>The most frequent transcriptomic class was the hepatic stem-like class (37% [90/246] in the discovery set). Our model showed good to very good performance in predicting the four most frequent transcriptomic classes in the discovery set (AUC 0.63-0.84), especially for the hepatic stem-like class (AUC 0.84). The model performed equally well in predicting these transcriptomic classes in the two validation sets, with AUCs ranging from 0.76 to 0.80 in the TCGA set and 0.62 to 0.92 in the French external set.</div></div><div><h3>Conclusions</h3><div>We developed and validated an SSL-based model capable of predicting iCCA transcriptomic classes from routine histological slides of both biopsy and surgical samples. This approach may facilitate the clinical implementation of transcriptomic classification, improve prognostic assessment, and guide therapeutic decision-making in iCCA.</div></div><div><h3>Impact and implications</h3><div>Predicting transcriptomic classes directly from routine histological slides has the potential to enhance the clinical management of intrahepatic cholangiocarcinoma, enabling more accurate prognostication and supporting therapeutic decision-making. By eliminating the need for manual slide annotation, large tissue samples, or resource-intensive molecular analyses, our self-supervised learning-based model offers a practical and scalable solution that can be applied to both biopsy and surgical specimens. This approach could accelerate the adoption of transcriptomic classification in everyday practice and help guide more personalized treatment strategies for patients with intrahepatic cholangiocarcinoma.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101675"},"PeriodicalIF":7.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145814291","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}

{"title":"Evaluation and Management of Primary Sclerosing Cholangitis Patients Awaiting Liver Transplantation","authors":"A.D. Frolkis ,&nbsp;J.S. Nayagam ,&nbsp;A. Parente ,&nbsp;M. Seager ,&nbsp;M.D. Sadler ,&nbsp;A.J. Montano-Loza ,&nbsp;D. Joshi","doi":"10.1016/j.jhepr.2026.101748","DOIUrl":"10.1016/j.jhepr.2026.101748","url":null,"abstract":"<div><div>Primary sclerosing cholangitis (PSC) is a rare, progressive cholestatic liver disease characterized by biliary strictures, increased risk of cholangiocarcinoma, and a strong association with inflammatory bowel disease. Despite its low prevalence, PSC accounts for up to 17% of all liver transplants (LT) performed globally. Transplant-free survival ranges from a median of 9 to 21 years from diagnosis. LT is the only definitive treatment with post-LT survival in PSC exceeding 80% at 5 years. However, PSC recurs in approximately 25% of individuals. The absence of disease modifying therapy necessitates timely LT in select cases of hepatic decompensation, refractory pruritus, recurrent cholangitis, or selected early-stage malignancies. However, PSC poses unique challenges in pre-transplant assessment and timing due to its clinical heterogeneity and the suboptimal performance of conventional prognostic tools such as the MELD score. Although PSC specific scores offer improved risk stratification, they are not integrated into routine LT algorithms.</div><div>This review synthesizes current landscape of prognostic modeling in PSC, focusing on validated tools and their role in transplant decision making. We examine the range of LT indications in PSC, explore the interplay between PSC and inflammatory bowel disease with attention to malignancy surveillance and immunosuppression planning. We review the transplant evaluation process, including hepatobiliary imaging, endoscopy, and multidisciplinary approaches to high grade stricture evaluation and oncologic risk assessment.</div><div>By integrating contemporary evidence and expert opinion, this review aims to guide clinicians in the nuanced assessment and management of PSC patients in the peri-transplant period, emphasizing the need for individualized risk assessment and early referral to transplantation centres with hepatobiliary surgery and transplant expertise.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 4","pages":"Article 101748"},"PeriodicalIF":7.5,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147449983","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}

{"title":"Interleukin-18 binding protein deficiency results in gut microbiota dysbiosis and aggravated diet-induced MASH in mice","authors":"Emmanuel Somm ,&nbsp;Elodie Perroud ,&nbsp;Yunju Jo ,&nbsp;Karina Lindner ,&nbsp;Frédérique Ino ,&nbsp;Sophie A. Montandon ,&nbsp;Christelle Veyrat-Durebex ,&nbsp;Franck Bontems ,&nbsp;Florian Visentin ,&nbsp;Nadia Gaïa ,&nbsp;Vladimir Lazarevic ,&nbsp;Anne-Claude Gavin ,&nbsp;Jacques Schrenzel ,&nbsp;Dongryeol Ryu ,&nbsp;Karim Gariani ,&nbsp;Cem Gabay ,&nbsp;François R. Jornayvaz","doi":"10.1016/j.jhepr.2025.101629","DOIUrl":"10.1016/j.jhepr.2025.101629","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) are now the most prevalent hepatic disorders worldwide. Growing evidence implicates physiological alterations in the gut–liver axis and gut microbiota dysbiosis in this process. IL-18-binding protein (IL-18BP) forms high affinity complexes with IL-18, thus blocking its interaction with IL-18 receptors.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We used high-fat diet (HFD) and methionine choline deficient (MCD) diet to model MASLD/MASH in wild-type (WT) male mice (n = 6–8 mice per group). We also studied antimicrobial peptides (AMPs) production, gut microbiota composition, and liver phenotype in &lt;em&gt;Il18bp&lt;/em&gt;&lt;sup&gt;&lt;em&gt;-/-&lt;/em&gt;&lt;/sup&gt; male mice on both HFD and MCD diets (n = 5–7 mice per group). We manipulated gut microbiota of &lt;em&gt;Il18bp&lt;/em&gt;&lt;sup&gt;&lt;em&gt;-/-&lt;/em&gt;&lt;/sup&gt; and WT male mice through administration of phages, antibiotics, and through co-housing experiments (n = 4–8 mice per group).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Feeding WT mice with a HFD or an MCD diet led to a decrease in ileal AMPs expressions (respectively, by 63% and 37% for &lt;em&gt;Lyz1&lt;/em&gt;; by 47% and 84% for &lt;em&gt;Ang4&lt;/em&gt;; by 86% and 46% for &lt;em&gt;Pla2g2a&lt;/em&gt;) and an enrichment in gut proteobacteria (respectively, by 7- and 23-fold for α-proteobacteria; by 2.1- and 1.7-fold for δ-proteobacteria; by 14- and 20-fold for γ-proteobacteria) when compared with standard chow diet (&lt;em&gt;p&lt;/em&gt; &lt;0.05). These changes were associated with a reduction in the ileal &lt;em&gt;Il18bp&lt;/em&gt; expression (respectively, by 77% and 46%) in HFD and MCD diet-fed WT mice &lt;em&gt;vs.&lt;/em&gt; chow diet-fed WT mice (&lt;em&gt;p&lt;/em&gt; &lt;0.05). &lt;em&gt;Il18bp&lt;/em&gt;&lt;sup&gt;&lt;em&gt;-/-&lt;/em&gt;&lt;/sup&gt; mice exhibited a decrease in gut AMPs expression and storage (AMP granules area/crypt respectively decreased by 57% and 62.5% in &lt;em&gt;Il18bp&lt;/em&gt;&lt;sup&gt;&lt;em&gt;-/-&lt;/em&gt;&lt;/sup&gt; &lt;em&gt;vs.&lt;/em&gt; WT mice on HFD and MCD diets). Moreover, &lt;em&gt;Clostridium/Turicimonas/Escherichia&lt;/em&gt; bacteria were constitutively over-represented in gut microbiota of &lt;em&gt;Il18bp&lt;/em&gt;&lt;sup&gt;&lt;em&gt;-/-&lt;/em&gt;&lt;/sup&gt; &lt;em&gt;vs.&lt;/em&gt; WT mice in a diet-amplified manner. Compared with WT mice, &lt;em&gt;Il18bp&lt;/em&gt;&lt;sup&gt;&lt;em&gt;-/-&lt;/em&gt;&lt;/sup&gt; mice exhibited increased diet-induced hepatic damage (circulating alanine aminotransferase 84 &lt;em&gt;vs.&lt;/em&gt; 41 U/L on HFD; 1,218 &lt;em&gt;vs.&lt;/em&gt; 738 U/L on MCD diet, &lt;em&gt;p&lt;/em&gt; &lt;0.05), inflammation (liver tumor necrosis factor-alpha content 72 &lt;em&gt;vs.&lt;/em&gt; 35 pg/g protein on HFD; 441 &lt;em&gt;vs.&lt;/em&gt; 169 pg/g protein on MCD diet, &lt;em&gt;p&lt;/em&gt; &lt;0.05), and fibrosis (Sirius red 1.45 &lt;em&gt;vs.&lt;/em&gt; 0.36% on HFD; 1.64 &lt;em&gt;vs.&lt;/em&gt; 0.65% on MCD diet, &lt;em&gt;p&lt;/em&gt; &lt;0.01). These changes occurred independently of steatosis modification. Phages, antibiotic, and co-housing experiments revealed that specific gut microbiota featuring &lt;em&gt;Il18bp&lt;/em&gt;&lt;sup&gt;&lt;em&gt;-/-&lt;/em&gt;&lt;/sup&gt; mice is implicated in their exacerbated liver inflammation and fibro","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101629"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733852","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}

{"title":"HBV X protein regulates cancer stemness and tumor invasiveness through SENP1 in hepatocellular carcinoma","authors":"Yu-Chih Wu ,&nbsp;Yen-Chiao Huang ,&nbsp;Yung-Che Kuo ,&nbsp;Mai-Huong Thi Ngo ,&nbsp;Kam-Fai Lee ,&nbsp;Yen-Tseng Sung ,&nbsp;Hsiao-Feng Wang ,&nbsp;Shin-Lian Doong ,&nbsp;Liang-Mou Kuo ,&nbsp;Te-Sheng Chang ,&nbsp;Yen-Hua Huang","doi":"10.1016/j.jhepr.2025.101620","DOIUrl":"10.1016/j.jhepr.2025.101620","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The niche in hepatocellular carcinoma (HCC) critically influences cancer stem cell (CSC)-associated properties, including stemness, early recurrence, and poor prognoses. HBV infection acts as a niche driver for tumor progression and malignancy. While the HBV X (HBx) protein has been linked to CSC-associated properties, the underlying molecular mechanisms remain unclear.</div></div><div><h3>Methods</h3><div>Paired tumor and peritumor tissues from 211 patients with HCC were analyzed to correlate <em>SENP1</em>, <em>OCT4</em>, <em>SNAIL</em>, <em>PIN1</em>, and <em>TWIST</em> expression with overall survival (OS) and disease-free survival (DFS) using a Kaplan-Meier survival analysis. Validation was performed using HCC microarray data (n = 167). HBx-SENP1’s role in regulating CSC-associated properties was examined <em>in vitro</em> (stemness expression, sphere formation, CD133⁺ cells, migration/invasion, and sorafenib sensitivity) and <em>in vivo</em> using an orthotopic xenograft model.</div></div><div><h3>Results</h3><div>Clinically, SENP1 expression was correlated with OCT4, SNAIL, and TWIST (<em>p &lt;</em>0.001), and was associated with poor OS (69.2 <em>vs.</em> 172.8 months, <em>p</em> &lt;0.001) and DFS (15.8 <em>vs.</em> 39.7 months, <em>p &lt;</em>0.001). SENP1 expression was correlated with gene sets linked to HCC recurrence and embryonic stem cell signatures. In HBV-related HCC, elevated SENP1 (7.8 <em>vs.</em> 15.7 months, <em>p</em> = 0.003), OCT4 (7.8 <em>vs.</em> 16.7 months, <em>p</em> &lt;0.001), SNAIL (8.6 <em>vs.</em> 15.7 months, <em>p</em> = 0.012), and TWIST (8.2 <em>vs.</em> 15.5 months, <em>p</em> = 0.028) were linked to early recurrence. Mechanistically, HBx induced CSC-associated properties through SENP1, including sphere formation, CD133⁺ cells, migration/invasion, and sorafenib resistance. SENP1-knockdown decreased HBx-induced pulmonary metastases and sorafenib refractoriness <em>in vivo</em>.</div></div><div><h3>Conclusions</h3><div>HBx-induced SENP1 is critical for CSC properties. SENP1 can serve as a novel biomarker for early recurrence, metastasis, and drug resistance, particularly in HBV-related HCC.</div></div><div><h3>Impact and implications</h3><div>Early recurrence, tumor metastasis, and drug resistance are significant therapeutic challenges in hepatocellular carcinoma (HCC), which are closely associated with cancer stem cell (CSC)-related properties. In this study, we demonstrated that HBx-induced SENP1 expression regulates CSC-related properties and tumor metastasis, particularly in HBV-related HCC, in clinical, <em>in vitro</em>, and <em>in vivo</em> settings. Findings from this research highlight that HBx-induced SENP1 is crucial for promoting CSC-associated properties in HCC. SENP1 could serve as a novel biomarker of early tumor recurrence and metastasis, especially for HBV-related HCC.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101620"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682323","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}

{"title":"Enhanced nuclear localization of small heterodimer partner in metabolic dysfunction-associated steatohepatitis","authors":"Shih-Chieh Chien ,&nbsp;Chiung-Yu Chen ,&nbsp;Hung-Wen Tsai ,&nbsp;Yih-Jyh Lin ,&nbsp;Shu-Chu Shiesh ,&nbsp;Pin-Nan Cheng ,&nbsp;Hung-Chih Chiu ,&nbsp;Yen-Cheng Chiu ,&nbsp;Ya-Han Lin ,&nbsp;Min-Shan Wu ,&nbsp;Mei-Juan Zheng ,&nbsp;Kung-Chia Young ,&nbsp;Yau-Sheng Tsai","doi":"10.1016/j.jhepr.2025.101616","DOIUrl":"10.1016/j.jhepr.2025.101616","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The nuclear factor small heterodimer partner (SHP) plays a dual function in maintaining bile acid (BA) homeostasis and exerting anti-inflammatory effects. While SHP might be associated with metabolic dysfunction-associated steatohepatitis (MASH), its role in patients remains unclear.</div></div><div><h3>Methods</h3><div>Liver tissue and serum samples were collected from 69 patients with MASH and 10 healthy controls. The subcellular distribution of SHP and related proteins in liver tissue were analyzed to correlate with MASH-associated pathological characteristics. <em>In vitro</em> studies were conducted to elucidate the underlying mechanisms and clinical relevance of SHP nuclear translocation in MASH.</div></div><div><h3>Results</h3><div>Compared with controls, patients with MASH demonstrated a higher nuclear SHP ratio (51.7% <em>vs.</em> 1.55%, <em>p</em> &lt;0.001), which correlated with the severity of hepatitis and steatosis, but not with serum BA levels. The nuclear SHP ratio increased in parallel with atypical protein kinase C zeta (PKCζ) signal intensity and showed high co-localization with nucleoporin RanBP2. <em>In vitro</em> experiments demonstrated that both toxic fatty acid and inflammatory cytokine could induce SHP nuclear translocation, which was blocked by PKCζ inhibition. <em>SHP</em> knockdown increased basal innate immune activity, accelerated intracellular lipid accumulation, and recapitulated a MASH-like gene profile that facilitates BA accumulation.</div></div><div><h3>Conclusions</h3><div>Nuclear SHP accumulation is a distinctive feature of MASH pathology. This PKCζ-dependent process may exert anti-inflammation and anti-cholestasis function in patients with MASH.</div></div><div><h3>Impact and implications</h3><div>The nuclear factor small heterodimer partner (SHP) plays a dual role in maintaining bile acid homeostasis and suppressing inflammation. In patients with metabolic dysfunction-associated steatohepatitis (MASH), we identified a pathological increase in the hepatocellular nuclear SHP ratio, likely triggered by lipid overload and inflammatory stimuli, and dependent on PKCζ activation. <em>SHP</em> knockdown <em>in vitro</em> induced cellular steatosis, innate immune responses, and leading to a cholestatic gene expression profile. These findings highlight SHP as a potential therapeutic target in MASH.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101616"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682290","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}

{"title":"Liver transplantation for hepatopulmonary syndrome: A systematic review and meta-analysis","authors":"Maïté Verstraeten ,&nbsp;Mattice De Clercq ,&nbsp;Hanne De Craemer ,&nbsp;Xavier Verhelst ,&nbsp;Sander Lefere ,&nbsp;Lindsey Devisscher ,&nbsp;Anja Geerts ,&nbsp;Hans Van Vlierberghe ,&nbsp;Michael B. Fallon ,&nbsp;Sarah Raevens","doi":"10.1016/j.jhepr.2025.101659","DOIUrl":"10.1016/j.jhepr.2025.101659","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Hepatopulmonary syndrome (HPS) is a severe pulmonary vascular complication of liver disease. Liver transplantation (LT) is the only definitive treatment, yet a contemporary synthesis of LT outcomes in HPS, alongside persisting uncertainties, is lacking.</div></div><div><h3>Methods</h3><div>We conducted a systematic review and meta-analysis of 22 studies to evaluate HPS prevalence, post-LT survival, and HPS resolution.</div></div><div><h3>Results</h3><div>Pooled HPS prevalence was 17.2% (11.6–24.7%, n = 1,171 studied patients) among patients with cirrhosis evaluated for LT, 26.1% (18.5–35.5%, n = 629) in patients with portal hypertension evaluated for LT and 21.6% (11.2–37.4%, n = 737) in LT recipients. Under current model for end-stage liver disease (MELD) exception policies, waitlist mortality was 13.1% (0.6–78.5%, n = 1,240 studied patients). Post-LT survival in patients with HPS was comparable to that in patients without HPS and aligned with international benchmarks. Pooled 1-year post-LT survival rates were 85.5% in prospective studies from the pre- and post-MELD era (n = 240 studied patients), 93.9% in the post-MELD era (n = 99), and 83.8% in registry-based studies (n = 800). Pooled estimates for 5-year post-LT survival rates were 85% (n = 144 studied patients), 92.9% (n = 99), and 76% (n = 739), respectively. Lower pre-LT PaO₂ correlated with poorer post-LT survival, especially in very severe HPS. HPS resolved after LT in 90.1% (71.7-97.0%, n = 80 studied patients) of patients at 6 months, with complete resolution within 1 year in all patients assessed. Key gaps remain regarding the influence of underlying liver disease on HPS progression, the optimal timing of LT, and factors affecting post-LT recovery.</div></div><div><h3>Conclusions</h3><div>LT offers substantial survival and clinical benefits for patients with HPS, with high rates of HPS resolution within a year. Patients with very severe HPS warrant closer monitoring, and further research is needed to address unresolved questions regarding disease trajectory and post-transplant outcomes.</div></div><div><h3>Impact and implications</h3><div>This systematic review and meta-analysis shows that liver transplantation (LT) is an effective treatment for hepatopulmonary syndrome (HPS), resulting in high rates of syndrome resolution and post-transplant survival comparable to patients without HPS. These findings support the continued use of MELD exception policies and underscore the importance of timely referral for LT. While outcomes are generally favorable, patients with very severe HPS may experience worse post-transplant outcomes, highlighting the need for more tailored clinical management. A key unmet need remains in understanding the role of underlying liver disease severity in the natural history of HPS, as well as the optimal timing for LT and factors influencing post-transplant recovery.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101659"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836509","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}

{"title":"Navigating second-line therapy after immunotherapy in advanced HCC☆","authors":"Arndt Vogel ,&nbsp;Anna Saborowski ,&nbsp;Lorenza Rimassa ,&nbsp;Anthony El-Khoueiry","doi":"10.1016/j.jhepr.2025.101630","DOIUrl":"10.1016/j.jhepr.2025.101630","url":null,"abstract":"<div><div>In recent years, systemic treatment options for hepatocellular carcinoma have expanded significantly, with pivotal phase III trials reporting unprecedented improvements in survival and response outcomes. However, these advances have largely focused on first-line strategies, challenging existing treatment sequences and raising questions about the optimal therapeutic approach following disease progression. Several therapeutic options are available in second and later lines — including immunotherapies, tyrosine kinase inhibitors, and local therapies — but so far comprehensive head-to-head comparisons to establish the ideal treatment sequence are lacking. Consequently, most evidence guiding second-line therapy has been derived from <em>post hoc</em> analyses, real-world data, and select prospective studies, primarily based on phase II designs. In clinical practice, treatment decisions integrate this evolving evidence base with patient-specific factors such as prior treatment response, liver function, and performance status, often within the constraints of regulatory and accessibility considerations. Ongoing research is investigating novel approaches, including the continuation of immunotherapy following progression, the application of CAR T cells, and targeted treatments against specific markers like fibroblast growth factor 19 and glypican-3. This review summarises the current evidence for second-line and subsequent therapies, explores key considerations in treatment sequencing, and highlights emerging strategies that may further refine the therapeutic landscape for hepatocellular carcinoma.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101630"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786930","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}

{"title":"Liver transplantation for HCC with macrovascular invasion: A systematic review and meta-analysis of observational studies","authors":"Farah Ladak ,&nbsp;Christian Tibor Josef Magyar ,&nbsp;Felipe D. Gaviria ,&nbsp;Woo Jin Choi ,&nbsp;Anudari Zorigtbaatar ,&nbsp;Roxana Bucur ,&nbsp;Nadia Rukavina ,&nbsp;Arndt Vogel ,&nbsp;Grainne Mary O’Kane ,&nbsp;Zhihao Li ,&nbsp;Marina Englesakis ,&nbsp;Gonzalo Sapisochin","doi":"10.1016/j.jhepr.2025.101566","DOIUrl":"10.1016/j.jhepr.2025.101566","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Traditional guidelines discourage liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) with macrovascular invasion (MVI). However, emerging evidence suggests that long-term survival is possible when LT is preceded by downstaging therapies. Thus, a pooled analysis of time-dependent risk factor effect size on overall survival (OS) is warranted to determine the effect size of MVI, estimate risk mitigation through downstaging, and design future trials.</div></div><div><h3>Methods</h3><div>MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and the Cochrane Register were systematically searched from their inception to 24 January 2023. Studies with comparative oncological outcome data between patients with HCC and MVI (MVI group) and HCC patients without MVI (non-MVI group) were included. Frequentist pairwise meta-analysis (random-effects model) was performed for primary outcomes of OS and recurrence-free survival (RFS) at 5 years. Only studies with adjusted effect estimates were considered for analysis.</div></div><div><h3>Results</h3><div>In total, 10 studies were included in this systematic review and meta-analysis, contributing 15,899 patients. Seven studies included deceased donor LT, and four studies included living donor LT. In the quantitative analysis of studies reporting adjusted effect estimates, presence of MVI was associated with lower 5-year OS (hazard ratio (HR) 2.03; 95% CI 1.60–2.57; <em>p</em> &lt;0.001; I² = 55%; <em>p</em> = 0.05) and 5-year RFS (HR 2.55; 95% CI 1.69–3.85; <em>p</em> &lt;0.001; I² = 87%; <em>p</em> &lt;0.01). When downstaging was uniformly applied, no statistically significant difference for 5-year OS was observed between the MVI group and non-MVI group (HR 1.55; 95% CI 0.88–2.73; <em>p</em> =0.129; I² = 46%; <em>p</em> = 0.17).</div></div><div><h3>Conclusions</h3><div>Effective downstaging in carefully selected patients with HCC with MVI could achieve survival outcomes approaching those of patients without MVI. Further studies are essential to validate these findings and to clarify which downstaging approaches and tumor characteristics are most likely to confer a transplant benefit.</div></div><div><h3>Impact and implications</h3><div>This meta-analysis provides the first pooled HRs for the effect of MVI on LT outcomes, emphasizing the potential for downstaging therapies to mitigate poor prognosis in HCC. The findings advocate for redefining LT eligibility criteria to incorporate successful downstaging protocols, potentially expanding treatment options for advanced HCC. These insights underline the need for standardized downstaging protocols and prospective trials to optimize patient selection and outcomes globally for LT.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101566"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682287","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}

{"title":"PNPLA3 and TM6SF2 exacerbate the impact of alcohol and metabolic dysfunction on liver fibrosis","authors":"Sophie Gensluckner ,&nbsp;Helle Lindholm Schnefeld ,&nbsp;Jan Embacher ,&nbsp;Camilla Dalby Hansen ,&nbsp;Lorenz Balcar ,&nbsp;Katrine Tholstrup Bech ,&nbsp;Paul Thöne ,&nbsp;Nikolaj Torp ,&nbsp;Bernhard Wernly ,&nbsp;Laura Maarit Pikkupeura ,&nbsp;Stephan Zandanell ,&nbsp;Christian Datz ,&nbsp;Michael Strasser ,&nbsp;Mads Israelsen ,&nbsp;Mattias Mandorfer ,&nbsp;Torben Hansen ,&nbsp;Aleksander Krag ,&nbsp;Elmar Aigner ,&nbsp;Maja Thiele ,&nbsp;Georg Semmler","doi":"10.1016/j.jhepr.2025.101649","DOIUrl":"10.1016/j.jhepr.2025.101649","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Genetic predisposition (especially variants in <em>PNPLA3</em> and <em>TM6SF2</em>), metabolic dysfunction, and alcohol consumption are established risk factors for steatotic liver disease (SLD) and progression of fibrosis. However, the clinical relevance of their interaction and its implications for patient management remain unclear.</div></div><div><h3>Methods</h3><div>We cross-sectionally analyzed data from two cohorts: patients referred to tertiary liver care (N = 1,554) and individuals at risk for SLD (N = 1,728). Multivariable regression models with and without interaction terms were used to assess the independent and interactive effects of genetic risk variants, metabolic dysfunction (HOMA-IR, BMI), and alcohol intake on liver fibrosis severity as assessed by liver stiffness measurement (LSM).</div></div><div><h3>Results</h3><div>Mean age was 52 and 56 years in the Tertiary-care cohort and the At-risk cohort, respectively. Most participants were male, 23% and 53% suffered from obesity, and 39% and 58% were categorized as insulin resistant, respectively. Median LSM was 5.5 kPa and 4.7 kPa, with 21% and 9.6% having LSM ≥8 kPa, respectively. In total, 48% and 44% carried at least one <em>PNPLA3</em> G-allele (C/G or G/G), and 18% and 15% the <em>TM6SF2</em> T-allele (C/T or T/T), respectively. In multivariable regression without interaction terms, LSM was associated with HOMA-IR, alcohol consumption, BMI (At-risk cohort), <em>PNPLA3</em> and <em>TM6SF2</em>. However, when allowing for interactions, the independent effects of genetic risk variants disappeared. Instead, <em>PNPLA3</em> potentiated the association of HOMA-IR (<em>p</em> &lt;0.001/<em>p</em> = 0.016) and severe alcohol consumption (<em>p</em> &lt;0.001/<em>p</em> = 0.093) with LSM. <em>TM6SF2</em> amplified the effect of BMI (<em>p</em> = 0.006) and severe alcohol consumption (<em>p</em> &lt;0.001) on LSM in the Tertiary-care-cohort.</div></div><div><h3>Conclusions</h3><div>Our findings indicate that <em>PNPLA3</em> and <em>TM6SF2</em> variants do not act as independent determinants of liver fibrosis once gene–environment interactions are considered. Instead, they amplify the harmful effects of metabolic dysfunction and alcohol consumption in individuals evaluated for SLD, creating a synergistic risk profile.</div></div><div><h3>Impact and implications</h3><div>Our findings indicate that fibrosis progression in steatotic liver disease is mediated by an interaction of environmental risk factors (obesity, insulin resistance, alcohol consumption) and genetic risk variants, such as <em>PNPLA3</em> and <em>TM6SF2</em>, but not by genetic variants alone. This highlights the importance of acknowledging these gene–environment interactions for patient counselling and risk stratification.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101649"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733850","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}

{"title":"Acknowledging our reviewers","authors":"","doi":"10.1016/j.jhepr.2025.101632","DOIUrl":"10.1016/j.jhepr.2025.101632","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101632"},"PeriodicalIF":7.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145977092","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}