JHEP Reports最新文献

{"title":"Impact of age on clinical outcomes among patients with hepatocellular carcinoma: A systematic review and meta-analysis","authors":"Olgert Bardhi ,&nbsp;Darine Daher ,&nbsp;Mausam Patel ,&nbsp;Karim Seif El-Dahan ,&nbsp;Nicole E. Rich ,&nbsp;Sukul Mitta ,&nbsp;Neehar D. Parikh ,&nbsp;Anjana Pillai ,&nbsp;Laura M. Kulik ,&nbsp;Ju Dong Yang ,&nbsp;Anand V. Kulkarni ,&nbsp;Purva Gopal ,&nbsp;Amit G. Singal","doi":"10.1016/j.jhepr.2025.101368","DOIUrl":"10.1016/j.jhepr.2025.101368","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Older adults have lower treatment eligibility and worse survival across cancer types; however, the association between age and outcomes in patients with hepatocellular carcinoma (HCC) has not been well characterized.</div></div><div><h3>Methods</h3><div>We performed a search of the PubMed, Ovid MEDLINE, and EMBASE databases from January 2000 to July 2022 to identify studies reporting tumor stage, curative treatment, and overall survival among patients with HCC, stratified by age. Using the DerSimonian and Laird method for a random-effects model, we calculated pooled risk ratios (RRs) for curative treatment receipt and hazard ratios (HRs) for overall survival among younger and older patients (per age thresholds in each study).</div></div><div><h3>Results</h3><div>We identified 103 studies (n = 154,152 patients) that reported outcomes in younger <em>vs</em>. older patients with HCC. Younger patients were more likely to undergo curative treatment (RR 1.48, 95% CI 1.24–1.77; I² = 99%), although few studies reported treatment among those with early-stage HCC. Younger patients had better survival than older patients (HR 0.87, 95% CI 0.83–0.92; I² = 89%), which was consistent in subgroups using age thresholds of &lt;70 years (HR 0.94, 95% CI 0.89–0.99; I² = 78%) and &lt;75 years (HR 0.83, 95% CI 0.70–0.98; I² = 79%). Younger patients also had better survival in studies of patients with early-stage HCC (HR 0.78, 95% CI 0.65–0.94; I² = 60%) and those undergoing curative therapy (HR 0.87, 95% CI 0.77–0.98; I² = 87%).</div></div><div><h3>Conclusions</h3><div>Older patients with HCC are less likely to receive curative treatment and have worse survival than their younger counterparts. Studies to identify factors associated with worse prognosis can inform intervention targets.</div></div><div><h3>Impact and implications</h3><div>Older adults have worse survival across cancer types, although there are discordant data about the association between age and clinical outcomes in patients with hepatocellular carcinoma (HCC). Lower curative treatment receipt among older patients, despite similar early-stage presentation compared with younger patients, requires future studies to identify mediators that can inform intervention strategies that can increase curative treatment use. Worse survival observed among older patients appears to be primarily driven by non-liver-related mortality; however, few studies distinguish between liver and non-liver mortality. A better understanding of the prognostic value of comorbidity burden, in addition to age, can inform clinical decisions about stopping rules for HCC surveillance as well as the potential for HCC overdiagnosis and overtreatment.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 6","pages":"Article 101368"},"PeriodicalIF":9.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144090170","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":"Thyroid dysfunction in MASLD: Results of a nationwide study","authors":"Shuai Yuan ,&nbsp;Fahim Ebrahimi ,&nbsp;David Bergman ,&nbsp;Marijana Vujković ,&nbsp;Eleonora Scorletti ,&nbsp;Xixin Ruan ,&nbsp;Jie Chen ,&nbsp;Hannes Hagström ,&nbsp;Jonas F. Ludvigsson","doi":"10.1016/j.jhepr.2025.101369","DOIUrl":"10.1016/j.jhepr.2025.101369","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Thyroid hormones are known to be potent modulators of hepatic metabolism and targeting the thyroid hormone receptor was recently approved as the first treatment for metabolic-associated steatotic liver disease (MASLD); however, the exact relationship between thyroid disorders and biopsy-confirmed MASLD remains unclear.</div></div><div><h3>Methods</h3><div>We conducted a nationwide matched case–control study leveraging data from the Swedish Epidemiology Strengthened by histoPathology Reports in Sweden (ESPRESSO) cohort, which includes liver biopsy data spanning from 1969 to 2017. We identified 12,172 patients with MASLD and 56,831 matched general-population controls, including 5,478 patients with MASLD with 10,682 sibling controls. Conditional logistic regression was used to calculate odds ratios for hypothyroidism and hyperthyroidism defined through ICD codes or prescription records. Causal inference was examined using Mendelian randomization (MR). Both observational and MR mediation analyses were performed to explore the roles of metabolic features.</div></div><div><h3>Results</h3><div>Hypothyroidism was associated with 1.68-fold increased odds of MASLD (95% CI 1.36–2.06). The association remained stable in the analysis using siblings as controls. However, in absolute terms, hypothyroidism was uncommon and seen in 2.5% in people with MASLD and in 1.4% of controls. Higher genetically predicted thyroid-stimulating hormone levels and hypothyroidism were linked to increased MASLD risk. Mediation analysis showed that metabolic disorders contributed ∼41% to this risk. Furthermore, there was an inverse association between hyperthyroidism and MASLD (adjusted odds ratio 0.17, 95% CI 0.05–0.56); however, the association did not reach statistical significance in the MR analysis.</div></div><div><h3>Conclusions</h3><div>The findings suggest that hypothyroidism is associated with a heightened risk of MASLD and that hyperthyroidism is potentially protective against MASLD.</div></div><div><h3>Impact and implications</h3><div>The approval by the US FDA of resmetirom, a thyroid hormone receptor β-selective agonist for non-cirrhotic metabolic dysfunction-associated steatohepatitis with stage 2–3 fibrosis, highlights the potential role of thyroid dysfunction in metabolic-associated steatotic liver disease (MASLD). This study identified hypothyroidism as a risk factor for MASLD, especially in men and individuals younger than 40 years, with the association peaking at non-cirrhotic fibrosis. Metabolic disorders mediated ∼41% of the hypothyroidism–MASLD association. Hyperthyroidism was potentially inversely associated with MASLD. Despite its low prevalence (2.5% in MASLD cases, 1.4% in controls), the population health impact of hypothyroidism warrants further attention.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101369"},"PeriodicalIF":9.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870817","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":"Reply to: “Comment on “Lower incidence of hepatocellular carcinoma with tenofovir alafenamide in chronic hepatitis B: Evidence from a large-scale cohort””","authors":"Jisoo Lee ,&nbsp;Jae-Young Kim ,&nbsp;Jeong-Ju Yoo ,&nbsp;Hye Won Lee ,&nbsp;Sang Gyune Kim ,&nbsp;Young Seok Kim","doi":"10.1016/j.jhepr.2025.101371","DOIUrl":"10.1016/j.jhepr.2025.101371","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101371"},"PeriodicalIF":9.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered liver sinusoidal endothelial cells in MASLD and their evolution following lanifibranor treatment","authors":"Pierre-Emmanuel Rautou ,&nbsp;Shivani Chotkoe ,&nbsp;Louise Biquard ,&nbsp;Guillaume Wettstein ,&nbsp;Denise van der Graaff ,&nbsp;Yao Liu ,&nbsp;Joris De Man ,&nbsp;Christophe Casteleyn ,&nbsp;Sofie Thys ,&nbsp;Winnok H. De Vos ,&nbsp;Pierre Bedossa ,&nbsp;Michael P. Cooreman ,&nbsp;Martine Baudin ,&nbsp;Jean-Louis Abitbol ,&nbsp;Philippe Huot-Marchand ,&nbsp;Lucile Dzen ,&nbsp;Miguel Albuquerque ,&nbsp;Pierre Broqua ,&nbsp;Jean-Louis Junien ,&nbsp;Luisa Vonghia ,&nbsp;Sven M. Francque","doi":"10.1016/j.jhepr.2025.101366","DOIUrl":"10.1016/j.jhepr.2025.101366","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Data on changes in liver sinusoidal endothelial cells (LSECs) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and their response to treatment are limited. This study aimed at determining (i) features associated with LSEC capillarisation in patients with MASLD; (ii) whether LSEC changes can regress with the pan-peroxisome proliferator-activated receptor (PPAR) agonist lanifibranor; (iii) the role of the different PPAR isotypes on LSEC changes in MASLD.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We analysed CD34 expression, a marker of LSEC capillarisation, on liver biopsies from patients considered for inclusion in the NATIVE trial at baseline (n = 249), and after 24 weeks of placebo or lanifibranor (n = 173). Two rat models of MASLD were used to investigate the effect of lanifibranor or of mono-PPAR agonists on LSECs.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Lobular CD34 staining was more intense in patients with isolated steatosis than in those with no MASLD (52% &lt;em&gt;vs.&lt;/em&gt; 10%; &lt;em&gt;p&lt;/em&gt; = 0.03). In the overall cohort, this staining was more intense in patients with metabolic dysfunction-associated steatohepatitis (MASH) than in those without (63% &lt;em&gt;vs.&lt;/em&gt; 41%; &lt;em&gt;p&lt;/em&gt; = 0.01) and strongly correlated with liver fibrosis and to a lesser extent with liver inflammation. Lanifibranor treatment was associated with more common improvement in CD34 periportal staining (&lt;em&gt;p&lt;/em&gt; = 0.025), and less frequent worsening of lobular staining (&lt;em&gt;p&lt;/em&gt; = 0.028). Compared with healthy rats, rats with MASLD had higher CD34 staining, portal venous pressure, intrahepatic vascular resistance, and impaired liver endothelial function. Lanifibranor normalised or strongly improved these abnormalities, whereas mono-PPAR agonists caused partial improvements.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;In patients, LSEC capillarisation was increased at the earliest stages of MASLD and was associated with liver fibrosis and inflammation. In both patients and rats with MASLD, lanifibranor treatment was associated with improvement in liver endothelial phenotype.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Data on changes in liver sinusoidal endothelial cells (LSECs) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and their response to treatment are limited. This study demonstrates that LSEC capillarisation is already present in the lobular zone of the liver of patients and rats at the stage of isolated steatosis, before metabolic dysfunction-associated steatohepatitis (MASH) onset, and progresses with liver fibrosis, and to a lesser extent with liver inflammation. Lanifibranor treatment, a pan-peroxisome proliferator-activated receptor agonist currently tested in a phase III clinical trial, improves LSEC capillarisation but also intrahepatic vascular resistance and portal pressure in MASLD. Targeting LSECs appears to be a promising approach to improve MASH.&lt;/","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 6","pages":"Article 101366"},"PeriodicalIF":9.5,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143934908","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":"Towards precision medicine strategies using plasma proteomic profiling for suspected gallbladder cancer: A pilot study","authors":"Ghada Nouairia ,&nbsp;Martin Cornillet ,&nbsp;Hannes Jansson ,&nbsp;Annika Bergquist ,&nbsp;Ernesto Sparrelid","doi":"10.1016/j.jhepr.2025.101365","DOIUrl":"10.1016/j.jhepr.2025.101365","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Currently, preoperative diagnostic methods that can distinguish cancer from benign disease of the gallbladder are insufficient, and several surgical resections can be avoided if the pathology is known prior to surgery. This study aimed to assess whether preoperative plasma proteins can distinguish gallbladder cancer (GBC) from cholecystitis, with the main goal of identifying proteins for multivariate description of the postoperative diagnosis, before surgery.</div></div><div><h3>Methods</h3><div>Samples from 82 individuals with suspected GBC who underwent bisegmentectomy and lymphadenectomy at Karolinska University Hospital between 2009 and 2020 were included in this retrospective, observational, single-center study. Preoperative plasma samples were analyzed using a 7,500 proteomics panel from SomaScan®. High-dimensional statistical methods including machine learning regularization, were used to analyze the data.</div></div><div><h3>Results</h3><div>In our study, we identified and characterized a panel of 651 proteins that exhibited differential expression between GBC and cholecystitis. Through multivariate analysis, we demonstrated that circulating proteomics data provide valuable insights for diagnosing GBC before surgical intervention. Notably, we identified a subset of eight plasma proteins (PAHX, CD8A, HRG, CRIS2, Dynactin subunit 2, AT2A3, CSTN2, and DEPP) that effectively differentiated GBC from cholecystitis with a diagnostic accuracy of 94% when validated on a test set. These findings hold potential for clinical validation and could significantly aid in preoperative decision-making when GBC is suspected.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that the preoperative assessment of plasma proteins can accurately differentiate cholecystitis from malignancy, supporting the potential development of a noninvasive test to assist preoperative decision-making when GBC is suspected.</div></div><div><h3>Impact and implications</h3><div>This study highlights the potential of plasma proteomic profiling to significantly improve the preoperative diagnostic accuracy of gallbladder cancer <em>vs.</em> cholecystitis. Using machine learning models, we identified biologically relevant plasma proteins associated with the diagnosis of gall bladder cancer. A noninvasive preoperative test based on selected plasma proteins could potentially enhance clinical decision-making, reduce unnecessary surgeries, and mitigate the associated risks for patients with suspected GBC, marking a step forward in precision medicine.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 6","pages":"Article 101365"},"PeriodicalIF":9.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143918306","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":"Randomised trial comparing weight loss through lifestyle and GLP-1 receptor agonist therapy in people with MASLD","authors":"Ahmad Moolla ,&nbsp;Toryn Poolman ,&nbsp;Nantia Othonos ,&nbsp;Jiawen Dong ,&nbsp;Kieran Smith ,&nbsp;Thomas Cornfield ,&nbsp;Sarah White ,&nbsp;David W. Ray ,&nbsp;Sofia Mouchti ,&nbsp;Ferenc E. Mózes ,&nbsp;Helena Thomaides-Brears ,&nbsp;Stefan Neubauer ,&nbsp;Jeremy F. Cobbold ,&nbsp;Leanne Hodson ,&nbsp;Jeremy W. Tomlinson","doi":"10.1016/j.jhepr.2025.101363","DOIUrl":"10.1016/j.jhepr.2025.101363","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Glucagon-like peptide 1 receptor agonist (GLP-1RA) therapies deliver histological benefit in people with metabolic dysfunction-associated steatotic liver disease (MASLD). Multiple mechanisms may be important including weight loss, improved glycaemic control and putative direct tissue-specific actions. Following cessation of GLP1-RA therapy, weight regain is common. To dissect the mechanisms underpinning their benefits, we conducted a prospective, randomised, experimental medicine study in people with MASLD, comparing GLP-1RA treatment (liraglutide) to matched lifestyle-induced weight loss and assessed the impact of treatment withdrawal.</div></div><div><h3>Methods</h3><div>Twenty-nine participants with MASLD, without type 2 diabetes underwent metabolic phenotyping including measurement <em>de novo</em> lipogenesis (DNL), liver magnetic resonance imaging, body composition, adipose tissue RNA sequencing, circulating proteome, and stool microbiome analysis. Participants were randomised to lifestyle (∼500 kcal energy deficit) or GLP1-RA treatment for 12 weeks, after which investigations were repeated, and treatment stopped; investigations were also repeated 12 weeks after treatment withdrawal.</div></div><div><h3>Results</h3><div>Matched weight loss was achieved in both arms. Body composition changes, reductions in alanine aminotransferase, liver steatosis, and disease activity were similar following both treatments. GLP-1RA treatment, but not lifestyle, improved glucose handling, fasting lipids, and significantly deceased DNL. The subcutaneous adipose transcriptome, circulating proteome profile and stool microbiome were not different between groups after treatment. However, 12 weeks after GLP1-RA (but not lifestyle) withdrawal, circulating MMP-10, IL10RB, FGF-23, and Flt3L were elevated, alongside dysregulated adipose gene expression.</div></div><div><h3>Conclusions</h3><div>Although matched weight loss through lifestyle or GLP-1RA have comparable effects on hepatic steatosis, GLP-1RA treatment had additional metabolic benefits on glucose homeostasis, lipid profiles, and DNL. However, GLP-1RA withdrawal may adversely impact the circulating proteome, adipose tissue gene expression, and the stool microbiome, predisposing to weight regain.</div></div><div><h3>Impact and implications</h3><div>Weight loss, through either lifestyle intervention or pharmacotherapy with GLP-1RA has an equally beneficial impact on the liver, and both strategies should be considered in the management of people with MASLD. GLP-1RA therapy may have additional benefits to improve glucose homeostasis even in the absence of pre-existing type 2 diabetes. Further research is needed to explore the differential impact of treatment withdrawal and the resultant metabolic consequences.</div></div><div><h3>Clinical Trials Registration</h3><div>This study is registered at EudraCT (2016-002045-36).</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101363"},"PeriodicalIF":9.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870816","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":"Serum FGF21 as a predictor of response to atezolizumab and bevacizumab in HCC","authors":"Risako Kohya ,&nbsp;Goki Suda ,&nbsp;Masatsugu Ohara ,&nbsp;Shunichi Hosoda ,&nbsp;Takuya Sho ,&nbsp;Makoto Chuma ,&nbsp;Atsumasa Komori ,&nbsp;Yuki Kugiyama ,&nbsp;Yutaka Yasui ,&nbsp;Kaoru Tsuchiya ,&nbsp;Masayuki Kurosaki ,&nbsp;Joji Tani ,&nbsp;Shun Kaneko ,&nbsp;Mina Nakagawa ,&nbsp;Yasuhiro Asahina ,&nbsp;Shinya Maekawa ,&nbsp;Nobuyuki Enomoto ,&nbsp;Yoshiya Yamamoto ,&nbsp;Masaru Baba ,&nbsp;Ren Yamada ,&nbsp;Naoya Sakamoto","doi":"10.1016/j.jhepr.2025.101364","DOIUrl":"10.1016/j.jhepr.2025.101364","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Fibroblast growth factor 21 (FGF21) is a crucial regulator of cell metabolism. Tumour-secreted FGF21 has shown immune-checkpoint factor functions, and high FGF21 levels are associated with a poor prognosis for patients. However, its prognostic value and impact on treatment response in patients with hepatocellular carcinoma (HCC) treated with immune-checkpoint inhibitors (ICIs) remain unclear. Thus, this study investigated the potential of high FGF21 levels as a prognostic marker and whether traditional ICI-based therapy can improve the prognosis of patients with high FGF21 levels.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;In this retrospective multicentre study, patients with unresectable HCC who received atezolizumab/bevacizumab in the NORTE study group (n = 117) were classified into high (≥915 pg/ml; n = 29) and non-high (n = 88) FGF21 groups. For validation, we investigated patients treated with atezolizumab/bevacizumab in an independent cohort (n = 285). Overall survival, progression-free survival, and treatment response were compared between patients with and without high baseline FGF21 levels.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The median overall survival (&lt;em&gt;p&lt;/em&gt; &lt;0.001) and progression-free survival (&lt;em&gt;p&lt;/em&gt; = 0.045) were significantly shorter in the high FGF21 group than in the non-high FGF21 group. Independent cohort analysis validated these results. In the overall cohort, the median progression-free survival (5.75 &lt;em&gt;vs.&lt;/em&gt; 8.84 months; &lt;em&gt;p&lt;/em&gt; = 0.027) and median overall survival (14.13 &lt;em&gt;vs.&lt;/em&gt; 22.08 months; &lt;em&gt;p&lt;/em&gt; &lt;0.001) were significantly shorter in the high FGF21 group than in the non-high FGF21 group. The durable response (≥6 months) + complete response rate was significantly decreased in the high FGF21 group (&lt;em&gt;p&lt;/em&gt; = 0.045). No patient with a high FGF21 level achieved a complete response, whereas this was achieved in 4.1% (13/319) of patients with non-high FGF21 levels. Multivariate Cox regression analysis identified high baseline serum FGF21 as an independent poor prognostic factor for overall survival (hazard ratio 2.20, &lt;em&gt;p&lt;/em&gt; &lt;0.001).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Serum FGF21 may be a robust, non-invasive prognostic and treatment response marker for unresectable HCC treated with atezolizumab/bevacizumab.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;FGF21 has been reported to act as a secreted immune-checkpoint factor, and elevated levels of FGF21 are associated with a poor prognosis in patients with HCC. It is not fully understood whether ICIs can overcome the impact of high FGF21 levels on the shortened prognosis of patients with HCC. In this multicentre retrospective study, patients with HCC and high baseline levels of serum FGF21 who received atezolizumab/bevacizumab treatment exhibited a significantly shorter overall survival and shorter progression-free survival. These findings suggest serum FGF21 as a robust prognostic marker","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101364"},"PeriodicalIF":9.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143748544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surveillance for hepatocellular carcinoma in patients with primary biliary cholangitis: For all or just for some?","authors":"Edoardo G. Giannini ,&nbsp;Andrea Pasta ,&nbsp;Sara Labanca ,&nbsp;Giulia Pieri ,&nbsp;Simona Marenco ,&nbsp;Maria Corina Plaz Torres","doi":"10.1016/j.jhepr.2025.101362","DOIUrl":"10.1016/j.jhepr.2025.101362","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 6","pages":"Article 101362"},"PeriodicalIF":9.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069566","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":"AI-Cirrhosis-ECG (ACE) score for predicting decompensation and liver outcomes","authors":"Joseph C. Ahn ,&nbsp;Puru Rattan ,&nbsp;Patrick Starlinger ,&nbsp;Adrià Juanola ,&nbsp;Maria José Moreta ,&nbsp;Jordi Colmenero ,&nbsp;Bashar Aqel ,&nbsp;Andrew P. Keaveny ,&nbsp;Aidan F. Mullan ,&nbsp;Kan Liu ,&nbsp;Zachi I. Attia ,&nbsp;Alina M. Allen ,&nbsp;Paul A. Friedman ,&nbsp;Vijay H. Shah ,&nbsp;Peter A. Noseworthy ,&nbsp;Julie K. Heimbach ,&nbsp;Patrick S. Kamath ,&nbsp;Pere Gines ,&nbsp;Douglas A. Simonetto","doi":"10.1016/j.jhepr.2025.101356","DOIUrl":"10.1016/j.jhepr.2025.101356","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Accurate prediction of disease severity and prognosis are challenging in patients with cirrhosis. We evaluated whether the deep learning-based AI-Cirrhosis-ECG (ACE) score could detect hepatic decompensation and predict clinical outcomes in cirrhosis.</div></div><div><h3>Methods</h3><div>We analyzed 2,166 ECGs from 472 patients in a retrospective Mayo Clinic cohort, 420 patients in a prospective Mayo transplant cohort, and 341 patients in an external validation cohort from Hospital Clínic de Barcelona. The ACE score's performance was assessed using receiver-operating characteristic analysis for decompensation detection and competing risks Cox regression for outcome prediction.</div></div><div><h3>Results</h3><div>The ACE score showed high accuracy in detecting hepatic decompensation (area under the curve 0.933, 95% CI: 0.923–0.942) with 88.0% sensitivity and 84.3% specificity at an optimal threshold of 0.25. In multivariable analysis, each 0.1-point increase in ACE score was independently associated with increased risk of liver-related death (hazard ratio [HR] 1.44, 95% CI 1.32–1.58, <em>p</em> &lt;0.001). Adding ACE to model for end-stage liver disease-sodium significantly improved prediction of adverse outcomes across all cohorts (c-statistics: retrospective cohort 0.903 <em>vs.</em> 0.844; prospective cohort 0.779 <em>vs.</em> 0.735; external validation 0.744 <em>vs.</em> 0.732; all <em>p</em> &lt;0.001).</div></div><div><h3>Conclusions</h3><div>The ACE score accurately identifies hepatic decompensation and independently predicts liver-related outcomes in cirrhosis. This non-invasive tool enhances current prognostic models and may improve risk stratification in cirrhosis management.</div></div><div><h3>Impact and implications</h3><div>This study demonstrates the potential of artificial intelligence to enhance prognostication in liver disease, addressing the critical need for improved risk stratification in cirrhosis management. The AI-Cirrhosis-ECG (ACE) score, derived from widely available ECGs, shows promise as a non-invasive tool for detecting hepatic decompensation and predicting liver-related outcomes, which could significantly impact clinical decision-making and resource allocation in hepatology. These findings are particularly important for hepatologists, transplant surgeons, and patients with cirrhosis, as they offer a novel approach to complement existing prognostic models such as model for end-stage liver disease-sodium. In practical terms, the ACE score could be integrated into routine clinical assessments to provide more accurate risk predictions, potentially improving the timing of interventions, optimizing transplant listing decisions, and ultimately enhancing patient outcomes. However, further validation in diverse populations and integration with other established predictors is necessary before widespread clinical implementation.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101356"},"PeriodicalIF":9.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143815576","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":"Salsalate improves the anti-tumor efficacy of Lenvatinib in MASH-driven hepatocellular carcinoma.","authors":"Evangelia E. Tsakiridis ,&nbsp;Elham Ahmadi ,&nbsp;Jaya Gautam ,&nbsp;Yi Ran Hannah She ,&nbsp;Russta Fayyazi ,&nbsp;James S.V. Lally ,&nbsp;Simon Wang ,&nbsp;Fiorella Di Pastena ,&nbsp;Celina M. Valvano ,&nbsp;Daniel Del Rosso ,&nbsp;Olga-Demetra Biziotis ,&nbsp;Brandon Meyers ,&nbsp;Paola Muti ,&nbsp;Theodoros Tsakiridis ,&nbsp;Gregory Steinberg","doi":"10.1016/j.jhepr.2025.101354","DOIUrl":"10.1016/j.jhepr.2025.101354","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Metabolic dysfunction associated steatohepatitis (MASH) is a growing contributor of hepatocellular carcinoma (HCC) worldwide. The complex microenvironment of these tumors, characterized by metabolic dysfunction, hypoxia, steatosis, and fibrosis limits, the effectiveness of standard of care therapies such as the multi-tyrosine kinase inhibitor Lenvatinib. Salsalate, a rheumatoid arthritis therapy that stimulates AMP-activated protein kinase (AMPK) enhances fatty acid oxidation and reduces de-novo lipogenesis, fibrosis and cell proliferation pathways. We hypothesise that addition of Salsalate could improve the efficacy of Lenvatinib in MASH-HCC.</div></div><div><h3>Methods</h3><div>We assessed the efficacy of combination therapy using clinically relevant concentrations of Lenvatinib and Salsalate in human HCC cell models, orthotopic xenograft and MASH-HCC mouse models. Additionally, in vitro assays assessing fat oxidation and lipogenesis, protein immunoblotting and RNA-sequencing were employed to understand mechanisms at play.</div></div><div><h3>Results</h3><div>Combined Lenvatinib plus Salsalate synergistically suppressed proliferation and clonogenic survival in cells (p≤0.0001), prolonged survival in an orthotopic xenograft model (p=0.02) and reduced angiogenesis, fibrosis and steatosis (p≤0.05) in a MASH-HCC model. These effects were associated with activation of AMPK and inhibition of the mTOR-HIF1α and Erk1/2 signaling pathways. RNA-sequencing analysis in both Hep3B cells and livers of the MASH-HCC mouse model revealed that Salsalate enhanced mitochondria fatty acid oxidation and suppressed fibrosis and cell cycle progression while Lenvatinib reduced angiogenesis with regulatory network analysis suggesting a potential role for Activating Transcription Factor 3 and ETS-proto-oncogene-1.</div></div><div><h3>Conclusions</h3><div>These data indicate that combining Lenvatinib and Salsalate which exert distinct effects leading to improvements in the liver microenvironment (steatosis, angiogenesis and fibrosis) and inhibition of tumor proliferation, may have therapeutic potential for MASH driven HCC.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101354"},"PeriodicalIF":9.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143815574","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}