Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality, particularly in patients with advanced stage. Atezolizumab plus bevacizumab (Ate/Bev) is the standard first-line therapy; however, its efficacy may be further enhanced using combination strategies.
Methods
This study evaluated the clinical impact of proton beam therapy (PBT) with Ate/Bev in patients with unresectable HCC (uHCC). We retrospectively evaluated 362 patients with uHCC treated with Ate/Bev between November 2020 and June 2023 at two centers in Taiwan. The patients were divided into the Ate/Bev-PBT and Ate/Bev groups based on whether they received first-line Ate/Bev combined with PBT or Ate/Bev alone. Propensity score matching was performed at a 1:2 ratio to reduce selection bias.
Results
There were 39 and 71 patients in the Ate/Bev-PBT and Ate/Bev groups, respectively. Treatment-related adverse events were comparable between the two groups and were manageable, primarily involving mild-to-moderate liver inflammation. Compared with the Ate/Bev group, the Ate/Bev-PBT group demonstrated significantly better objective response rates (56.8% vs 17.3%, p < 0.001), disease control rates (75.7% vs 44.2%, p < 0.001), progression-free survival (7.3 vs 2.3 months, p < 0.001), and overall survival (16.7 vs 7.1 months, p = 0.02). In the multivariate analysis, Ate/Bev-PBT was strongly associated with reduced mortality (hazard ratio [HR], 0.406; 95% confidence interval [CI]: 0.236–0.700, p = 0.001) after adjusting for preserved liver function, prognostic nutritional index and receiving sequential therapy.
Conclusion
The addition of PBT to Ate/Bev was associated with improved treatment response and survival in patients with uHCC without compromising safety of the treatment. This combined approach may represent a promising therapeutic strategy that warrants prospective validation.
肝细胞癌（HCC）是癌症相关死亡的主要原因，特别是在晚期患者中。Atezolizumab联合贝伐单抗（Ate/Bev）是标准的一线治疗；然而，其疗效可以通过联合策略进一步提高。方法：本研究评估质子束治疗（PBT）联合Ate/Bev治疗不可切除肝癌（uHCC）的临床效果。我们回顾性评估了2020年11月至2023年6月在台湾两个中心接受Ate/Bev治疗的362例uHCC患者。根据患者是否接受一线Ate/Bev联合PBT或单独Ate/Bev治疗，将患者分为Ate/Bev-PBT组和Ate/Bev组。倾向得分匹配以1:2的比例进行，以减少选择偏差。结果：Ate/Bev- pbt组39例，Ate/Bev组71例。治疗相关的不良事件在两组之间具有可比性，并且是可控的，主要涉及轻度至中度肝脏炎症。与Ate/Bev组相比，Ate/Bev-PBT组表现出明显更好的客观缓解率（56.8% vs 17.3%）， p结论：在Ate/Bev中添加PBT与uHCC患者的治疗反应和生存相关，且不影响治疗的安全性。这种联合方法可能是一种有前景的治疗策略，值得前瞻性验证。
{"title":"Proton Beam Therapy Boosts Outcomes of Atezolizumab/Bevacizumab in Advanced Hepatocellular Carcinoma: A Propensity Score Analysis","authors":"Yuan-Hung Kuo, Wei Teng, Po-Ting Lin, Yen-Hao Chen, Chung-Wei Su, Eric Yi-Liang Shen, Bing-Shen Huang, Tsung-Han Wu, Jen-Yu Cheng, Yi-Chung Hsieh, Wei-Ting Chen, Chao-Hung Hung, Shi-Ming Lin, Chen-Chun Lin, Jing-Houng Wang, Chun-Yen Lin","doi":"10.1111/liv.70465","DOIUrl":"10.1111/liv.70465","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality, particularly in patients with advanced stage. Atezolizumab plus bevacizumab (Ate/Bev) is the standard first-line therapy; however, its efficacy may be further enhanced using combination strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study evaluated the clinical impact of proton beam therapy (PBT) with Ate/Bev in patients with unresectable HCC (uHCC). We retrospectively evaluated 362 patients with uHCC treated with Ate/Bev between November 2020 and June 2023 at two centers in Taiwan. The patients were divided into the Ate/Bev-PBT and Ate/Bev groups based on whether they received first-line Ate/Bev combined with PBT or Ate/Bev alone. Propensity score matching was performed at a 1:2 ratio to reduce selection bias.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>There were 39 and 71 patients in the Ate/Bev-PBT and Ate/Bev groups, respectively. Treatment-related adverse events were comparable between the two groups and were manageable, primarily involving mild-to-moderate liver inflammation. Compared with the Ate/Bev group, the Ate/Bev-PBT group demonstrated significantly better objective response rates (56.8% vs 17.3%, <i>p</i> < 0.001), disease control rates (75.7% vs 44.2%, <i>p</i> < 0.001), progression-free survival (7.3 vs 2.3 months, <i>p</i> < 0.001), and overall survival (16.7 vs 7.1 months, <i>p</i> = 0.02). In the multivariate analysis, Ate/Bev-PBT was strongly associated with reduced mortality (hazard ratio [HR], 0.406; 95% confidence interval [CI]: 0.236–0.700, <i>p</i> = 0.001) after adjusting for preserved liver function, prognostic nutritional index and receiving sequential therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The addition of PBT to Ate/Bev was associated with improved treatment response and survival in patients with uHCC without compromising safety of the treatment. This combined approach may represent a promising therapeutic strategy that warrants prospective validation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"46 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cristina Della Corte, Daphne D'Amato, Adele Rocchetti, Andrea Martini, Maria Cristina Morelli, Francesca Terracciani, Michele Campigotto, Nicola Pugliese, Giulia Pieri, Loredana Simone, Federica Malinverno, Elisabetta Degasperi, Raffaella Reati, Alessandro Federico, Raffaella Gallo, Chiara Colarossi, Gianluca Svegliati-Baroni, Ester Morana, Rachele Rapetti, Lorenzo Surace, Ilaria Arena, Giovanni Perricone, Gianluca Ferrari, Marco Silano, Paola Torreri, Pietro Invernizzi, Umberto Vespasiani-Gentilucci, Alessio Aghemo, Edoardo Giovanni Giannini, Emanuele Durante-Mangoni, Gabriele Missale, Simone Saibeni, Germana de Nucci, Giampiero Manes, Mauro Viganò, Marco Carbone
Background and Aims
Sarcoidosis is a rare systemic granulomatous disease involving the liver in up to 20% of cases. Data on hepatic sarcoidosis (HS) prevalence and management remain limited. This study aims to provide a comprehensive analysis of HS patients across Italy, focusing on diagnostic pathways, management strategies, and prognostic factors.
Methods
This multicenter retrospective study, conducted from April 2022 to December 2023, includes data from 36 hepatology units, affiliated with the Italian Association for the Study of the Liver (AISF), invited to analyse consecutive cases of HS reported between 2003 and 2023.
Results
A total of 78 patients with HS were identified, with complete data available for 58 (median age 53 years; 57% female; 81% Caucasian), prospectively followed for a median of 41 months. Pulmonary and lymphatic involvement were present in 45% and 34% of cases, respectively. Isolated hepatic involvement was seen in 10%. Liver biopsy revealed granulomas in all specimens. Histological cirrhosis and clinically significant portal hypertension (CSPH) were observed in 10% and 14% of patients, respectively. Patients with CSPH had a significantly higher body mass index (BMI) compared to those without (33 vs. 25, p = 0.002). Steroids and ursodeoxycholic acid were the first-line treatments for 80% and 28% of patients, respectively, while 29% required second-line therapies. One patient died from liver-related complications.
Conclusions
This nationwide study underscores the variability in HS presentation and management across Italy. Liver biopsy remains essential for diagnosis and staging. While steroids are the primary treatment, many patients require second-line therapies. Our finding of a higher BMI in patients with CSPH suggests that metabolic factors may play a role in disease progression, warranting further investigation.
背景和目的：结节病是一种罕见的累及肝脏的系统性肉芽肿性疾病，发生率高达20%。肝结节病（HS）的患病率和管理数据仍然有限。本研究旨在对意大利HS患者进行全面分析，重点关注诊断途径、管理策略和预后因素。方法：这项多中心回顾性研究于2022年4月至2023年12月进行，包括来自意大利肝脏研究协会（AISF）下属的36个肝病学单位的数据，这些单位应邀分析了2003年至2023年期间报告的连续HS病例。结果：共发现78例HS患者，其中58例（中位年龄53岁，57%为女性，81%为白人）获得完整数据，前瞻性随访中位时间为41个月。肺和淋巴受累分别占45%和34%。孤立性肝脏受累发生率为10%。肝活检均发现肉芽肿。组织学肝硬化和临床显著门静脉高压症（CSPH）分别占10%和14%。CSPH患者的身体质量指数（BMI）明显高于无CSPH患者（33 vs. 25, p = 0.002）。类固醇和熊去氧胆酸分别为80%和28%的患者的一线治疗，而29%的患者需要二线治疗。一名患者死于肝脏相关并发症。结论：这项全国性的研究强调了意大利HS表现和管理的可变性。肝活检仍然是诊断和分期的必要条件。虽然类固醇是主要治疗方法，但许多患者需要二线治疗。我们发现CSPH患者的BMI较高，这表明代谢因素可能在疾病进展中起作用，值得进一步研究。
{"title":"Clinical Features, Management and Prognosis of Hepatic Sarcoidosis: Insights From a Nationwide Italian Study","authors":"Cristina Della Corte, Daphne D'Amato, Adele Rocchetti, Andrea Martini, Maria Cristina Morelli, Francesca Terracciani, Michele Campigotto, Nicola Pugliese, Giulia Pieri, Loredana Simone, Federica Malinverno, Elisabetta Degasperi, Raffaella Reati, Alessandro Federico, Raffaella Gallo, Chiara Colarossi, Gianluca Svegliati-Baroni, Ester Morana, Rachele Rapetti, Lorenzo Surace, Ilaria Arena, Giovanni Perricone, Gianluca Ferrari, Marco Silano, Paola Torreri, Pietro Invernizzi, Umberto Vespasiani-Gentilucci, Alessio Aghemo, Edoardo Giovanni Giannini, Emanuele Durante-Mangoni, Gabriele Missale, Simone Saibeni, Germana de Nucci, Giampiero Manes, Mauro Viganò, Marco Carbone","doi":"10.1111/liv.70459","DOIUrl":"10.1111/liv.70459","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Sarcoidosis is a rare systemic granulomatous disease involving the liver in up to 20% of cases. Data on hepatic sarcoidosis (HS) prevalence and management remain limited. This study aims to provide a comprehensive analysis of HS patients across Italy, focusing on diagnostic pathways, management strategies, and prognostic factors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This multicenter retrospective study, conducted from April 2022 to December 2023, includes data from 36 hepatology units, affiliated with the Italian Association for the Study of the Liver (AISF), invited to analyse consecutive cases of HS reported between 2003 and 2023.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 78 patients with HS were identified, with complete data available for 58 (median age 53 years; 57% female; 81% Caucasian), prospectively followed for a median of 41 months. Pulmonary and lymphatic involvement were present in 45% and 34% of cases, respectively. Isolated hepatic involvement was seen in 10%. Liver biopsy revealed granulomas in all specimens. Histological cirrhosis and clinically significant portal hypertension (CSPH) were observed in 10% and 14% of patients, respectively. Patients with CSPH had a significantly higher body mass index (BMI) compared to those without (33 vs. 25, <i>p</i> = 0.002). Steroids and ursodeoxycholic acid were the first-line treatments for 80% and 28% of patients, respectively, while 29% required second-line therapies. One patient died from liver-related complications.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This nationwide study underscores the variability in HS presentation and management across Italy. Liver biopsy remains essential for diagnosis and staging. While steroids are the primary treatment, many patients require second-line therapies. Our finding of a higher BMI in patients with CSPH suggests that metabolic factors may play a role in disease progression, warranting further investigation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"46 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145648721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lucia Dansero, Lorenzo Milani, Carlotta Sacerdote, Pietro Ferrari, Mazda Jenab, Fulvio Ricceri
Background
Steatotic liver disease (SLD), formerly known as fatty liver disease, is associated with increased cancer risk. However, the impact of socioeconomic inequities remains understudied. This study investigates the relationship between SLD, socioeconomic position (SEP) and cancer risk using a syndemic framework.
Methods
Using UK Biobank data, we defined metabolic dysfunction-associated SLD (MASLD), MASLD with increased alcohol intake (MetALD) and alcoholic liver disease (ALD), based on the Fatty Liver Index, cardiometabolic criteria and alcohol consumption. SEP was derived via latent class analysis using education, household income and employment. We used Cox proportional hazards models to examine the associations between MASLD, MetALD and ALD and the incidence of any, obesity-related and digestive cancers. We then evaluated the combined effect of these SLD subcategories and SEP on cancer outcomes.
Results
Among 325 476 individuals, 91 651 had MASLD, 25 649 MetALD and 8005 ALD. Over 11.7 years median follow-up, 35 775 first incident cancers occurred (15 426 obesity-related; 6959 digestive). MASLD, MetALD and ALD were each associated with an increased risk of all cancer outcomes (hazard ratios [HR] ranging from 1.09 to 1.73). The combination of MASLD and low SEP was associated with an increased risk of any (HR: 1.14, 95% CI: 1.08–1.19), obesity-related (HR: 1.25, 95% CI: 1.16–1.33) and digestive cancers (HR: 1.37, 95% CI: 1.23–1.53). Similar trends were observed for individuals with MetALD or ALD and low SEP across all cancer outcomes.
Conclusion
SLD is independently associated with increased risk of any, obesity-related and digestive cancers. These risks are amplified by socioeconomic inequities, highlighting the need for integrated approaches that consider both clinical and social determinants of health.
{"title":"Exploring the Syndemic of Steatotic Liver Disease, Socioeconomic Inequities and Cancer Risk in the UK Biobank","authors":"Lucia Dansero, Lorenzo Milani, Carlotta Sacerdote, Pietro Ferrari, Mazda Jenab, Fulvio Ricceri","doi":"10.1111/liv.70458","DOIUrl":"10.1111/liv.70458","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Steatotic liver disease (SLD), formerly known as fatty liver disease, is associated with increased cancer risk. However, the impact of socioeconomic inequities remains understudied. This study investigates the relationship between SLD, socioeconomic position (SEP) and cancer risk using a syndemic framework.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using UK Biobank data, we defined metabolic dysfunction-associated SLD (MASLD), MASLD with increased alcohol intake (MetALD) and alcoholic liver disease (ALD), based on the Fatty Liver Index, cardiometabolic criteria and alcohol consumption. SEP was derived via latent class analysis using education, household income and employment. We used Cox proportional hazards models to examine the associations between MASLD, MetALD and ALD and the incidence of any, obesity-related and digestive cancers. We then evaluated the combined effect of these SLD subcategories and SEP on cancer outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 325 476 individuals, 91 651 had MASLD, 25 649 MetALD and 8005 ALD. Over 11.7 years median follow-up, 35 775 first incident cancers occurred (15 426 obesity-related; 6959 digestive). MASLD, MetALD and ALD were each associated with an increased risk of all cancer outcomes (hazard ratios [HR] ranging from 1.09 to 1.73). The combination of MASLD and low SEP was associated with an increased risk of any (HR: 1.14, 95% CI: 1.08–1.19), obesity-related (HR: 1.25, 95% CI: 1.16–1.33) and digestive cancers (HR: 1.37, 95% CI: 1.23–1.53). Similar trends were observed for individuals with MetALD or ALD and low SEP across all cancer outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>SLD is independently associated with increased risk of any, obesity-related and digestive cancers. These risks are amplified by socioeconomic inequities, highlighting the need for integrated approaches that consider both clinical and social determinants of health.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"46 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145648728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alani Perkin, Sebastian M. Armasu, Winnie Z. Fan, Naana N. Yalley, Irene K. Yan, Fowsiyo Y. Ahmed, Laura Izquierdo-Sanchez, Loreto Boix, Angela Rojas, Jesus M. Banales, Maria Reig, Per Stål, Manuel Romero Gómez, Amit G. Singal, Lewis R. Roberts, Kirk J. Wangensteen, Anders Berglund, Tushar Patel, Samuel O. Antwi
Introduction
Hepatocellular carcinoma (HCC) development in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health concern, but the underlying mechanisms are not fully understood. Epigenetic aging biomarkers, reflecting cellular and tissue aging, have been linked to various age-related pathologies, but their association with MASLD-HCC is unknown. We investigated associations between five epigenetic aging biomarkers and MASLD-HCC risk.
Methods
We performed whole blood DNA methylation assay (Infinium 850k array) and calculated principal components-based (PC) versions of HorvathAge, HannumAge, PhenoAge and GrimAge and the DunedinPACE aging rate. We further calculated relative age accelerations for PCHorvathAge, PCHannumAge, PCPhenoAge and PCGrimAge. The aging biomarkers were modelled as continuous variables and categorised into tertiles based on distributions among controls. Associations between each aging biomarker and MASLD-HCC were examined using logistic regression, calculating odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for covariates.
Results
Data on 272 MASLD-HCC cases and 316 cancer-free MASLD controls recruited from six sites and matched on chronological age, sex and study site were analysed. Higher relative age accelerations of PCPhenoAge (ORT3 vs. T1 = 2.25, 95% CI: 1.45–3.50; ORcontinuous = 1.04, 95% CI: 1.02–1.07, p = 0.009), PCGrimAge (ORT3 vs. T1 = 3.97, 95% CI: 2.41–6.64; ORcontinuous = 1.16, 95% CI: 1.10–1.24, p = 8.76 × 10−07) and DunedinPACE (ORT3 vs. T1 = 3.45, 95% CI: 2.17–5.55; ORcontinuous = 1.72, 95% CI: 1.43–2.10, p = 2.58 × 10−08) were associated with MASLD-HCC, but not PCHorvathAge or PCHannumAge.
Conclusion
Higher relative age accelerations of PCPhenoAge, PCGrimAge and DunedinPACE aging rate are associated with risk of MASLD-HCC. These aging biomarkers could improve HCC risk assessment and facilitate risk stratification in patients with MASLD.
代谢功能障碍相关脂肪变性肝病（MASLD）患者的肝细胞癌（HCC）发展是一个日益受到关注的健康问题，但其潜在机制尚不完全清楚。反映细胞和组织衰老的表观遗传衰老生物标志物与各种年龄相关的病理有关，但它们与MASLD-HCC的关系尚不清楚。我们研究了五种表观遗传衰老生物标志物与MASLD-HCC风险之间的关系。方法采用Infinium 850k阵列进行全血DNA甲基化分析，计算基于主成分（PC）的HorvathAge、HannumAge、PhenoAge和GrimAge基因版本和DunedinPACE衰老率。我们进一步计算了PCHorvathAge、PCHannumAge、PCPhenoAge和PCGrimAge的相对年龄加速度。老化生物标志物被建模为连续变量，并根据对照组的分布进行分类。每个衰老生物标志物与MASLD-HCC之间的关联使用逻辑回归进行检验，计算优势比（ORs）和95%置信区间（CIs），调整协变量。结果分析了从六个地点招募的272例MASLD- hcc患者和316例无癌MASLD对照者的数据，这些数据在实足年龄、性别和研究地点上相匹配。PCPhenoAge （ORT3 vs. T1 = 2.25, 95% CI: 1.45-3.50； or连续= 1.04,95% CI: 1.02-1.07, p = 0.009）、PCGrimAge （ORT3 vs. T1 = 3.97, 95% CI: 2.41-6.64； or连续= 1.16,95% CI: 1.10-1.24, p = 8.76 × 10−07）和DunedinPACE （ORT3 vs. T1 = 3.45, 95% CI: 2.17-5.55； or连续= 1.72,95% CI: 1.43-2.10, p = 2.58 × 10−08）与MASLD-HCC相关，但与PCHorvathAge或PCHannumAge无关。结论PCPhenoAge、PCGrimAge和DunedinPACE衰老率的相对年龄加速与MASLD-HCC发生风险相关。这些衰老生物标志物可以改善肝癌风险评估，促进MASLD患者的风险分层。
{"title":"Association of Epigenetic Aging Biomarkers With Risk of MASLD-Related HCC","authors":"Alani Perkin, Sebastian M. Armasu, Winnie Z. Fan, Naana N. Yalley, Irene K. Yan, Fowsiyo Y. Ahmed, Laura Izquierdo-Sanchez, Loreto Boix, Angela Rojas, Jesus M. Banales, Maria Reig, Per Stål, Manuel Romero Gómez, Amit G. Singal, Lewis R. Roberts, Kirk J. Wangensteen, Anders Berglund, Tushar Patel, Samuel O. Antwi","doi":"10.1111/liv.70464","DOIUrl":"https://doi.org/10.1111/liv.70464","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) development in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health concern, but the underlying mechanisms are not fully understood. Epigenetic aging biomarkers, reflecting cellular and tissue aging, have been linked to various age-related pathologies, but their association with MASLD-HCC is unknown. We investigated associations between five epigenetic aging biomarkers and MASLD-HCC risk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed whole blood DNA methylation assay (Infinium 850k array) and calculated principal components-based (PC) versions of HorvathAge, HannumAge, PhenoAge and GrimAge and the DunedinPACE aging rate. We further calculated relative age accelerations for PCHorvathAge, PCHannumAge, PCPhenoAge and PCGrimAge. The aging biomarkers were modelled as continuous variables and categorised into tertiles based on distributions among controls. Associations between each aging biomarker and MASLD-HCC were examined using logistic regression, calculating odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for covariates.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Data on 272 MASLD-HCC cases and 316 cancer-free MASLD controls recruited from six sites and matched on chronological age, sex and study site were analysed. Higher relative age accelerations of PCPhenoAge (OR<sub>T3 vs. T1</sub> = 2.25, 95% CI: 1.45–3.50; OR<sub>continuous</sub> = 1.04, 95% CI: 1.02–1.07, <i>p</i> = 0.009), PCGrimAge (OR<sub>T3 vs. T1</sub> = 3.97, 95% CI: 2.41–6.64; OR<sub>continuous</sub> = 1.16, 95% CI: 1.10–1.24, <i>p</i> = 8.76 × 10<sup>−07</sup>) and DunedinPACE (OR<sub>T3 vs. T1</sub> = 3.45, 95% CI: 2.17–5.55; OR<sub>continuous</sub> = 1.72, 95% CI: 1.43–2.10, <i>p</i> = 2.58 × 10<sup>−08</sup>) were associated with MASLD-HCC, but not PCHorvathAge or PCHannumAge.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Higher relative age accelerations of PCPhenoAge, PCGrimAge and DunedinPACE aging rate are associated with risk of MASLD-HCC. These aging biomarkers could improve HCC risk assessment and facilitate risk stratification in patients with MASLD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"46 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145626830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Despite the advances in systemic therapy for unresectable hepatocellular carcinoma (HCC), patients with Child–Pugh class B (CP-B) liver function face a significant unmet need. This study evaluated the efficacy and safety of atezolizumab plus bevacizumab (Atez/Bev) in patients with unresectable HCC and CP-B.
Methods
This retrospective study included 796 patients who received Atez/Bev between October 2020 and July 2024 from 10 institutions in Japan. The median observation period was 14.6 months. The liver function was assessed using the CP classification and modified ALBI (mALBI) grade. The progression-free survival (PFS), overall survival (OS) and median survival time (MST) were evaluated.
Results
Patients with CP-B had significantly shorter PFS and OS than those with CP-A (median PFS, 4.6 months vs. 7.0 months; MST, 10.3 months vs. 23.2 months) (PFS, p = 0.009; OS, p < 0.001). Although CP-B was associated with a higher incidence of bleeding-related events, the discontinuation rate due to adverse events did not differ from that of CP-A. As a factor for stratifying CP-B outcomes, significant differences in the PFS, OS and response rate were observed between mALBI grades ≤ 2b and 3 (PFS, p = 0.004; OS, p = 0.024; response rate, p = 0.001). In multivariate analysis, the mALBI grade (hazard ratio [95% CI]: 2.388 [1.186–4.810]; p = 0.014) was extracted as a factor contributing to OS in patients with CP-B.
Conclusion
Atez/Bev therapy demonstrated efficacy and safety in patients with CP-B, especially when hepatic reserve is maintained within mALBI grade 2b.
背景和目的尽管不可切除的肝细胞癌（HCC）的全身治疗取得了进展，但Child-Pugh B级（CP-B）肝功能患者仍面临着显著的未满足需求。本研究评估了atezolizumab联合贝伐单抗（Atez/Bev）在不可切除的HCC和CP-B患者中的疗效和安全性。方法本回顾性研究纳入了2020年10月至2024年7月来自日本10家机构的796例接受Atez/Bev治疗的患者。中位观察期14.6个月。采用CP分级和改良ALBI （mALBI）分级评估肝功能。评估无进展生存期（PFS）、总生存期（OS）和中位生存期（MST）。结果CP-B患者的PFS和OS均明显短于CP-A患者（中位PFS， 4.6个月vs 7.0个月；MST， 10.3个月vs 23.2个月）（PFS, p = 0.009； OS, p < 0.001）。虽然CP-B与较高的出血相关事件发生率相关，但因不良事件引起的停药率与CP-A没有差异。作为区分CP-B结局的一个因素，mALBI分级≤2b和3级之间的PFS、OS和有效率存在显著差异（PFS, p = 0.004； OS, p = 0.024；有效率，p = 0.001）。在多因素分析中，提取mALBI分级（风险比[95% CI]: 2.388 [1.186-4.810]; p = 0.014）作为CP-B患者OS的影响因素。结论Atez/Bev治疗在CP-B患者中显示出有效性和安全性，特别是当肝储备维持在mALBI 2b级时。
{"title":"Efficacy and Safety of Atezolizumab Plus Bevacizumab for Patients With Hepatocellular Carcinoma and Child–Pugh Class B","authors":"Ryu Sasaki, Shigeo Shimose, Issei Saeki, Takanori Ito, Yasuto Takeuchi, Joji Tani, Tetsu Tomonari, Kyo Sasaki, Satoru Kakizaki, Takeshi Hatanaka, Satoshi Miuma, Tomotake Shirono, Hideki Iwamoto, Norikazu Tanabe, Takafumi Yamamoto, Yuki Kanayama, Atsushi Naganuma, Sohji Nishina, Tetsuji Takayama, Hideki Kobara, Motoyuki Otsuka, Hiroki Kawashima, Taro Takami, Takumi Kawaguchi, Hisamitsu Miyaaki, Hepatology InVestigator Experts in Japan (HIVE-J) Study Group","doi":"10.1111/liv.70466","DOIUrl":"https://doi.org/10.1111/liv.70466","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background & Aims</h3>\u0000 \u0000 <p>Despite the advances in systemic therapy for unresectable hepatocellular carcinoma (HCC), patients with Child–Pugh class B (CP-B) liver function face a significant unmet need. This study evaluated the efficacy and safety of atezolizumab plus bevacizumab (Atez/Bev) in patients with unresectable HCC and CP-B.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This retrospective study included 796 patients who received Atez/Bev between October 2020 and July 2024 from 10 institutions in Japan. The median observation period was 14.6 months. The liver function was assessed using the CP classification and modified ALBI (mALBI) grade. The progression-free survival (PFS), overall survival (OS) and median survival time (MST) were evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Patients with CP-B had significantly shorter PFS and OS than those with CP-A (median PFS, 4.6 months vs. 7.0 months; MST, 10.3 months vs. 23.2 months) (PFS, <i>p</i> = 0.009; OS, <i>p</i> < 0.001). Although CP-B was associated with a higher incidence of bleeding-related events, the discontinuation rate due to adverse events did not differ from that of CP-A. As a factor for stratifying CP-B outcomes, significant differences in the PFS, OS and response rate were observed between mALBI grades ≤ 2b and 3 (PFS, <i>p</i> = 0.004; OS, <i>p</i> = 0.024; response rate, <i>p</i> = 0.001). In multivariate analysis, the mALBI grade (hazard ratio [95% CI]: 2.388 [1.186–4.810]; <i>p</i> = 0.014) was extracted as a factor contributing to OS in patients with CP-B.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Atez/Bev therapy demonstrated efficacy and safety in patients with CP-B, especially when hepatic reserve is maintained within mALBI grade 2b.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"46 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70466","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145626814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Miguel Sogbe, Brittany Bromfield, Roberto Tellez, Pamela M. Bloomer, Nelson Bennett, Christopher B. Hughes, Michael A. Dunn, Astrid Ruiz-Margáin, Andres Duarte-Rojo
Background and Aims
Hypogonadism is frequent in AdvCLD and associated with frailty and poor outcomes. This study aimed to evaluate the association between free testosterone (FT) levels and all-cause mortality in male patients with AdvCLD awaiting liver transplantation (LT), and to compare the prognostic value of FT with total testosterone (TT).
Methods
In this prospective cohort study, 191 male patients with AdvCLD awaiting LT underwent FT and TT evaluation. The primary outcome was all-cause mortality, assessed using a competing-risk model with LT as the competing event.
Results
Among the 191 patients, 41 (21.5%) had low FT levels. This group was more likely to have a higher Child-Turcotte-Pugh class and MELD-Na score, as well as higher proportion of individuals with a history of hepatic encephalopathy (HE) compared to those with normal FT levels (p < 0.05). Patients with low FT also exhibited greater frailty (liver frailty index: 4.2 ± 0.8 vs. 3.6 ± 0.9, p < 0.001, respectively). After adjustment for MELD-Na, low FT was significantly associated with increased mortality risk (adjusted subdistribution hazard ratio [aSHR] 1.97; 95% CI: 1.07–3.61). Additionally, patients with low FT had a lower cumulative probability of undergoing LT compared to those with normal FT levels (43.4% vs. 74.3%). In contrast, low TT was not associated with mortality (aSHR: 1.65; 95% CI: 0.90–3.02).
Conclusion
Low FT levels are independently associated with higher mortality and lower LT probability in men with AdvCLD and outperform TT as a prognostic marker. These findings support FT as a valuable biomarker to identify high-risk patients and guide future interventional strategies.
{"title":"Free Testosterone Is Associated With Worse Survival in Patients With Advanced Chronic Liver Disease Awaiting Liver Transplantation","authors":"Miguel Sogbe, Brittany Bromfield, Roberto Tellez, Pamela M. Bloomer, Nelson Bennett, Christopher B. Hughes, Michael A. Dunn, Astrid Ruiz-Margáin, Andres Duarte-Rojo","doi":"10.1111/liv.70393","DOIUrl":"10.1111/liv.70393","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Hypogonadism is frequent in AdvCLD and associated with frailty and poor outcomes. This study aimed to evaluate the association between free testosterone (FT) levels and all-cause mortality in male patients with AdvCLD awaiting liver transplantation (LT), and to compare the prognostic value of FT with total testosterone (TT).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this prospective cohort study, 191 male patients with AdvCLD awaiting LT underwent FT and TT evaluation. The primary outcome was all-cause mortality, assessed using a competing-risk model with LT as the competing event.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among the 191 patients, 41 (21.5%) had low FT levels. This group was more likely to have a higher Child-Turcotte-Pugh class and MELD-Na score, as well as higher proportion of individuals with a history of hepatic encephalopathy (HE) compared to those with normal FT levels (<i>p</i> < 0.05). Patients with low FT also exhibited greater frailty (liver frailty index: 4.2 ± 0.8 vs. 3.6 ± 0.9, <i>p</i> < 0.001, respectively). After adjustment for MELD-Na, low FT was significantly associated with increased mortality risk (adjusted subdistribution hazard ratio [aSHR] 1.97; 95% CI: 1.07–3.61). Additionally, patients with low FT had a lower cumulative probability of undergoing LT compared to those with normal FT levels (43.4% vs. 74.3%). In contrast, low TT was not associated with mortality (aSHR: 1.65; 95% CI: 0.90–3.02).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Low FT levels are independently associated with higher mortality and lower LT probability in men with AdvCLD and outperform TT as a prognostic marker. These findings support FT as a valuable biomarker to identify high-risk patients and guide future interventional strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 12","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145604806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Interpreting the Clinical Significance of Spleen Stiffness in Baveno VII Risk Stratification","authors":"Yuanyuan Yang","doi":"10.1111/liv.70457","DOIUrl":"10.1111/liv.70457","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 12","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cheng-Yeh Yang, Chun-Yen Lin, Rong-Nan Chien, Sheng-Nan Lu
{"title":"Response to Letter to the Editor ‘Key Considerations to Broaden the Validity of HCV-Related LC/CLD Mortality Research in Taiwan’","authors":"Cheng-Yeh Yang, Chun-Yen Lin, Rong-Nan Chien, Sheng-Nan Lu","doi":"10.1111/liv.70455","DOIUrl":"10.1111/liv.70455","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 12","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ellina Lytvyak, Gideon Hirschfield, Devika Shreekumar, Yu Jun Wong, Aldo J. Montano-Loza
{"title":"Author Response to Letter to the Editor: Tofacitinib as a Steroid-Free Induction in Autoimmune Hepatitis: An Initial Experience","authors":"Ellina Lytvyak, Gideon Hirschfield, Devika Shreekumar, Yu Jun Wong, Aldo J. Montano-Loza","doi":"10.1111/liv.70446","DOIUrl":"10.1111/liv.70446","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 12","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145587949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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