BACKGROUND & AIMS:While patients with grade 3 acute-on-chronic liver failure (ACLF-3), have high mortality, there is a subset requiring maximal life support. We report post liver transplant (LT) outcomes and identify factors associated with futility in extreme ACLF-3 (eACLF-3) recipients, all requiring intubation, vasopressors, and dialysis at LT. METHODS:We identified adult eACLF-3 LT recipients between January 2010 and December 2021. Pre-LT characteristics were compared among eACLF-3 recipients with and without the futile outcome (one-year or in-hospital mortality), predictors of futility were identified, and a logistic regression model was evaluated using 5-fold cross validation. Findings were validated using the Multi-Organ Dysfunction and Evaluation for Liver Transplantation (MODEL) Consortium. RESULTS:Of 1,608 adult LT recipients at our center, 177 (11%) were eACLF-3. Thirty-five (20%) eACLF-3 recipients experienced futility. Predictors of futility were previous upper abdominal surgery (OR=4.6, P=0.002), sepsis within 14 days prior to LT (OR= 5.9, P= 0.013), intubation due to pneumonia or acute respiratory distress syndrome (OR= 3.5, P= 0.010), worsening PaO2:FiO2 ratio (OR= 3.9, P=0.008), and pre-LT base deficit (OR=1.27, P=0.007). Futility was predicted with an AUROC of 0.74 (SD 0.15). When compared to the MODEL Consortium, our cohort had improved three-, six-, and twelve-month survivals of 89%, 85%, and 80%, compared to 83%, 79%, and 70% (p=0.048); however overall 5-year survival was similar (63% vs 59%, p=0.14). CONCLUSIONS:We report the largest single-center experience of LT for eACLF-3 patients, demonstrating acceptable survival despite high acuity, validated in the MODEL Consortium dataset. Prospective validation of the predictive model and identified risk factors is necessary, and may aid in appropriate selection of ACLF-3 patients requiring maximal life support prior to LT. IMPACT AND IMPLICATIONS:There has been persistent interest in the liver transplant community regarding transplant for acute-on-chronic liver failure grade 3 (ACLF-3) recipients. In this work, we report on a large single-center experience transplanting ACLF-3 recipients, specifically investigating an extreme subset of these patients who were all mechanically ventilated, receiving vasopressors, and receiving hemodialysis at time of transplant. We characterized their outcomes, identifying clear risk factors associated with futility in this hyper-acute subgroup and demonstrating that with appropriate selection, even patients in this extreme subgroup can experience acceptable five-year post-transplant survival. While we could not externally validate our model due to data availability, the obtained external patient cohort of extreme ACLF-3 patients broadly validates our findings. We feel that these results represent an important contribution to the liver transplant community given concerns about transplanting this hyper-acute subpopulation. These results may help guide physicians in selecting appropriate candidates for transplant.

BACKGROUND:Hepatocellular carcinoma (HCC) has a poor long-term prognosis due to high recurrence and cirrhosis-related mortality, even after potentially curative treatments such as liver transplantation (LT), surgical resection, or ablation. This study aimed to identify factors associated with ≥10-year survival in HCC patients. METHODS:A retrospective cohort study was conducted among HCC patients diagnosed between 2004 and 2022 using the National Cancer Database. Multivariable Cox regression was used to identify predictors of overall survival, and logistic regression was used to identify predictors of ≥10-year survival. RESULTS:Among 249,600 HCC patients, 177,585 (71.2%) died within 5 years, 8613 (3.5%) died at 5-10 years, 54,988 (22.0%) were alive with <10 years of follow-up, and 8219 (3.3%) survived ≥10 years. LT, resection, and ablation were performed in 6.6%, 9.3%, and 11% of patients, respectively. Compared with ablation as the reference group, LT [adjusted odds ratio (aOR) 11.96, 95% confidence interval (CI): 11.27-13.29] and resection (aOR: 2.83, 95% CI: 2.57-3.08) increased the odds of ≥10-year survival, while non-curative treatments reduced the odds compared with ablation (aOR: 0.50, 95% CI: 0.47-0.55). Cox regression results were consistent with the logistic model, confirming the association. Decision tree analysis confirmed LT as the dominant determinant of long-term survival. Black individuals were associated with lower odds of ≥10-year survival (aOR: 0.88, 95% CI: 0.820-0.96) and decreased likelihood of receiving LT (aOR: 0.73, 95% CI: 0.55-0.96). CONCLUSIONS:LT offers the best chance of ≥10-year survival in HCC. Ensuring equitable access is essential, especially for Black patients who have lower transplant rates and worse outcomes.

Chronic inflammation is an established driver of tumorigenesis across multiple organs, including the liver. Yet, the precise mechanisms linking persistent inflammatory signaling to tumorigenesis remain unclear. While classic tumor immunology focuses on immune-mediated tumor eradication, in hepatocellular carcinoma (HCC), growing evidence highlights a paradoxical immune capacity to foster malignant growth. HCC is a major health burden, most often arising in the setting of chronic inflammatory liver disease and cirrhosis. Nonetheless, some HCC cases occur in patients lacking cirrhosis or its traditional triggers, underscoring gaps in our mechanistic understanding. The immune system orchestrates a highly regulated defense network; however, neoplastic cells can subvert this network by sculpting an immune-modulating milieu that mimics protective inflammation while promoting tumor survival and expansion. In HCC, immune influences are bidirectional and stage dependent. As liver disease evolves to cirrhosis, the interplay among the inflammatory response, immune response, cirrhosis-associated immune dysfunction syndrome, and the tumor microenvironment becomes increasingly intricate. This review delineates these overlapping but distinct processes, dissects their individual contributions to HCC pathogenesis, and highlights immune-cell compositional changes across disease stages. We contrast protective immune-inflammatory responses that contain early chronic liver injury with the pro-tumorigenic environment characteristic of cirrhosis. Finally, we propose that mapping stage-specific biomarker signatures could transform inflammatory staging into a precision modality, informing immune-based prevention strategies and guiding individualized systemic therapies for HCC.

Binge drinking and excessive alcohol consumption are major public health concerns, and the COVID-19 pandemic may have exacerbated these issues. We aimed to compare the prevalence of binge and excessive alcohol use, as well as advanced liver fibrosis, among U.S. adults before and after the pandemic onset. We analysed 9533 adult participants from the National Health and Nutrition Examination Survey (NHANES) between 2017 and 2023. Pre-pandemic (2017–2020) and post-pandemic (2021–2023) cycles were identified. Binge drinking was defined as ≥ 5 drinks/occasion for men or ≥ 4 for women, and excessive alcohol use as ≥ 2 drinks/day (men) or ≥ 1 (women). Advanced fibrosis was assessed using transient elastography (≥ 9.6 kPa). Logistic regression models, incorporating NHANES weights, were used to evaluate associations. Among 9533 participants, binge drinking prevalence increased from 21.5% (2017–2020) to 27.9% (2021–2023; p  < 0.001), while excessive alcohol use rose from 12.5% to 14.3% ( p  = 0.040). Notable increases in binge drinking were observed across multiple demographic groups, especially in older adults (≥ 60 years) and women. The prevalence of advanced fibrosis also significantly increased from 6.1% to 8.4% ( p  = 0.011). Binge drinking was independently associated with an elevated risk of advanced fibrosis after adjusting for age, sex, and metabolic risk factors (OR = 1.496 [95% CI, 1.084–2.065]). Binge and excessive drinking increased notably in the post-pandemic period, accompanied by rising rates of advanced liver fibrosis. These findings highlight the need for proactive screening, behavioural interventions, and policy measures to limit high-risk alcohol use, particularly as populations at historically lower risk appear at higher risk.

BACKGROUND:Acamprosate is generally considered safe in patients with liver disease because it is renally cleared. Baclofen has been shown to be safe and effective in patients with alcohol use disorder and alcohol-associated cirrhosis. Both medications are guideline-endorsed pharmacotherapies for patients with alcohol-associated cirrhosis. However, the safety of baclofen relative to acamprosate remains uncertain. AIMS:To compare the safety profiles of baclofen and acamprosate in patients with alcohol-associated cirrhosis. METHODS:We conducted a nationwide, multicenter cohort study using a target trial emulation framework. Adults with compensated alcohol-associated cirrhosis who received a first prescription of baclofen or acamprosate within 6 months of diagnosis were included. Propensity score matching (1:1) was used to balance 60 covariates. The primary outcome was major adverse liver outcomes (MALO), defined as a composite of hepatic decompensation events within 12 months. Secondary outcomes included individual decompensation events and mortality. RESULTS:After matching, 571 baclofen and 571 acamprosate initiators were analysed. The 1-year incidence of MALO was higher in the baclofen group (34.3%) than in the acamprosate group (27.4%), corresponding to a hazard ratio (HR) of 1.32 (95% CI, 1.02-1.70). Among individual events, baclofen was associated with a higher risk of hepatic encephalopathy (HR 1.80; 95% CI, 1.21-2.69). No significant differences in other individual events or mortality were observed. Subgroup analyses suggested greater risk among patients aged 56-70 years. CONCLUSIONS:In this large real-world study, baclofen was associated with a higher risk of hepatic encephalopathy compared with acamprosate in patients with compensated alcohol-associated cirrhosis.

Introduction:The high response rates observed with immunotherapy may allow downstaging to curative treatment in hepatocellular carcinoma (HCC). We aimed to investigate the factors associated with curative treatment receipt after immunotherapy and its outcomes. Methods:HCC patients who received immunotherapy as a first-line treatment during 2017-2020 were identified from the US National Cancer Database. Patients were classified into two groups: immunotherapy with subsequent curative treatment (resection, transplantation, and local ablation) and immunotherapy without curative treatment. Multivariable Cox regression analysis was performed to determine factors associated with OS, followed by propensity score (PS) matching and inverse probability of treatment weighting (IPTW)-adjusted analysis. Results:Of the 4,329 HCC patients (median age 66 years, 81% male, 33% T4, 22% N1, and 32% M1 stage) who received immunotherapy as a first-line treatment, 138 (3.2%) received subsequent curative treatment after immunotherapy, with a median interval of 3.0 months between the two treatments. Curative treatment receipt was independently associated with care in an academic health system (odds ratio: 3.40, 95% CI: 1.68-7.38). OS was significantly longer in those with curative treatment conversion (hazard ratio [HR]: 0.15, 95% CI: 0.11-0.22), including after PS matching (HR: 0.20, 95% CI: 0.13-0.30) and IPTW-adjusted (HR: 0.19, 95% CI: 0.11-0.31) analyses. The median survival was not reached versus 10 months for those with and without subsequent curative treatment. Conclusion:Curative treatment conversion after immunotherapy was infrequent but was associated with significantly improved survival. Care at an academic center increases the probability of receiving subsequent curative treatment and favorable outcomes.

With the expansion of solid organ transplantation activities in the United States, there is a critical need for more transplant care providers and trainees to sustain and advance the field of transplantation. However, there has been a pending shortage of trainees pursuing transplant fellowship training in the United States in recent years. To address this issue, the American Society of Transplantation (AST) organized the fellows' task force, including representatives of all 4 major organs from various AST communities of practice, to understand the drivers of this pending shortage and develop strategies to increase interest in transplant specialization. The task force identified 4 areas of focus, including early and sustained exposure to transplant medicine, awareness through education, flexible fellowships and pathways to transplant, and work-life resources. Based on these focus areas, the task force developed recommendations and action items, which were compiled into a report to be implemented by individuals, institutions, communities of practice (work groups), and societies such as the AST. We hope that this report will be the first step in overcoming barriers and concerns to encourage the pursuit of specialization in transplantation in the United States.

Background: Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is becoming a leading indication for liver transplantation in the United States. In this growing recipient population, the combined effects of underlying liver disease etiology and associated comorbidities on the evaluation pathway to transplantation warrant closer examination of patient outcomes. Methods: We analyzed adult liver transplant referrals (n = 9981) from the California Liver Network, a multi-center retrospective cohort spanning six high-volume California transplant centers between 2018 and 2020. A total of 6709 patients who underwent formal evaluation were included. Patients were stratified by MASLD vs. non-MASLD etiology and compared for demographics, comorbidities, transplant evaluation timelines, listing rates, and outcomes. Results: MASLD patients (n = 1477) were older, had higher BMI, and had greater prevalence of metabolic comorbidities than non-MASLD patients (n = 5232; p < 0.001 for all). Compared to non-MASLD candidates, MASLD patients were more likely to be waitlisted (OR 1.52, 95% CI 1.33-1.74; p < 0.001). However, MASLD and non-MASLD patients had no statistically significant difference in the rate of transplant (p = 0.182), with clinically similar but statistically inferior post-transplant survival outcomes at 5 years post-transplant (88% vs. 83%; p = 0.014). Competing-risk analysis showed that MASLD candidates had higher cumulative incidence of death on the waitlist (p < 0.001), although MASLD was not independently associated with waitlist mortality when adjusting for covariates (p = 0.300). MASLD patients demonstrated increased mortality following waitlist removal (HR 1.64, 95% CI 1.14-2.35; p = 0.008), primarily among those removed for clinical deterioration (HR 1.50, 95% CI 1.01-2.23; p = 0.044). Conclusions: MASLD patients face unique challenges in liver transplant evaluation. MASLD patients are associated with higher comorbidities, increased incidence of waitlist mortality, and significantly higher mortality rate following waitlist removal. However, transplantation provides significant survival benefit with comparable outcomes to non-MASLD recipients; thus, early access to transplant may optimize outcomes for MASLD liver transplant candidates.

There are no validated biomarkers for assessing hepatocellular carcinoma (HCC) treatment response (TR). Extracellular vesicles (EVs) are promising circulating biomarkers that may detect minimal residual disease in patients with treated HCC. We developed the HCC EV TR Score using HCC EV Digital Scoring Assay involving click chemistry-mediated enrichment of HCC EVs, followed by absolute quantification of HCC EV-specific genes by RT-digital PCR. Six HCC EV-specific genes were selected and validated through i) a comprehensive data analysis pipeline with an unprecedentedly large collection of liver transcriptome datasets (n = 9,160), ii) RNAscope validation on HCC tissues (n = 6), and iii) a pilot study on early- or intermediate-stage HCC and liver cirrhosis patients (n = 70). The performance of HCC EV TR Score was assessed in a phase-2 retrospective case–control study (n = 100). HCC EV TR Scores, calculated from pre- and post-treatment plasma samples in the phase-2 case–control study, accurately differentiated post-treatment viable from nonviable HCC in the training (area under the ROC curve [AUROC] of 0.90, n = 49) and validation set (AUROC of 0.88, n = 51). At an optimal cutoff of 0.76 identified in the training set, HCC EV TR Score had high accuracy in detecting viable tumors (sensitivity: 76.5