BACKGROUND & AIMS:Highly effective second-line treatments for hepatocellular carcinoma remain an unmet need. The GOING investigator-initiated Phase I/IIa trial evaluated regorafenib plus nivolumab (add-on) in patients who progressed on sorafenib (Cohort-A) or discontinued atezolizumab-bevacizumab (Cohort-B). METHODS:Patients received regorafenib for two 28-day cycles, adding nivolumab in cycle 3, until unacceptable adverse events, symptomatic progression, withdrawal or death. Primary endpoint was safety. Secondary endpoints included overall survival, time to progression, post-progression survival, objective response rate and incidence of new-extrahepatic-spread. RESULTS:Of 85 patients screened, 67 were enrolled (75.5% BCLC-C). All experienced adverse events and 9% led to discontinuation. Severe treatment-related adverse events occurred in 28.4% overall, 32.1% in Cohort-A, and 14.3% in Cohort-B. Median overall survival was 20.0 (95% CI 11-37) months, with 40.6% survival at 36 months. In Cohort-A, median overall survival was 25 (95% CI 14-39) months with 45% survival at 36 months, while Cohort-B median overall survival was 8 (95% CI 4-NE) months with 28.6% survival at 24 months. Objective response rate was 16.4%; median time to progression and post-progression survival were 5 (95% CI 4-9) months and 14 (95% CI 8-33) months. Intrahepatic growth was the most common progression pattern, followed by new-extrahepatic-spread. CONCLUSIONS:The add-on strategy of regorafenib plus nivolumab in second-line had manageable safety and significant clinical activity with a noteworthy median overall survival of 20 months. Among those progressing on sorafenib, 45% were alive at 3 years. These findings support further evaluation with mechanism-guided trials after progression on immunotherapy. TRIAL REGISTRATION:EudraCT number: 2019-003108-10; https://www.clinicaltrialsregister.eu.

BACKGROUND & AIMS:Portopulmonary hypertension (PoPH) is a severe complication of cirrhosis and portal hypertension. In 2022, a European task force revised the diagnostic criteria for pulmonary arterial hypertension (PAH), defining early stages as a mean pulmonary arterial pressure (mPAP) of 20.5-24.5 mmHg and pulmonary vascular resistance (PVR) >2 Wood units. We evaluated the prognostic value of these revised criteria in patients with cirrhosis. METHODS:In this longitudinal, multicenter, observational cohort, 428 adults with cirrhosis and portal hypertension underwent right-heart catheterization between 2015 and 2023 and were stratified into five groups: normal, early PoPH, classic PoPH, post-capillary pulmonary hypertension, and unclassified profiles. All-cause mortality was analyzed by multivariable Cox regression and competing-risk models, with liver transplantation as an intercurrent event. RESULTS:Over a median follow-up time of 20.0 months (IQR 8.0-36.0), 3-year survival rates were 76.7%, 49.5%, and 42.0% in the normal mPAP, early PoPH, and classic PoPH groups, respectively. After adjustment for age, sex, liver function, and portal hypertension severity, both early PoPH (hazard ratio 3.5; 95% CI 1.9-6.3; p <0.01) and classic PoPH (hazard ratio 4.5; 2.6-7.6; p <0.01) remained independent predictors of mortality vs. normal mPAP; these associations persisted in competing-risk analysis, whereas post-capillary pulmonary hypertension and unclassified groups did not differ from the normal mPAP cohort. CONCLUSION:Applying the 2022 ESC/ERC definitions of PAH identifies a subset of patients with cirrhosis with early-stage PoPH, characterized by mild pulmonary vascular resistance elevation, who nevertheless face a markedly increased risk of death, emphasizing the need for systematic screening and early targeted intervention. IMPACT AND IMPLICATIONS:Portopulmonary hypertension (PoPH) is a severe and often overlooked complication of cirrhosis. Using the updated 2022 ESC/ERS diagnostic criteria, this multicenter study identified a previously unrecognized subgroup of patients with cirrhosis and early-stage PoPH, defined by mildly elevated pulmonary vascular resistance and mean pulmonary artery pressure. Despite their subtle hemodynamic changes, these patients showed significantly reduced survival, independent of liver disease severity. These results highlight the prognostic relevance of early PoPH and suggest that applying the new criteria may help refine risk stratification and guide closer follow-up or earlier consideration of targeted interventions in selected patients.

Background & Aims: The epidemiological landscape of hepatocellular carcinoma (HCC) in Europe is evolving. This study aims to provide an updated description of the current epidemiology of liver cancer in Spain. Methods: This multicenter prospective study collected demographic and clinical data on primary liver cancer between October 2022 and January 2023. We conducted descriptive and comparative analyses with data collected in 2008 and 2014. Results: Of the 767 cases of primary liver cancer collected from 52 centers, 91% were diagnosed as HCC. The majority of patients were male (83.3%), average age 68 years, 80.7% had cirrhosis. The primary causes were alcohol (29.9% alone, 55% combined with other etiologies), liver disease related to metabolic syndrome (LDrMS, 23%) and hepatitis C (17.3%). Treatments included ablation (15.7%), systemic therapy (14.7%), and chemoembolization (14.6%). Data from 29 centers (n = 1,351) across three registries revealed a significant increase in LDrMS (from 4.9% to 24%) and HCC in non-cirrhotic livers (from 4.2% to 7.9%). Meanwhile, hepatitis C decreased sharply (from 43% to 17.5%). Alcohol-related cases remained stable. There was a slight increase in male patients and hypertension, diabetes, and obesity. Patients with cirrhosis diagnosed outside of screening programs presented with larger tumors and more advanced disease. This led to fewer evaluations for curative treatments. Conclusions: Alcohol accounts for 30% of HCC cases and is the main etiology. The registry shows a decrease in hepatitis Crelated HCC, an increase in LDrMS and HCC in non-cirrhotic livers. Surveillance was implemented in X80% of the recommended population. There is a need for improved screening and prevention strategies, particularly for alcohol abuse and LDrMS, to enhance HCC management. (c) 2025 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND AND AIMS:Esophageal varices (EV) are common in adults with Fontan-type circulation and may arise via distinct hemodynamic mechanisms depending on their anatomic location. We aimed to determine the prevalence, anatomical distribution, and hemodynamic correlates of EV in this population. APPROACH AND RESULTS:In this prospective cohort study, 114 consecutive adults with Fontan-type circulation underwent combined hepatic and cardiac catheterization, esophagogastroduodenoscopy, and liver biopsy. Patients were classified by endoscopic findings into those with and without EV, and the EV cohort was further stratified by location (proximal or distal). EV were present in 36.8% (95% CI, 27.9-45.8%), including 28.9% with distal EV and 17.5% with proximal EV. Over a median follow-up of 48.9 months (IQR, 27.1-85.5), only one variceal bleeding event occurred. Patients with distal EV exhibited the highest cardiac index and pulmonary, systemic and hepatic venous pressures, as well as the lowest systemic vascular resistance (all p <0.01). Severe hepatic fibrosis was more frequent in this group (87.9%) than in patients without EV (33.8%) or those with proximal EV (25.0%). Non-invasive fibrosis markers (liver stiffness, FIB-4, Forns index, FonLiver risk score) were significantly elevated in patients with distal EV (all p <0.05), despite similar biochemical profiles. CONCLUSIONS:Distal EVs are frequent and characterize a distinct hemodynamic phenotype, featuring elevated Fontan pathway pressures, severe hepatic fibrosis, portal hypertension, and a hyperdynamic circulatory state.

Background & Aims: Etiologic factor removal (ER) drives recompensation and improves portal hypertension in cirrhosis. Esophageal varices (EV) and portosystemic shunts (PSS) have been found in patients despite hepatic venous pressure gradient (HVPG) dropping below 10 mmHg after ER, questioning HVPG accuracy in reflecting true portal pressure in the setting of ER. We aim to evaluate the correlation of HVPG with direct portal pressure (DPP) in patients with persistence of EV after ER despite HVPG <10 mmHg. Methods: This is a bicentric 'proof of concept' study evaluating HVPG and ultrasound-guided percutaneous DPP in patients with HCV or alcohol-related cirrhosis with persistent varices and HVPG <10 mmHg after at least 5 years of ER. Results: Seven patients with HCV and three with alcohol-related cirrhosis with persistent varices and HVPG <10 mmHg after at least 5 years of ER were included. At evaluation, all patients had a patent portal vein and were compensated. The median platelet count was 129.5 (IQR 95-145) x 109/ml, 9 /ml, and the median liver stiffness measurement was 16.15 (IQR 14.4-22.3) kPa. In five patients, EV remained the same size (two large and three small), and five downsized to small after ER. Wedge hepatic vein pressure (median 19 [IQR 16.5-20] mmHg) and portal pressure (median 18 [IQR 15-19.5] mmHg) had an excellent correlation (R = 0.93, p <0.0001). Portal pressure gradient (PPG) confirmed the absence of clinically significant portal hypertension as identified by HVPG across all the patients. Conclusions: HVPG accurately reflects PPG in the context of HCV and alcohol-related cirrhosis regression. After ER, EV may persist despite HVPG <10 mmHg. The benefit of prophylaxis in patients with EV and HVPG <10 mmHg is unknown. Future studies with clinical endpoints are needed to validate our findings. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND & AIMS:Previous meta-analyses demonstrated the safety and efficacy of anticoagulation in the recanalization of portal vein thrombosis in patients with cirrhosis. Whether this benefit translates into improved survival is unknown. We conducted an individual patient data (IPD) meta-analysis to assess the effect of anticoagulation on all-cause mortality in patients with cirrhosis and portal vein thrombosis. METHODS:In this IPD meta-analysis, we selected studies comparing anticoagulation vs. no treatment in patients with cirrhosis and portal vein thrombosis from PubMed, Embase, and Cochrane databases (until June 2020) (PROSPERO no.: CRD42020140026). IPD were subsequently requested from authors. The primary outcome - the effect of anticoagulation on all-cause mortality - was assessed by a one-step meta-analysis based on a competing-risk model with liver transplantation as the competing event. The model was adjusted for clinically relevant confounders. A multilevel mixed-effects logistic regression model was used to determine the effect of anticoagulation on recanalization. RESULTS:Individual data on 500 patients from five studies were included; 205 (41%) received anticoagulation and 295 did not. Anticoagulation reduced all-cause mortality (adjusted subdistribution hazard ratio 0.59; 95% CI 0.49-0.70), independently of thrombosis severity and recanalization. The effect of anticoagulation on all-cause mortality was consistent with a reduction in liver-related mortality. The recanalization rate was higher in the anticoagulation arm (adjusted odds ratio 3.45; 95% CI 2.22-5.36). The non-portal-hypertension-related bleeding rate was significantly greater in the anticoagulation group. CONCLUSIONS:Anticoagulation reduces all-cause mortality in patients with cirrhosis and portal vein thrombosis independently of recanalization, but at the expense of increasing non-portal hypertension-related bleeding. PROSPERO REGISTRATION NUMBER:CRD42020140026. IMPACT AND IMPLICATIONS:Anticoagulation is effective in promoting recanalization of portal vein thrombosis in patients with cirrhosis, but whether this benefit translates into improved survival is controversial. Our individual patient data meta-analysis based on a competing-risk model with liver transplantation as the competing event shows that anticoagulation reduces all-cause mortality in patients with cirrhosis and portal vein thrombosis independently of recanalization. According to our findings, portal vein thrombosis may identify a group of patients with cirrhosis that benefit from long-term anticoagulation.

Portal vein thrombosis is an uncommon complication in patients with cirrhosis, typically manifesting in the advanced stages of the disease. Although robust evidence is lacking, anticoagulation is indicated in specific patient subgroups, either those with severe portal occlusion or those requiring attempted portal recanalization due to their unique transplant situation. Beyond recanalization, anticoagulation appears to exert a beneficial effect on the natural history of cirrhosis, which raises uncertainties about the appropriateness of discontinuing it once initiated.

428 Background: Regorafenib (Rego) improves survival in patients with hepatocellular carcinoma (HCC) (RESORCE trial) while nivolumab (Nivo) is also safe and active in terms of radiologic response (15-20% objective response) in second-line. The GOING trial (NCT04170556) is an investigator-initiated phase I/IIa study assessing the safety of Rego plus Nivo in HCC patients who progress and tolerate sorafenib (Cohort A) or who discontinue atezolizumab plus bevacizumab (Cohort B). Methods: Patients from cohort A receive Rego as monotherapy for the first 2 cycles (starting dose 160 mg/day, 3 weeks on/1 week off and adjusted for adverse events [AEs]) and Nivo is added at day 1 of cycle 3 (the first 10 patients at 3 mg/kg; since they did not present serious-AE (SAE), the final dose is 240 mg every two weeks). Treatment continues until unacceptable AEs, symptomatic tumor progression, patient decision or death. Safety is measured by the rate of AEs, rate of treatment related-AEs (Tr-AE), rate of AEs leading to treatment discontinuation and rate of death. Severity of AEs are evaluated according to CTCAE v.5.0. A futility analysis using the non-binding Lan & DeMets beta-spending functions with a boundary of p=0.814 is mandated when 32.8% of cohort A has data of tumor assessment at least at week 16 by RECIST 1.1. Results: Fifty-one patients have been enrolled in cohort A as of May 15, 2021. The first 30 (BCLC-C 73%) were considered in this safety analysis. All patients developed at least one AE, 29 (96.7%) had Tr-AEs of any grade and 10 (33.3%) had grade 3 (no grades 4 or 5 have been reported). Ten (33.3%) patients had a Rego-related AE, 4 (13.3%) Nivo-related, and 4 (13.3%) Tr-AE grade 3 of special interest. The table describes the profile Tr-AE occurring in > 10% of patients. Only 4 (13.3%) patients developed Tr-SAE, 3 (10 %) Rego-related and 3 (10 %) Nivo-related. Four patients discontinued the study due to physician decision, 2 for progression, and 2 for AEs (one related to study treatment). One patient had surgical resection after treatment discontinuation and a complete necrosis was observed at pathology. Conclusions: The sequential combination of Rego-Nivo has a manageable safety profile. Less than one third of the patients developed grade 3/4 Tr-AE and there was no treatment-related death. Futility analysis allowed to continuing recruitment. Clinical trial information: NCT04170556. [Table: see text]

Development of portal hypertension is the most critical hallmark in the natural history of advanced chronic liver disease, as it is responsible for most liver decompensations. Correct risk stratification allows the design of personalized treatment strategies. In addition, the dynamic nature of chronic liver disease requires a refinement of both invasive and non-invasive diagnostic methods at every stage. Treatment with non-selective beta blockers and suppression of the etiologic factor improve portal hypertension and decrease the probability of decompensation in high-risk patients. Patients admitted for variceal hemorrhage also benefit from personalized management, where insertion of a preventive TIPS plays a relevant role.

Fontan-associated liver disease encompasses all liver disturbances arising from the precarious hemodynamic system after the Fontan procedure. The natural history of this form of liver disease has been poorly explained. Although the histological changes present in the liver are similar to those seen in other forms of cardiac liver disease, some differences have been described in this population. Many Fontan patients can develop portal hypertension-related complications such as esophageal varices, ascites, malnutrition, and encephalopathy. Moreover, an elevated risk of hepatocellular carcinoma has been well documented. Adequate staging and management of liver damage are essential to implement screening strategies and improve global outcomes.

Portal vein thrombosis is common in patients with cirrhosis, especially in those with decompensated disease. Complete portal vein thrombosis can worsen outcomes in liver transplantation candidates, but otherwise, its impact on cirrhosis progression is controversial. Anticoagulation is safe to promote recanalization, and recent evidence also shows an improvement in overall survival.