Long-term albumin improves the outcomes of patients with decompensated cirrhosis and diabetes mellitus: Post hoc analysis of the ANSWER trial.

Type-2 diabetes mellitus is a frequent comorbidity of cirrhosis independently associated with cirrhosis-related complications and mortality. This post hoc analysis of the ANSWER trial database assessed the effects of long-term human albumin (HA) administration on top of the standard medical treatment (SMT) on the clinical outcomes of a subgroup of 85 outpatients with liver cirrhosis, uncomplicated ascites and insulin-treated diabetes mellitus type 2 (ITDM). Compared to patients in the SMT arm, the SMT + HA group showed a better overall survival (86% vs. 57%, p = .016) and lower incidence rates of paracenteses, overt hepatic encephalopathy, bacterial infections, renal dysfunction and electrolyte disorders. Hospital admissions did not differ between the two arms, but the number of days spent in hospital was lower in the SMT + HA group. In conclusion, in a subgroup of ITDM outpatients with decompensated cirrhosis and ascites, long-term HA administration was associated with better survival and a lower incidence of cirrhosis-related complications.

A holistic evaluation of patients with chronic Hepatitis D virus (HDV) infection enrolled in the Italian PITER-B and delta cohort.

BACKGROUND AND AIMS: We aimed to characterize the epidemiologic and comorbidities profiles of patients with chronic Hepatitis D (CHD) followed in clinical practice in Italy and explored their interferon (IFN) eligibility. METHODS: This was a cross-sectional study of the PITER cohort consisting of consecutive HBsAg-positive patients from 59 centers over the period 2019-2023. Multivariable analysis was performed by logistic regression model. RESULTS: Of 5492 HBsAg-positive enrolled patients, 4152 (75.6%) were screened for HDV, 422 (10.2%) were anti-HDV positive. Compared with HBsAg mono-infected, anti-HDV positive patients were more often younger, non-Italians, with a history of drug use, had elevated alanine transaminase (ALT), cirrhosis, or hepatocellular carcinoma (HCC). Compared with Italians, anti-HDV positive non-Italians were younger (42.2% age ≤ 40 years vs. 2.1%; P < 0.001), more often females (males 43.0% vs. 68.6%; P < 0.001) with less frequent cirrhosis and HCC. HDV-RNA was detected in 63.2% of anti-HDV-positive patients, who were more likely to have elevated ALT, cirrhosis, and HCC. Extrahepatic comorbidities were present in 47.4% of anti-HDV positive patients and could affect the eligibility of IFN-containing therapies in at least 53.0% of patients in care. CONCLUSIONS: CHD affects young, foreign-born patients and older Italians, of whom two-thirds had cirrhosis or HCC. Comorbidities were frequent in both Italians and non-Italians and impacted eligibility for IFN.

Incidence and Predictors of Esophagogastric Varices Bleeding in Patients with Hepatocellular Carcinoma in Lenvatinib.

Introduction: Lenvatinib is indicated for the forefront treatment of advanced hepatocellular carcinoma (aHCC), but its use may be limited by the risk of esophagogastric varices (EGV) bleeding. This study assessed the prevalence, predictors, and complications of EGV in aHCC patients treated with lenvatinib. Methods: In this multicenter international retrospective study, cirrhotic patients treated with lenvatinib for aHCC, were enrolled if upper-gastrointestinal endoscopy was available within 6 months before treatment. Primary endpoint was the incidence of EGV bleeding during lenvatinib therapy; secondary endpoints were predictors for EGV bleeding, prevalence, and risk factors for the presence of EGV and high-risk EGV at baseline, as well as impact of EGV bleeding on patients' survival. Results: 535 patients were enrolled in the study (median age: 72 years, 78% male, 63% viral etiology, 89% Child-Pugh A, 16% neoplastic portal vein thrombosis [nPVT], 56% Barcelona Clinic Liver Cancer-C): 234 had EGV (44%), 70 (30%) were at high risk and 59 were on primary prophylaxis. During lenvatinib treatment, 17 patients bled from EGV (3 grade 5), the 12-month cumulative incidence being 3%. The only baseline independent predictor of EGV bleeding was the presence of baseline high-risk EGV (hazard ratio: 6.94, 95% confidence interval [CI]: 2.23-21.57, p = 0.001). In these patients the 12-month risk was 17%. High-risk varices were independently associated with Child-Pugh B score (odds ratio [OR]: 2.12; 95% CI: 1.08-4.17, p = 0.03), nPVT (OR: 2.54; 95% CI: 1.40-4.61, p = 0.002), and platelets <150,000/µL (OR: 2.47; 95% CI: 1.35-4.50, p = 0.003). Conclusion: In hepatocellular carcinoma patients treated with lenvatinib, the risk of EGV bleeding was mostly low but significant only in patients with high-risk EGV at baseline.

Liver Resection vs Nonsurgical Treatments for Patients With Early Multinodular Hepatocellular Carcinoma.

Importance: The 2022 Barcelona Clinic Liver Cancer algorithm currently discourages liver resection (LR) for patients with multinodular hepatocellular carcinoma (HCC) presenting with 2 or 3 nodules that are each 3 cm or smaller. Objective: To compare the efficacy of liver resection (LR), percutaneous radiofrequency ablation (PRFA), and transarterial chemoembolization (TACE) in patients with multinodular HCC. Design, Setting, and Participants: This cohort study is a retrospective analysis conducted using data from the HE.RC.O.LE.S register (n = 5331) for LR patients and the ITA.LI.CA database (n = 7056) for PRFA and TACE patients. A matching-adjusted indirect comparison (MAIC) method was applied to balance data and potential confounding factors between the 3 groups. Included were patients from multiple centers from 2008 to 2020; data were analyzed from January to December 2023. Interventions: LR, PRFA, or TACE. Main Outcomes and Measures: Survival rates at 1, 3, and 5 years were calculated. Cox MAIC-weighted multivariable analysis and competing risk analysis were used to assess outcomes. Results: A total of 720 patients with early multinodular HCC were included, 543 males (75.4%), 177 females (24.6%), and 350 individuals older than 70 years (48.6%). There were 296 patients in the LR group, 240 who underwent PRFA, and 184 who underwent TACE. After MAIC, LR exhibited 1-, 3-, and 5-year survival rates of 89.11%, 70.98%, and 56.44%, respectively. PRFA showed rates of 94.01%, 65.20%, and 39.93%, while TACE displayed rates of 90.88%, 48.95%, and 29.24%. Multivariable Cox survival analysis in the weighted population showed a survival benefit over alternative treatments (PRFA vs LR: hazard ratio [HR], 1.41; 95% CI, 1.07-1.86; P = .01; TACE vs LR: HR, 1.86; 95% CI, 1.29-2.68; P = .001). Competing risk analysis confirmed a lower risk of cancer-related death in LR compared with PRFA and TACE. Conclusions and Relevance: For patients with early multinodular HCC who are ineligible for transplant, LR should be prioritized as the primary therapeutic option, followed by PRFA and TACE when LR is not feasible. These findings provide valuable insights for clinical decision-making in this patient population.

Adverse Events as Potential Predictive Factors of Activity in Patients with Advanced HCC Treated with Atezolizumab Plus Bevacizumab.

BACKGROUND: In the context of patients with hepatocellular carcinoma (HCC) treated with systemic therapy, the correlation between the appearance of adverse events (AEs) and reported efficacy outcomes is well-known and widely investigated. From other pathological settings, we are aware of the prognostic and predictive value of the occurrence of immune-related AEs in patients treated with immune-checkpoint inhibitors. OBJECTIVE: This retrospective multicenter real-world study aims to investigate the potential prognostic value of AEs in patients with HCC treated with atezolizumab plus bevacizumab in the first-line setting. PATIENTS AND METHODS: The study population consisted of 823 patients from five countries (Italy, Germany, Portugal, Japan, and the Republic of Korea). RESULTS: Of the patients, 73.3% presented at least one AE during the study period. The most common AEs were proteinuria (29.6%), arterial hypertension (27.2%), and fatigue (26.0%). In all, 17.3% of the AEs were grade (G) 3. One death due to bleeding was reported. The multivariate analysis confirmed the appearance of decreased appetite G < 2 [versus G ≥ 2; hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.13-0.90; p < 0.01] and immunotoxicity G < 2 (versus G ≥ 2; HR: 0.70; 95% CI 0.24-0.99; p = 0.04) as independent prognostic factors for overall survival, and the appearance of decreased appetite G < 2 (versus G ≥ 2; HR: 0.73; 95% CI 0.43-0.95; p = 0.01), diarrhea (yes versus no; HR: 0.57, 95% CI 0.38-0.85; p = 0.01), fatigue (yes versus no; HR: 0.82, 95% CI 0.65-0.95; p < 0.01), arterial hypertension G < 2 (versus G ≥ 2; HR: 0.68, 95% CI 0.52-0.87; p < 0.01), and proteinuria (yes versus no; HR: 0.79, 95% CI 0.64-0.98; p = 0.03) as independent prognostic factors for progression-free survival. CONCLUSIONS: As demonstrated for other therapies, there is also a correlation between the occurrence of AEs and outcomes for patients with HCC for the combination of atezolizumab plus bevacizumab.

Prediction of cardiovascular risk in patients with hepatocellular carcinoma receiving anti-angiogenic drugs: lessons from sorafenib.

Antiangiogenics are associated with an increased risk of major adverse cardiac and cerebrovascular events (MACE). The identification of at-risk subjects is relevant in the case of hepatocellular carcinoma (HCC), for which anti-angiogenic TKIs and bevacizumab are used in first and subsequent lines of therapy, to select alternative drugs for patients with excessive risk. We verified the ability to predict MACE in sorafenib-treated patients of the 2022 European Society of Cardiology (ESC-2022) score for anti-angiogenics and the recently proposed CARDIOSOR score. A retrospective analysis was conducted of prospectively collected data of the ARPES and ITA.LI.CA databases. All patients received sorafenib for unresectable HCC from 2008 to 2018. Baseline information to calculate the ESC-2022 and CARDIOSOR scores and registration of evolutive events (including MACE) were available for all patients. The predictive ability of both scores was verified using competing risk regressions and tests for goodness of fit. This study included 843 patients (median follow-up 11.3 months). Thirty-four (4.0%) patients presented a MACE. The four-tier ESC-2022 classification showed a progressive risk increase for every class (cumulative risk 1.7%, 2.7%, 4.3%, and 15.0% in the low, medium, high, and high-risk tiers, respectively). The dichotomous CARDIOSOR scale identified a high-risk group with a fourfold increased risk of MACE (sHR 4.66, p = 0.010; cumulative risk 3.8% and 16.4%). ESC-2022 showed a better goodness of fit compared to the CARDIOSOR score [C-index 0.671 (0.583-0.758) vs 0.562 (0.501-0.634), p = 0.021], but this gap was eliminated using the linear version of CARDIOSOR. Both the ESC-2022 and CARDIOSOR scores discriminated patients at increased risk for MACE. The use of these scores in clinical practice should be encouraged, since therapeutic measures can mitigate the cardiovascular risk.

Impact of body mass index on the prognosis of unresectable HCC patients receiving first-line Lenvatinib or atezolizumab plus bevacizumab.

INTRODUCTION: Overweight is a negative prognostic factor in the general population in the long term. However, the role of body mass index (BMI) in the short-mid term in advanced tumours is unclear. The present analysis investigates the role of BMI weight classes in a large sample of patients affected by HCC and receiving atezolizumab plus bevacizumab or lenvatinib as first-line treatment. METHODS AND MATERIAL: The cohort included consecutive patients affected by BCLC-c and BCLC-B HCC patients from a multicenter international study group who received atezolizumab plus bevacizumab or lenvatinib as first-line therapy. Population was stratified according to the BMI in under-, over- and normal-weight according to the conventional thresholds. The primary objective of the study was to evaluate the prognostic and predictive impact of BMI in patients affected by advanced or intermediate HCC. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analysed with log-rank tests. RESULTS: 1292 consecutive patients with HCC were analysed. 466 (36%) patients were treated with lenvatinib and 826 (64%) patients were treated with atezolizumab plus bevacizumab. In the atezolizumab plus bevacizumab arm, 510 (62%) patients were normal-weight, 52 (6%) underweight and 264 (32%) overweight. At the univariate analysis for OS, underweight patients had significantly shorter OS compared to normal-weight patients, whereas no differences were found between normal-weight versus overweight. Multivariate analysis confirmed that underweight patients had significantly shorter OS compared to normal-weight patients (HR: 1.7; 95% CI: 1.0-2.8; p = .0323). In the lenvatinib arm, 26 patients (5.6%) were categorized as underweight, 256 (54.9%) as normal-weight, and 184 (39.5%) as overweight. At the univariate analysis for OS, no significant differences were found between normal-weight versus underweight and between normal-weight versus overweight, which was confirmed at multivariate analysis. CONCLUSION: Our analysis highlighted a prognostic role of BMI in a cohort of patients with advanced HCC who received atezolizumab plus bevacizumab, while no prognostic role for low BMI was apparent in patients who received lenvatinib.

Characteristics and outcome of anti-hepatitis D virus positive patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Chronic hepatitis D virus (HDV) often leads to end-stage liver disease and hepatocellular carcinoma (HCC). Comprehensive data pertaining to large populations with HDV and HCC are missing, therefore we sought to assess the characteristics, management, and outcome of these patients, comparing them to patients with hepatitis B virus (HBV) infection. METHODS: We analysed the Italian Liver Cancer database focusing on patients with positivity for HBV surface antigen and anti-HDV antibodies (HBV/HDV, n = 107) and patients with HBV infection alone (n = 588). Clinical and oncological characteristics, treatment, and survival were compared in the two groups. RESULTS: Patients with HBV/HDV had worse liver function [Model for End-stage Liver Disease score: 11 vs. 9, p < .0001; Child-Turcotte-Pugh score: 7 vs. 5, p < .0001] than patients with HBV. HCC was more frequently diagnosed during surveillance (72.9% vs. 52.4%, p = .0002), and the oncological stage was more frequently Milan-in (67.3% vs. 52.7%, p = .005) in patients with HBV/HDV. Liver transplantation was more frequently performed in HBV/HDV than in HBV patients (36.4% vs. 9.5%), while the opposite was observed for resection (8.4% vs. 20.1%, p < .0001), and in a competing risk analysis, HBV/HDV patients had a higher probability of receiving transplantation, independently of liver function and oncological stage. A trend towards longer survival was observed in patients with HBV/HDV (50.4 vs. 44.4 months, p = .106). CONCLUSIONS: In patients with HBV/HDV, HCC is diagnosed more frequently during surveillance, resulting in a less advanced cancer stage in patients with more deranged liver function than HBV alone. Patients with HBV/HDV have a heightened benefit from liver transplantation, positively influencing survival.

Sorafenib and Metronomic Capecitabine in Child-Pugh B patients with advanced HCC: A real-life comparison with best supportive care.

BACKGROUND AND AIMS: The efficacy of systemic therapy for unresectable advanced hepatocellular carcinoma (aHCC) has not been proven in patients with Child-Pugh (C-P) B cirrhosis. Nevertheless, in real-world these patients are treated both with tyrosine kinase inhibitors (TKIs) and with metronomic capecitabine (MC). This study aimed to compare sorafenib and MC outcomes versus best supportive care (BSC) in C-P B patients. METHOD: Between 2008 and 2020, among 774 C-P B patients with aHCC not amenable/responsive to locoregional treatments, 410 underwent sorafenib, 62 MC, and 302 BSC. The propensity score matching method was used to correct the baseline unbalanced prognostic factors. RESULTS: In the unmatched population, median OS was 9.7 months in patients treated with sorafenib, 8.0 with MC, and 3.9 months with BSC. In sorafenib vs. BSC-matched patients (135 couples), median OS was 7.3 (4.9-9.6) vs. 3.9 (2.6-5.2) months (p<0.001). ECOG-Performance Status, tumor size, macrovascular invasion, AFP, treatment-naive, and sorafenib were independent predictors of survival. In MC vs. BSC-matched patients (40 couples), median OS was 9.0 (0.2-17.8) vs.3.0 (2.2-3.8) months (p<0.001). Median OS did not differ (p = 0.283) in sorafenib vs. MC-matched patients (55 couples). CONCLUSION: C-P B patients with aHCC undergoing BSC have poor survival. Both Sorafenib and MC treatment improve their prognosis.

Safety and Efficacy of Lenvatinib in Very Old Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND: Data concerning the use of lenvatinib in very old patients (≥ 80 years) are limited, although the incidence of hepatocellular carcinoma (HCC) in this patient population is constantly increasing. OBJECTIVE: This analysis aimed to evaluate the efficacy and safety of lenvatinib in a large cohort of very old patients (≥ 80 years) with unresectable HCC. PATIENTS AND METHODS: The study was conducted on a cohort of 1325 patients from 46 centers in four Western and Eastern countries (Italy, Germany, Japan, and the Republic of Korea) who were undergoing first-line treatment with lenvatinib between July 2010 and February 2022. Patients were stratified according to age as very old (≥ 80 years) and not very old (< 80 years). RESULTS: The median overall survival (OS) was 15.7 months for patients < 80 years old and 18.4 months for patients ≥ 80 years old [hazard ratio (HR) = 1.02, 95% confidence interval (CI) 0.84-1.25, p = 0.8281]. Median progression free survival (PFS) was 6.3 months for patients < 80 years old and 6.5 months for patients ≥ 80 years old (HR = 1.07, 95% CI 0.91-1.25, p = 0.3954). No differences between the two study groups were found in terms of disease control rate (DCR; 80.8% versus 78.8%; p = 0.44) and response rate (RR; 38.2% versus 37.9%; p = 0.88). Patients < 80 years old experienced significantly more hand-foot skin reaction (HFSR) grade ≥ 2 and decreased appetite grade ≥ 2. Conversely, patients ≥ 80 years old experienced significantly more fatigue grade ≥ 2. In the very old group, parameters associated with prognosis were AFP, albumin-bilirubin (ALBI) grade, Barcelona Clinic Liver Cancer (BCLC), and Child-Pugh score. BCLC stage was the only independent predictor of overall survival (OS; HR = 1.59, 95% CI 1.11-2.29, p = 0.01115). CONCLUSIONS: Our study highlights the same efficacy and safety of lenvatinib between very old and not very old patients.

Comparative Analysis of Subclassification Systems in Patients with Intermediate-Stage Hepatocellular Carcinoma (Barcelona Clinic Liver Classification B) Receiving Systemic Therapy.

BACKGROUND: Intermediate-stage hepatocellular carcinoma (BCLC B HCC) occurs in a heterogeneous group of patients and can be addressed with a wide spectrum of treatments. Consequently, survival significantly varies among patients. In recent years, several subclassification systems have been proposed to stratify patients' prognosis. We analyzed and compared these systems (Bolondi, Yamakado, Kinki, Wang, Lee, and Kim criteria) in patients undergoing systemic therapy. METHODS: We considered 171 patients with BCLC B HCC treated with sorafenib as first-line systemic therapy in six Italian centers from 2010 to 2021 and retrospectively applied the criteria of six different subclassification systems. RESULTS: Except for the Yamakado criteria, all the subclassification systems showed a statistically significant correlation to overall survival (OS). In the postestimation analysis, the Bolondi criteria (OS of subgroups 22.5, 11.9, and 6.6 mo, respectively; C-index 0.586; AIC 1338; BIC 1344) and the Wang criteria (OS of subgroups 20.6, 11.9, and 7.0, respectively; C-index 0.607; AIC 1337; BIC 1344) presented the best accuracy. Further analyses of these two subclassification systems implemented with the prognostic factor of alpha-fetoprotein (AFP) > 400 ng/mL have shown an increase in accuracy for both systems (C-index 0.599 and 0.624, respectively). CONCLUSIONS: Intermediate-stage subclassification systems maintain their predictive value also in the setting of systemic therapy. The Bolondi and Wang criteria showed the highest accuracy. AFP > 400 ng/mL enhances the performance of these systems.

α-FAtE: A new predictive score of response to atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma.

Atezolizumab plus bevacizumab (AB) and lenvatinib can be alternatively used as first-line systemic treatment of unresectable hepatocellular carcinoma (HCC). However, no direct comparison of the two regimens has been performed in randomized clinical trials, making the identification of baseline differential predictors of response of major relevance to tailor the best therapeutic option to each patient. Baseline clinical and laboratory characteristics of real-world AB-treated HCC patients were analyzed in uni- and multivariate analyses to find potential prognostic factors of overall survival (OS). Significant variables were incorporated in a composite score (α-FAtE) and it was tested for specificity and sensitivity in receiver operating characteristic (ROC) curve and in multivariate analysis for OS. The score was applied in uni- and multivariate analyses for OS of a comparable lenvatinib-treated HCC population. Finally, comparison between treatments was performed in patients with low and high α-FAtE scores and predictivity estimated by interaction analysis. Time-to-progression (TTP) was a secondary endpoint. OS of AB-treated HCC patients was statistically longer in those with α-fetoprotein <400 ng/mL (HR 0.62, p = .0407), alkaline phosphatase (ALP) <125 IU/L (HR 0.52, p = .0189) and eosinophil count ≥70/µL (HR 0.46, p = .0013). The α-FAtE score was generated by the sum of single points attributed to each variable among the above reported. In ROC curve analysis, superior sensitivity and specificity were achieved by the score compared to individual variables (AUC 0.794, p < .02). Patients with high score had longer OS (HR 0.44, p = .0009) and TTP (HR 0.34, p < .0001) compared to low score if treated with AB, but not with lenvatinib. Overall, AB was superior to lenvatinib in high score patients (HR 0.55, p = .0043) and inferior in low score ones (HR 1.75, p = .0227). At interaction test, low α-FAtE score resulted as negative predictive factor of response to AB (p = .0004). In conclusion, α-FAtE is a novel prognostic and predictive score of response to first-line AB for HCC patients that, if validated in prospective studies, could drive therapeutic choice between lenvatinib and AB.

Development and internal validation of a multivariable model for the prediction of the probability of 1-year readmission to the emergency department for acute alcohol intoxication.

To develop and internally validate a multivariable logistic regression model (LRM) for the prediction of the probability of 1-year readmission to the emergency department (ED) in patients with acute alcohol intoxication (AAI). We developed and internally validated the LRM on a previously analyzed retrospective cohort of 3304 patients with AAI admitted to the ED of the Sant'Orsola-Malpighi Hospital (Bologna, Italy). The benchmark LRM employed readmission to the same ED for AAI within 1 year as the binary outcome, age as a continuous predictor, and sex, alcohol use disorder, substance use disorder, at least one previous admission for trauma, mental or behavioral disease, and homelessness as the binary predictors. Optimism correction was performed using the bootstrap on 1000 samples without replacement. The benchmark LRM was gradually simplified to get the most parsimonious LRM with similar optimism-corrected overall fit, discrimination and calibration. The 1-year readmission rate was 15.7% (95% CI 14.4-16.9%). A reduced LRM based on sex, age, at least one previous admission for trauma, mental or behavioral disease, and homelessness, performed nearly as well as the benchmark LRM. The reduced LRM had the following optimism-corrected metrics: scaled Brier score 17.0%, C-statistic 0.799 (95% CI 0.778 to 0.821), calibration in the large 0.000 (95% CI - 0.099 to 0.099), calibration slope 0.985 (95% CI 0.893 to 1.088), and an acceptably accurate calibration plot. An LRM based on sex, age, at least one previous admission for trauma, mental or behavioral disease, and homelessness can be used to estimate the probability of 1-year readmission to ED for AAI. To begin proving its clinical utility, this LRM should be validated in external cohorts.

Direct oral anticoagulants for the treatment of splanchnic vein thrombosis: A state of art.

Splanchnic vein thrombosis (SVT) is a manifestation of venous thromboembolism in an unusual site. Portal, mesenteric, and splenic veins are the most common vessels involved in SVT which occurs mainly in patients with liver cirrhosis, although non-cirrhotic patients could be affected as well. Thrombosis of hepatic veins, also known as Budd-Chiari syndrome, is another manifestation of SVT. Prompt diagnosis and intervention are mandatory in order to increase the recalization rate and reduce the risk of thrombus progression and hypertensive complications. Traditional anticoagulation with heparin and vitamin-K antagonists is the treatment of choice in these cases. However, recent studies have shown promising results on the efficacy and safety of direct oral anticoagulants (DOACs) in this setting. Available results are mainly based on retrospective studies with small sample size, but first clinical trials have been published in the last years. This manuscript aims to provide an updated overview of the current evidence regarding the role of DOACs for SVT in both cirrhotic and non-cirrhotic patients.

Predictors of non-transplantable recurrence in hepatocellular carcinoma patients treated with frontline liver resection.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) recurrence is common in patients treated with liver resection (LR). In this study, we aimed to evaluate the incidence and preoperative predictors of non-transplantable recurrence in patients with single HCC ≤5 cm treated with frontline LR. METHODS: From the Italian Liver Cancer (ITA.LI.CA) database, 512 patients receiving frontline LR for single HCC ≤5 cm were retrieved. Incidence and predictors of recurrence beyond Milan criteria (MC) and up-to-seven criteria were compared between patients with HCC <4 and ≥4 cm. RESULTS: During a median follow-up of 4.2 years, the overall recurrence rate was 55.9%. In the ≥4 cm group, a significantly higher proportion of patients recurred beyond MC at first recurrence (28.9% vs. 14.1%; p < 0.001) and overall (44.4% vs. 25.2%; p < 0.001). Similar results were found considering recurrence beyond up-to-seven criteria. Compared to those with larger tumours, patients with HCC <4 cm had a longer recurrence-free survival and overall survival. HCC size ≥4 cm and high alpha-fetoprotein (AFP) level at the time of LR were independent predictors of recurrence beyond MC (and up-to-seven criteria). In the subgroup of patients with available histologic information (n = 354), microvascular invasion and microsatellite lesions were identified as additional independent risk factors for non-transplantable recurrence. CONCLUSIONS: Despite the high recurrence rate, LR for single HCC ≤5 cm offers excellent long-term survival. Non-transplantable recurrence is predicted by HCC size and AFP levels, among pre-operatively available variables. High-risk patients could be considered for frontline LT or listed for transplantation even before recurrence.

Analysis of Patients' Characteristics and Treatment Profile of People Who Use Drugs (PWUDs) with and without a Co-Diagnosis of Viral Hepatitis C: A Real-World Retrospective Italian Analysis.

Purpose: Hepatitis C virus (HCV) spreads from contact with blood of an infected person. HCV infections are common among people who use drugs (PWUDs), when sharing needles, syringes, or other equipment for injected drugs. The advent of pangenotypic direct-antiviral agents (DAA) in 2017 transformed the treatment landscape for HCV, but PWUDs remain a complex and hard-to-treat population with high risk of HCV reinfection. The aim of this real-world analysis was to characterize the demographic and clinical features of PWUDs in Italy, also focusing on comorbidity profile, treatment with DAAs, resource consumptions for the National Health System (NHS). Patients and Methods: During 01/2011-06/2020, administrative databases of Italian healthcare entities, covering 3,900,000 individuals, were browsed to identify PWUDs with or without HCV infection. Among HCV+ patients, a further stratification was made into treated and untreated with DAAs. The date of PWUD or HCV first diagnosis or DAA first prescription was considered as index-date. Patients were then followed-up for one year. Alcohol-dependency was also investigated. Results: Total 3690 PWUDs were included, of whom 1141 (30.9%) PWUD-HCV+ and 2549 (69.1%) PWUD-HCV-. HCV-positive were significantly older (43.6 vs 38.5 years, p < 0.001), had a worse comorbidity profile (Charlson-index: 0.8 vs 0.4, p < 0.001), and high rates of psychiatric, respiratory, dermatological, musculoskeletal diseases and genitourinary (sexually transmitted) infections. Moreover, they received more drug prescriptions (other than DAAs, like anti-acids, antiepileptics, psycholeptics) and had undergone more frequent hospitalization, predominantly for hepatobiliary, respiratory system and mental disorders. DDA-untreated had significantly higher Charlson-index than DAA-treated (0.9 vs 0.6, p = 0.003). Alcoholism was found in 436 (11.8%) cases. Conclusion: This Italian real-world analysis suggests that PWUDs with HCV infection, especially those untreated with DAAs, show an elevated drug consumption due to their complex clinical profile. These findings could help to ameliorate the healthcare interventions on PWUDs with HCV infection.

Landscape of alcohol-related hepatocellular carcinoma in the last 15 years highlights the need to expand surveillance programs.

Background & Aims: Alcohol abuse and metabolic disorders are leading causes of hepatocellular carcinoma (HCC) worldwide. Alcohol-related aetiology is associated with a worse prognosis compared with viral agents, because of the lower percentage of patients diagnosed with HCC under routine surveillance and a higher burden of comorbidity in alcohol abusers. This study aimed to describe the evolving clinical scenario of alcohol-related HCC over 15 years (2006-2020) in Italy. Methods: Data from the Italian Liver Cancer (ITA.LI.CA) registry were used: 1,391 patients were allocated to three groups based on the year of HCC diagnosis (2006-2010; 2011-2015; 2016-2020). Patient characteristics, HCC treatment, and overall survival were compared among groups. Survival predictors were also investigated. Results: Approximately 80% of alcohol-related HCCs were classified as cases of metabolic dysfunction-associated fatty liver disease. Throughout the quinquennia, <50% of HCCs were detected by surveillance programmes. The tumour burden at diagnosis was slightly reduced but not enough to change the distribution of the ITA.LI.CA cancer stages. Intra-arterial and targeted systemic therapies increased across quinquennia. A modest improvement in survival was observed in the last quinquennia, particularly after 12 months of patient observation. Cancer stage, HCC treatment, and presence of oesophageal varices were independent predictors of survival. Conclusions: In the past 15 years, modest improvements have been obtained in outcomes of alcohol-related HCC, attributed mainly to underuse of surveillance programmes and the consequent low amenability to curative treatments. Metabolic dysfunction-associated fatty liver disease is a widespread condition in alcohol abusers, but its presence did not show a pivotal prognostic role once HCC had developed. Instead, the presence of oesophageal varices, an independent poor prognosticator, should be considered in patient management and refining of prognostic systems. Impact and Implications: Alcohol abuse is a leading and growing cause of hepatocellular carcinoma (HCC) worldwide and is associated with a worse prognosis compared with other aetiologies. We assessed the evolutionary landscape of alcohol-related HCC over 15 years in Italy. A high cumulative prevalence (78%) of metabolic dysfunction-associated fatty liver disease, with signs of metabolic dysfunction, was observed in HCC patients with unhealthy excessive alcohol consumption. The alcohol + metabolic dysfunction-associated fatty liver disease condition tended to progressively increase over time. A modest improvement in survival occurred over the study period, likely because of the persistent underuse of surveillance programmes and, consequently, the lack of improvement in the cancer stage at diagnosis and the patients' eligibility for curative treatments. Alongside the known prognostic factors for HCC (cancer stage and treatment), the presence of oesophageal varices was an independent predictor of poor survival, suggesting that this clinical feature should be carefully considered in patient management and should be included in prognostic systems/scores for HCC to improve their performance.

Sequential therapies after atezolizumab plus bevacizumab or lenvatinib first-line treatments in hepatocellular carcinoma patients.

INTRODUCTION: The aim of this retrospective proof-of-concept study was to compare different second-line treatments for patients with hepatocellular carcinoma and progressive disease (PD) after first-line lenvatinib or atezolizumab plus bevacizumab. MATERIALS AND METHODS: A total of 1381 patients had PD at first-line therapy. 917 patients received lenvatinib as first-line treatment, and 464 patients atezolizumab plus bevacizumab as first-line. RESULTS: 49.6% of PD patients received a second-line therapy without any statistical difference in overall survival (OS) between lenvatinib (20.6months) and atezolizumab plus bevacizumab first-line (15.7months; p = 0.12; hazard ratio [HR]= 0.80). After lenvatinib first-line, there wasn't any statistical difference between second-line therapy subgroups (p = 0.27; sorafenib HR: 1; immunotherapy HR: 0.69; other therapies HR: 0.85). Patients who underwent trans-arterial chemo-embolization (TACE) had a significative longer OS than patients who received sorafenib (24.7 versus 15.8months, p < 0.01; HR=0.64). After atezolizumab plus bevacizumab first-line, there was a statistical difference between second-line therapy subgroups (p < 0.01; sorafenib HR: 1; lenvatinib HR: 0.50; cabozantinib HR: 1.29; other therapies HR: 0.54). Patients who received lenvatinib (17.0months) and those who underwent TACE (15.9months) had a significative longer OS than patients treated with sorafenib (14.2months; respectively, p = 0.01; HR=0.45, and p < 0.05; HR=0.46). CONCLUSION: Approximately half of patients receiving first-line lenvatinib or atezolizumab plus bevacizumab access second-line treatment. Our data suggest that in patients progressed to atezolizumab plus bevacizumab, the systemic therapy able to achieve the longest survival is lenvatinib, while in patients progressed to lenvatinib, the systemic therapy able to achieve the longest survival is immunotherapy.

Nonalcoholic fatty liver disease: an update.

PURPOSE OF REVIEW: We discuss two recent controversial issues in the research field of fatty liver: the proposal to replace nonalcoholic fatty liver disease (NAFLD) with metabolically associated fatty liver disease (MAFLD) and the suggestion to extend to primary care the noninvasive testing for liver fibrosis that was developed for secondary care. RECENT FINDINGS: There is preliminary evidence that MAFLD-only patients are at greater risk of fibrosis than NAFLD-only patients. There are a large number of false positives associated with the downshift of noninvasive testing for liver fibrosis from secondary to primary care. SUMMARY: More studies are needed to compare the MAFLD and NAFLD operational definitions. Noninvasive testing of liver fibrosis also needs further evaluation before it can be used in primary care or in the general population.