Background and Aims: Liver transplantation (LT) represents a therapeutic option for patients with Wilson’s disease (WD) presenting with acute liver failure (ALF) or end-stage liver disease unresponsive to medical therapy. Data on long-term post-transplant outcomes in this population remain limited. This study evaluates patient (PS) and graft survival (GS) after LT for WD in Europe and identifies prognostic factors influencing outcomes over time.Methods: Data were extracted from the European Liver Transplant Registry (ELTR), including all patients who underwent LT for WD between 1986 and 2019. Baseline demographic and clinical variables were analyzed. Outcomes were compared between two transplant eras (1986–2000 vs. 2001–2019). PS and GS were estimated using Kaplan–Meier analysis and compared with log-rank test. Predictors of PS and GS were identified by multivariable Cox regression. Analyses were repeated after stratifying the cohort by age at LT (pediatric vs. adult). Results. In all, 1,615 patients underwent LT for WD (male 46%; ALF 10.1%; pediatrics 29.4%; mean MELD at LT 25±10). Overall, 1-, 5-, and 10-year PS rates were 88.6%, 85.2%, and 80.0%, respectively, whereas GS rates were 82.5%, 76.9%, and 70.5%. Median follow-up was 60 months, and the re-transplantation rate was 13.1%. Compared with the earlier period, PS significantly improved in the most recent era (2001–2019, p= 0.014), whereas GS showed a trend toward improvement (p=0.052; Figure 1). When stratified by age at LT, PS improved in the recent era among pediatric recipients only (p=0.008 vs. p=0.213 in adults), whereas no statistically significant improvement in GS was observed in either age group (p=0.155 and p=0.181, respectively). In multivariable Cox regression analysis, independent predictors of PS in the whole cohort included recipient age, UNOS status, and the need of reLT (Table 1). Among adults, ALF, UNOS status and recipient age remained independent predictors of PS, whereas in pediatric recipients, tacrolimus therapy and living donor LT remained independent predictors. In the whole cohort, year at LT, donor age, living donor LT, and mycophenolate therapy were independent predictors of GS. Donor age and mycophenolate therapy remained independent predictors of GS among adults, whereas tacrolimus therapy and living donor LT predicted GS in pediatric recipients. Conclusions: LT offers excellent long-term outcomes for patients with WD, both in terms of graft and patient survival. The outcome is influenced by different prognostic factors depending on age at transplantation.

BACKGROUND:In patients with hepatocellular carcinoma (HCC), extrahepatic progression (EHP) has a known dismal meaning. We evaluated the incidence and risk factors of EHP in HCC patients treated with transarterial chemoembolization (TACE), and the predictive role of tumour burden. METHODS:From the ITA.LI.CA database, 890 HCC patients undergoing first-line TACE were included. Tumour burden score (TBS) was calculated and, after identification of the best cut-point value, incidence and predictors of EHP were compared between TBS-low and TBS-high groups. Independent predictors of EHP at the first progression episode or at any time during follow-up were identified through multivariable Cox analysis. RESULTS:After TACE, 7.2% of patients experienced EHP at the first progression episode, while the overall EHP rate during the follow-up was 26.1%. The best cut-point for TBS was 3.66. TBS-high group (> 3.66) showed a significantly higher proportion of EHP both at first progression (10.4% vs. 3.6%; p < 0.001) and overall (32.6% vs. 18.7%; p < 0.001) compared to the TBS-low group. Moreover, TBS-high patients had shorter progression-free survival and overall survival. TBS-high and AFP levels emerged as independent predictors of EHP at the first progression episode and during the follow-up, and their combined evaluation accurately stratified patients for their risk of EHP. CONCLUSION:Extrahepatic dissemination is infrequent in HCC patients treated with TACE. TBS is easily calculable and helps in identifying patients at higher risk of metastasis development.

Background & Aims Venous thromboembolism (VTE) is a recognized complication of acutely ill patients, but its incidence and risk factors in those with cirrhosis are uncertain. Methods We retrospectively studied a consecutive cohort of cirrhosis patients non-electively admitted to our medical unit to determine the rates of symptomatic VTE during hospitalization. Firstly, we explored associations with baseline, clinical and laboratory characteristics using logistic regression. Secondly, we developed a clinical prediction model that could predict the risk of in-hospital VTE. Results We included 687 patients (median age 61 years old; 68% male; Child-Pugh A/B/C, 13%/40%/47%). During hospitalization, 34 patients (4.9%) experienced VTE. Multivariate analysis showed that male sex (OR: 2.56, p = 0.05), AKI (OR: 3.1, p = 0.001), bacterial infections (OR: 2.6, p = 0.008), Pugh score (OR: 1.6. p < 0.001), family history of thrombosis (OR: 3.1, p = 0.04), reduced mobility (OR: 4.6, p < 0.001), and C-reactive protein (OR: 1.1, p = 0.005) were independent predictors of VTE. We combined these variables in a prediction model (CirrhosisThrombosisModel) that accurately discriminated between high- and low-risk patients. The AUROC of CiThroModel was significantly higher than that of Padua prediction score (0.882 vs. 0.742). After validating the CiThroModel using bootstrapping, the adjusted model maintained optimal discrimination ability (0.862) and calibration. The adjusted formula to calculate the in-hospital risk of VTE was -9.00 + 0.82 [Male sex] + 1.14 [AKI] + 0.98 [Infection] + 0.48 * Child Pugh score + 1.14 [VTE family history] + 1.54 [Reduced mobility] + 0.15 * PCR/10. Conclusion The CiThroModel seems a valuable tool for identifying hospitalized patients with cirrhosis at risk of VTE (https://majinzin.shinyapps.io/vterisk/).

Background & Aims:For patients with single small (≤3 cm) hepatocellular carcinoma ablation is the first-line treatment, although a high rate of recurrence has been reported. The aim was to compare videolaparoscopic liver resection (laparoscopic resection group) vs. percutaneous thermoablation (ablation group) in terms of overall survival, recurrence-free survival and early recurrence in a real-life national scenario. Methods:The study is a retrospective collection with subsequent survival analysis. Data were collected from two Italian HCC registries, ITA.LI.CA and HE.RC.O.LE.S. An inverse probability of treatment weighting analysis was performed to balance baseline differences between groups. The Kaplan-Meier method and double-robust Cox multivariable regression were run to estimate the survival and the risk of mortality and recurrence. Results:Between 2008 and 2022, 1,465 patients were enrolled. The laparoscopic resection group and ablation group consisted of 496 and 969 patients, respectively. At baseline, the ablation group had more advanced liver disease, with higher rates of cirrhosis (90.7% vs. 77.3%, p <0.001) and Child-Pugh B status (18.4% vs. 8.8%, p <0.001). After a median follow-up of 59 months and after weighting median overall survival was 60 months (95% CI 52-66) for the ablation group and 93 months (95% CI 75-110) for the laparoscopic resection group (hazard ratio [HR] 0.607, 95% CI 0.533-0.691, p <0.001). Median recurrence-free survival was 26 months (95% CI 23-29) for the ablation group and 39 months (95% CI 30-55) for the laparoscopic resection group (HR 0.736, 95% CI 0.659-0.822, p = 0.0013). Laparoscopy was associated with a reduced risk of early recurrence (HR 0.747, 95% CI 0.655-0.853, p = 0.011). Conclusions:This study provides real-world evidence that for patients with single ≤3 cm HCC, videolaparoscopic liver resection offers superior long-term oncological outcomes compared with thermoablation. These findings support the preference for surgical treatment in this patient population. Impact and implications:Percutaneous thermoablation is considered an appropriate alternative to liver resection for small (≤3 cm) single hepatocellular carcinoma because of not-inferior overall survival, although several authors reported increased recurrence risk. Whether videolaparoscopic liver resection could guarantee comparable survival but superior oncologic control of the disease is a matter of debate. This study comparing videolaparoscopy vs. thermoablation in a large national cohort of 1,465 patients observed that the former guaranteed significant prolonged OS (93 months [95% CI 75-110] vs. 60 months [95% CI 52-66] for the ablation group) and recurrence-free survival (26 months [95% CI 23-29] for ablation patients and 39 months [95% CI 30-55] for laparoscopic resection patients) even after weighting all the preoperative and oncologic differences among the groups. Our results clearly address the need to rethink the role of thermoablation for single small HCC as a second-line treatment when laparoscopic liver resection is not feasible.

IntroductionOxidative stress, which characterizes inflammatory and autoimmune diseases, is involved in atrophic gastritis progression. We aimed to compare the presence and patterns of oxidative stress in autoimmune atrophic gastritis (AAG) and multifocal atrophic gastritis (MAG), investigating its role in disease progression and the development of genomic damage.Materials and methodsIn this study, 120 consecutive patients with atrophic gastritis (70 AAG and 50 MAG) were collected. Serum/plasma dynamic reactive oxygen metabolites (dROM test-spectrophotometry), nitric oxide (NO-ELISA), advanced oxidation protein products (AOPPs—spectrophotometry), tissue levels of cytokines (IL-10 and TNFα–ELISA), and 8-hydroxydeoxyguanosine (8-OHdG) (HPLC-ED) were evaluated.ResultsNo significant differences in dROMs, NO, and AOPP levels were demonstrated between AAG and MAG. In AAG patients, those with early atrophy exhibited higher levels of dROMs compared to those with advanced stages (p = 0.03), and those with early ECL-hyperplasia (ECL-H) exhibited higher dROMs and AOPP levels compared to those with advanced hyperplasia (p = 0.02). 8-OHdG levels were significantly higher in MAG patients than in AAG patients (p = 0.001). A ROC curve showed that patients with low 8-OHdG levels had a very low OR of belonging to the MAG group. A positive linear correlation was observed among serological biomarkers of atrophy and dROMs (p = 0.004). IL-10 was higher in patients with MAG vs. those with AAG (p = 0.008), and it was also higher when patients were sub-grouped according to the OLGA stages (p = 0.01).ConclusionInflammatory responses and oxidative stress characterize atrophic gastritis, irrespective of etiology. However, a boost in inflammation-induced genomic damage is observed only in MAG, since AAG showed significantly lower 8-OHdG levels. Therefore, oxidative stress seem to play a minor role in the development of carcinoid and gastric cancer in AAG, and this finding may explain the lower risk of tumors in these patients.

We aimed to evaluate the performance of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and their combination (combined NLR-PLR, CNP) in predicting overall survival (OS) and recurrence-free survival (RFS) in a large cohort of unselected hepatocellular carcinoma (HCC) patients. Training and validation cohort data were retrieved from the Italian Liver Cancer (ITA.LI.CA) database. The optimal cut-offs of NLR and PLR were calculated according to the multivariable fractional polynomial and the minimum p value method. The continuous effect and best cut-off categories of NLR and PLR were analyzed using multivariable Cox regression analysis. A shrinkage procedure adjusted over-fitting hazard ratio (HR) estimates of best cut-off categories. C-statistic and integrated discrimination improvement (IDI) were calculated to evaluate the discrimination properties of the biomarkers when added to clinical survival models. 2,286 patients were split into training (n = 1,043) and validation (n = 1,243) cohorts. The optimal cut-offs for NLR and PLR were 1.45 and 188, respectively. NLR (HR 1.58, 95

BACKGROUND/OBJECTIVES:Despite advances in hepatocellular carcinoma (HCC) management, prognosis remains poor. Advanced-stage diagnosis often excludes curative treatments, and current biomarkers (e.g., alpha-fetoprotein [AFP]) have limited utility in early detection. Liquid biopsy has emerged as a promising cancer detection tool, with circulating cell-free DNA (ccfDNA) showing significant diagnostic potential. This proof-of-concept study aimed to investigate the potential role of tumor fraction (TF) within ccfDNA as a biomarker in HCC patients. METHODS:A total of sixty patients were recruited, including thirteen with chronic liver disease (CLD), twenty-four with cirrhosis, and twenty-three with HCC. Plasma samples were collected, and ccfDNA was extracted for shallow whole genome sequencing (sWGS) analysis. The TF was calculated by focusing on somatic copy number alterations (SCNAs) within the ccfDNA. RESULTS:Among patients with CLD and cirrhosis (n = 37), ctDNA was undetectable in all but one cirrhotic patient who exhibited a significant tumor fraction (TF) of 17% and subsequently developed HCC. Conversely, five out of twenty-three HCC patients (21.7%) displayed detectable ctDNA with TF levels ranging from 3.0% to 32.6%. Patients with detectable ctDNA were characterized by more aggressive oncological features, including a higher number of nodules (p = 0.005), advanced-stage disease (60% BCLC C, p = 0.010), and poorer response to therapy (80% PD, p = 0.001). Moreover, the overall survival (OS) was significantly reduced in patients with detectable ctDNA (median OS: 17 months; CI 95% 4.5-26.5) compared to those without (median OS: 24.0 months; CI 95% 7.0-66.0; log-rank p = 0.002). CONCLUSIONS:Our results suggest that the analysis of TF by sWGS is a promising non-invasive tool for the identification of HCC with aggressive clinical behavior, whereas it is not sensitive enough for early HCC detection. This molecular assay can improve prognostic stratification in HCC patients.

BACKGROUND/AIMS:Adjuvant systemic therapy has been proposed in patients at high-risk of hepatocellular carcinoma (HCC) recurrence. This study assessed the outcomes of a real-world cohort treated with either resection or ablation, stratified according to the IMbrave050 trial criteria. METHODS:We selected, from the Italian Liver Cancer database, 1150 patients with HCC treated with upfront resection (n = 483, 64.2 % high-risk) or ablation (n = 667, 49.6 % high risk), fulfilling the inclusion criteria of the IMbrave050 trial. RESULTS:Median recurrence-free survival (RFS) was shorter in high-risk resected patients (29.0 vs. 43.0 months; p = 0.024), while no difference was observed after ablation (27.0 vs. 30.0 months; p = 0.098). Recurrence was borderline higher in high-risk resected patients [Hazard Ratio (HR) 1.26, 0.97-1.23; p = 0.052], but not ablated ones (HR 1.13, 0.92-1.38; p = 0.221). Independent predictors of recurrence were cirrhosis (HR 1.52, 1.13-2.05), multinodular HCC (HR 1.31, 1.14-1.52), and microvascular invasion (HR 1.39, 1.05-1.83) in resected, and alpha-fetoprotein (HR 1.15, 1.07-1.23) in ablated patients. Median overall survival was similar in resected risk-groups (147.0 vs. 130.0 months; p = 0.093), shorter in high-risk ablated patients (79.0 vs. 98.0 months; p = 0.021). CONCLUSIONS:The criteria used to assess HCC recurrence risk in the IMbrave050 trial find validation by real-world data in patients treated with resection, while they are inaccurate after ablation.

Introduction: The potential for curative conversion with immunotherapy-based systemic treatment used with noncurative intent in patients with hepatocellular carcinoma (HCC) remains debated. This study aimed to provide a reliable epidemiological snapshot of response patterns to Atezolizumab plus Bevacizumab (AB) therapy, with a focus on curative conversion rates. Methods: Patients with HCC undergoing first-line noncurative AB or Lenvatinib (LENV, used as reference) from 2019 to 2023 were included, using centre-level aggregate data from a broad international consortium. The primary endpoint was the curative conversion rate, differentiating potential conversion (PC) - when objective response (OR) resulted in a consistent decrease in tumour burden and alpha-fetoprotein levels - from actual conversion (AC), when OR led to curative treatment. Secondary endpoints included OR, under-conversion (UC; [PC - AC]/OR) rates, and crude survival rates of AC patients. A meta-analytic approach was employed to analyse aggregate data. Results: Forty-eight international centres treating 2,379 patients with HCC with a noncurative intent (1,401 with AB and 978 with LENV) were included. A significant discrepancy was observed between PC (16% and 13% for AB and LENV, p=0.03) and AC rates (3% for both AB and LENV, p=0.14). UC rates remained similarly high (40% and 36% for AB and LENV, p=0.93), despite differing OR rates (29% and 24% for AB and LENV, p=0.01). Subgroup and meta-regression analyses did not identify any clear treatment, centre, or patient patterns that explained the high UC rate. The 3-year survival rate for the 72 patients who underwent a curative conversion after AB was 93%. Conclusions: Although patients treated with AB achieved higher OR and PC rates than those treated with LENV, AC remained similarly low, highlighting a potentially worrisome UC phenomenon in real life, also with novel immunotherapy-based combinations.

Autoimmune atrophic gastritis (AAG) is a non-self-limiting immune-mediated disorder exerting growing interest. The main autoantigen, the beta subunit of the proton pump (H+, K+-ATPase), is localised on the oxyntic mucosa parietal cells, limiting the autoimmune inflammatory damage to this stomach compartment. Clinical manifestations of AAG may occur late, once corpus-fundus atrophy occurs, and are characterised by loss of gastric acidity, impaired iron and/or cobalamin malabsorption, and increased risk of gastric type 1 neuroendocrine neoplasms and possibly gastric adenocarcinoma. Many topics regarding epidemiology, clinical features, pathogenesis, diagnosis, and management remain to be clarified. AAG patients are frequently misdiagnosed or diagnosed with delay. AAG still represents a clinical challenge and a great opportunity for advancing our knowledge on gastrointestinal autoimmune diseases and gastric precancerous conditions. The timely and correct diagnosis of AAG patients is clinically relevant to avoid potentially harmful consequences due to micronutrient deficiencies and related anaemia and neoplastic complications. The current position paper addresses AAG in adults and reflects the views of the Autoimmune gastRitis Italian netwOrk Study grOup (ARIOSO) on its epidemiology, clinical features, pathogenesis, diagnosis, and management. Improving the understanding of AAG would facilitate timely and accurate diagnosis, enhance clinical management and patients' quality of life, and reduce the economic and social burden of this underrecognized condition.

ABSTRACTBackground and AimsPresence of active hepatitis C virus (HCV) infection may influence the outcome of patients treated for hepatocellular carcinoma (HCC), although this issue has never been adequately assessed in a large series of patients. The aim of this study was to evaluate whether the presence of active HCV affects the survival of patients treated for HCC.MethodsThis study assessed the outcome of 3123 anti‐HCV‐positive patients with HCC, subdivided according to the presence of active HCV infection or previous sustained virological response (SVR). Comparisons were also carried out after propensity score matching (PSM) considering demographic, clinical and oncological characteristics.ResultsThe median overall survival from HCC treatment was longer in patients with SVR than in those with active HCV infection both before (n = 2118: 61.0 months [95% confidence internal (CI): 56.5–65.5] vs. n = 1005: 51.0 months [95% CI: 43.4–58.6]; p = 0.003) and after PSM (n = 1285: 60.0 months [95% CI: 55.3–64.7] vs. n = 926: 54.0 months [95% CI: 46.7–61.3]; p = 0.030). Active HCV infection was associated with a greater risk of mortality (hazard ratio: 1.22–1.27, p = 0.001) independently of liver‐ and tumour‐related variables, and modality of HCC treatment. Death due to liver failure was more common in patients with active HCV infection (24.5% vs. 17.1%; p = 0.001), while non‐liver‐related causes of death were more common in patients with SVR (25.0% vs. 17.0%; p = 0.001).ConclusionsSVR is associated with a better outcome in patients undergoing HCC treatment, thus suggesting that these patients may benefit from antiviral therapy for HCV independently of cure of HCC.

The incidence of HCC in patients with autoimmune hepatitis (AIH) is low and, due to the paucity of data in the literature, a thorough characterization of these patients is missing. To describe the main characteristics and outcome of patients with AIH and HCC. Among patients with HCC included in the Italian Liver Cancer (ITA.LI.CA) database during the period 2009–2022, we selected those with AIH, and we described their liver disease characteristics, modality of HCC diagnosis, tumor stage, treatment, and outcome. Among 10,026 patients with HCC, we identified 23 patients (0.2

BACKGROUND:The Barcelona Clinic Liver Cancer staging system considers, among patients with HCC, "ideal candidates" (ICs) for hepatic resection (HR) those with a single lesion, normal bilirubin, and without clinically significant portal hypertension (CSPH). We compared the outcome of HR between ICs and non-ICs. METHODS:Retrospective analysis was conducted on Child-Pugh A patients. CSPH was defined by the presence of gastroesophageal varices and/or platelet count <100,000/mm3. Hyperbilirubinemia was accepted up to 2 mg/dL. The selected 1057 patients were distributed in 3 calendar periods (2000-2022). RESULTS:In all calendar periods, non-ICs were more prevalent than ICs. Among non-ICs, the proportion of patients with isolated CSPH did not change over time (from 22.6% to 30.3%; p=0.359), while patients with multinodular HCC (mHCC) increased (from 35.5% to 50.2%; p=0.042). Patients with hyperbilirubinemia decreased (from 20.4% to 10.1%; p=0.036), likewise those with hyperbilirubinemia+CSPH (from 21.5% to 9.4%; p=0.005). Over a median follow-up of 41.0 months, median overall survival was higher in ICs compared to non-ICs (104.9 vs. 75.3 months; p<0.001). However, compared to ICs, median overall survival did not differ in patients with isolated CSPH (93.1 mo; p=0.432) or isolated hyperbilirubinemia (86.0 mo; p=0.356), while it was lower in those with hyperbilirubinemia+CSPH (60.0 mo; p<0.001) or mHCC (61.9 mo; p<0.001). Compared to ICs, only hyperbilirubinemia+CSPH patients showed a higher perioperative mortality. CONCLUSIONS:In real-world practice, among resected patients, the proportion of non-ICs has remained constantly higher than that of non-ICs since 2000. HR can be offered to Child-Pugh A patients with CSPH or modest hyperbilirubinemia without compromising its outcome. For patients with 2 of these features or mHCC, which generate a poorer prognosis, studies comparing HR versus non-surgical therapies are warranted.