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.

Predictors of serious adverse events and non-response in cirrhotic patients with primary biliary cholangitis treated with obeticholic acid.

BACKGROUND & AIMS: Obeticholic acid (OCA) has recently been restricted in patients with primary biliary cholangitis (PBC) with "advanced cirrhosis" because of its narrow therapeutic index. We aimed to better define the predicting factors of hepatic serious adverse events (SAEs) and non-response in cirrhotic patients undergoing OCA therapy. METHODS: Safety and efficacy of treatment were evaluated in a cohort of consecutive PBC cirrhotic patients started with OCA. OCA response was evaluated according to the Poise criteria. Risk factors for hepatic SAEs and non-response were reported as risk ratios (RR) with 95% confidence intervals (CIs). RESULTS: One hundred PBC cirrhotics were included, 97 Child-Pugh class A and 3 class B. Thirty-one had oesophageal varices and 5 had a history of ascites. Thirty-three per cent and 32% of patients achieved a biochemical response at 6 and 12 months respectively. Male sex (adjusted-RR 1.75, 95%CI 1.42-2.12), INR (1.37, 1.00-1.87), Child-Pugh score (1.79, 1.28-2.50), MELD (1.17, 1.04-1.30) and bilirubin (1.83, 1.11-3.01) were independently associated with non-response to OCA. Twenty-two patients discontinued OCA within 12 months: 10 for pruritus, 9 for hepatic SAEs (5 for jaundice and/or ascitic decompensation; 4 for upper digestive bleeding). INR (adjusted-RR 1.91, 95%CI 1.10-3.36), lower albumin levels (0.18, 0.06-0.51), Child-Pugh score (2.43, 1.50-4.04), history of ascites (3.5, 1.85-6.5) and bilirubin (1.30, 1.05-1.56), were associated with hepatic SAEs. A total bilirubin≥1.4 mg/dl at baseline was the most accurate biochemical predictor of hepatic SAEs under OCA. CONCLUSIONS: An accurate baseline assessment is crucial to select cirrhotic patients who can benefit from OCA. Although OCA is effective in one third of cirrhotics, bilirubin level ≥1.4 mg/dl should discourage from its use.

Cirrhotic Patients with Bacterial Infection and Negative Cultures Have a More Advanced Disease and an Increased Short-Term Mortality Rate.

BACKGROUND: The negative clinical impact of bacterial infections (BI) in patients with cirrhosis is well documented. In cirrhotic patients, failure to isolate the pathogen is a frequent event, occurring in 30-40% of cases. AIM: The aim of this study was to compare the clinical characteristics, early (30-day) and short-term (90-day) mortality rates, in a cohort of cirrhotic patients with BI, between those with positive (C-pos) and those with negative (C-neg) microbiological cultures. METHODS: We retrospectively enrolled 279 consecutive hospitalized cirrhotic patients with BI. Survival and predictors of 30-day and 90-day mortality were assessed by Kaplan-Meier curves and logistic regression analysis, respectively. RESULTS: Cultures tested negative in 108/279 (38.7%) patients. C-neg patients were more frequently males (p = 0.035), had higher Child-Pugh-Turcotte (CPT; p = 0.007) and model for end-stage liver disease-sodium (MELD-Na; p = 0.043) scores, and had more frequently decompensated liver disease (p = 0.04). Mortality rate was higher in C-neg than in C-pos patients, both at 30 days (22.2% versus 11.7%, p = 0.024) and 90 days (46.3% versus 33.3%, p = 0.030). MELD-Na score and non-selective beta-blockers (NSBBs) were independent risk factors for 30-day and 90-day mortality. In particular, the use of NSBBs was independently associated with a lower 30-day and 90-day mortality risk (OR 0.41, CI95% 0.17-0.94, p = 0.040; and OR 0.43, CI95% 0.25-0.75, p = 0.003, respectively). CONCLUSIONS: Cirrhotic patients with BI and negative microbiological cultures have significantly higher mortality compared to those with positive cultures. Early mortality and short-term mortality are mainly influenced by the underlying severity of liver disease. In this contest, therapy with NSBBs has a positive impact on short-term survival.

Ficolin-2 Plasma Level Assesses Liver Fibrosis in Non-Alcoholic Fatty Liver Disease.

Fibrosis is the strongest predictor for disease-specific mortality in non-alcoholic fatty liver diseases (NAFLD), but the need for liver biopsy limits its diagnosis. We assessed the performance of plasma ficolin-2 (FCN-2) as a biomarker of fibrosis identified by an in silico discovery strategy. Two hundred and thirty-five morbidly obese (MO) subjects with biopsy-proven NAFLD stratified by fibrosis stage (F0, n = 44; F1, n = 134; F2, n = 46; F3/F4, n = 11) and 40 cirrhotic patients were enrolled. The cohort was subdivided into discovery (n = 76) and validation groups (n = 159). The plasma level of FCN-2 and other candidate markers was determined. FCN-2 was inversely correlated with the stage of liver fibrosis (ρ = −0.49, p < 0.001) independently of steatosis (p = 0.90), inflammation (p = 0.57), and ballooning (p = 0.59). In the global cohort, FCN-2 level decreased significantly in a stepwise fashion from F0/F1 (median 4753 ng/mL) to F2−F3−F4 (2760 ng/mL) and in cirrhotic subjects (1418 ng/mL). The diagnostic performance of FCN-2 in detecting F ≥ 2 was higher than other indexes (APRI, FIB-4) (AUROC 0.82, 0.68, and 0.6, respectively). The accuracy improved when combined with APRI score and HDL values (FCNscore, AUROC 0.85). Overall, the FCN-2 plasma level can accurately discriminate liver fibrosis status (minimal vs. moderate/advanced) significantly improving the fibrosis diagnostic algorithms.

Over time evaluation of glycaemic control in direct-acting antiviral-treated hepatitis C virus/diabetic individuals with chronic hepatitis or with cirrhosis.

BACKGROUND: Data concerning the impact of hepatitis C virus (HCV) cure on type 2 diabetes mellitus (T2DM) are controversial. The aim of the study was to evaluate the effects of anti-HCV direct-acting antiviral (DAA) treatments on long-term glucose control in HCV/T2DM patients with chronic hepatitis C (CHC) or with cirrhosis. METHODS: One hundred and eighty-two consecutive HCV/T2DM patients who achieved a viral clearance by DAA treatment were enrolled. Seventy or 182 of them had CHC, and 112 had cirrhosis. Clinical, biochemical and instrumental parameters were recorded at baseline and at 48, 96 and 120 weeks (48w, 96w and 120w, respectively) after stopping DAA therapy. RESULTS: At baseline, the overall study population had a mean of glycated haemoglobin (HbA1c) value of 7.2% (ranging from 5 to 11.2), without any significant differences between CHC and cirrhosis [7.1 and 7.2, respectively]. Evaluation over time of HbA1c variations showed a significant improvement of glucose control at all post-treatment time points compared with baseline in CHC patients (P = .001). In cirrhotic patients, a significant decrease of HbA1c levels was only found when comparing HbA1c values between baseline and 48w time-point (P = .001), whereas this improvement disappeared at both 98w and 120w (P = .8 and P = .3, respectively). Multivariate logistic regression analysis showed that patients with chronic hepatitis have a 2.5 (CI 1.066-5.945) times greater chance of achieving an improvement of glycaemic values than patients with liver cirrhosis (P = .035). CONCLUSION: DAA-based HCV cure induces a significant and persistent amelioration of glycaemic control in HCV/diabetic patients with chronic hepatitis, whereas cirrhotic HCV/diabetic subjects have only a transient benefit from the virus elimination.

Occult hepatitis B virus infection predicts non-alcoholic steatohepatitis in severely obese individuals from Italy.

BACKGROUND & AIMS: Obesity is associated with non-alcoholic fatty liver (NAFL), which may progress towards non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Occult hepatitis B virus infection (OBI) may contribute to hepatic damage in patients with chronic liver disease of different aetiologies (eg HCV, alcohol). However, information on the prevalence and clinical impact of OBI in obese individuals is lacking. The aims of this study were to investigate NASH prevalence and risk factors in obese people who underwent bariatric surgery. METHODS: Two-hundred and twenty-six subjects (160 females; mean age 42.9 years ±10.8 SD) without evidence of any further cause of liver disease consecutively underwent bariatric surgery in two Italian liver centers. During surgery, all patients underwent liver biopsy for histological evaluation and molecular studies. Liver DNA extracts were tested for PNPLA3, TM6SF2, MBOAT7, IRGM polymorphisms and for OBI. Univariate and multivariate analyses were used to identify predictors of NASH. RESULTS: Histology showed NASH in 115 (50.9%) and NAFL in 111 cases (49.1%). Twenty-nine/226 (12.8%) cases had OBI, 24 (82.8%) of whom had NASH and 5 (17.2%) NAFL, whereas among the 197 OBI-negative cases, 91 (46.2%) had NASH and 106 (53.8%) NAFL (P = .0002). Multivariate analysis showed that older age (P = .03, OR 1.034), alanine aminotransferase values (P = .005, OR 1.023), insulin resistance/diabetes (P = .02, OR 2.257), TM6SF2 polymorphism (P = .04, OR 3.168) and OBI (P = .004, OR 5.503) were independent predictors of NASH. CONCLUSION: NASH is highly prevalent in obese individuals undergoing bariatric surgery. OBI is one of the strongest risk factors of NASH in these patients.

Obesity and liver cancer.

Obesity prevalence is rapidly increasing worldwide. It is associated with huge economic and health costs due to its clinical consequences, which includes increased incidence of type 2 diabetes, cardiovascular diseases, and development of different malignancies. In particular, obesity is an independent risk factor for the development of hepatocellular carcinoma (HCC). Indeed, obesity is highly prevalent in patients with non-alcoholic fatty liver disease (NAFLD) that is becoming one of the most frequent causes of liver disease worldwide. NAFLD-related HCC is the most rapidly growing indication for liver transplantation in many countries. The higher mortality rates found in obese HCC patients might be related not only to a worse outcome after HCC treatments, but also to a delayed diagnosis related to a low frequency and a poorer quality of abdominal ultrasonography surveillance that is the test universally used for HCC screening. Given its diffusion, obesity is frequently present in patients with chronic liver diseases related to different etiologies, and in these cases it may increase the HCC risk, acting as an additional co-factor. Indeed, growing evidence demonstrates that a healthy diet and regular physical activity may have an impact in reducing the overall HCC risk. Finally, an impact of obesity in the development of intrahepatic cholangiocarcinoma has been postulated, but more extensive studies are needed to definitively confirm this association.

Anatomic variations: a rare variant of formation of the portal vein.

The portal vein derives from the vitelline veins, a component of the extraembryonic venous system, and is normally formed by the confluence of the superior mesenteric and splenic vein. The knowledge of the anatomy of the portal vein and its abnormalities is important for interventional and surgical procedures. Variant portal architecture is a common finding during imaging studies. Ultrasonography, computed tomography and magnetic resonance are non-invasive methods for studying and understanding portal vein's anatomy and abnormalities. We describe a rare case of variation in the formation and course of the portal vein. To the best of our knowledge, there is no evidence of this kind of abnormality in literature.

Integration of hepatitis B virus DNA in chronically infected patients assessed by Alu-PCR.

Hepatitis B virus (HBV) infection is the main risk factor for hepatocellular carcinoma (HCC) worldwide. Integration of HBV DNA into the human genome has been found in >80% of HBV-related HCC cases. Some studies have, however, found similar integration patterns in tumorous and nontumorous tissues. Thus, the role of integrations for the development of HCC as well as the rate of integration in different stages of infection remain unclear. The aim of this study was to investigate integrations in patients without HCC, representing different stages of chronic HBV (CHB) infection. Extracted DNA in liver biopsies from 74 patients (one with 2 available biopsies) with CHB infection was analyzed by Alu-PCR. Amplicons were further analyzed by Sanger sequencing. Integration was detected in 39 biopsies (52%) as an amplicon containing both human and HBV sequences by Alu-PCR with one primer targeting a region in the HBV genome. Integrations were found in patients representing the different stages of CHB infection. A majority of the HBV sequences were located upstream or downstream of nucleotide position 1820, which previously has been identified as a common breakpoint in the HBV genome in integrated sequences. Approximately 60% of the HBV integrations were found in noncoding regions of the human genome. Integrations of HBV DNA into the human genome is an event frequently found in mild phases of chronic hepatitis.

Hypergammaglobulinemia is a strong predictor of disease progression, hepatocellular carcinoma, and death in patients with compensated cirrhosis.

BACKGROUND & AIMS: The outcome of compensated cirrhosis may vary considerably and cannot be predicted by routinely performed tests at present. The aim of this study was to evaluate possible predictors of clinical evolution in patients with Child-Pugh (C-P) class A cirrhosis because of untreatable causes by analysing clinical/biochemical/instrumental parameters evaluated at the time of diagnosis and during the subsequent long-lasting follow-up. METHODS: Two hundred and seventy-two consecutive C-P class A cirrhotic patients (155 males; median age 63 years, range 34-81) were analysed. All patients were followed up for a median time of 96 months (range 21-144) through periodically performed clinical/biochemical/ultrasonographic and esophagogastroduodenoscopic examinations. RESULTS: During the follow-up, 97 individuals (36%) were clinically stable, 104 (38%) developed hepatocellular carcinoma (HCC) and 71 (26%) progressed towards C-P class B/C without developing cancer. One hundred and thirty-one patients (48%) died or underwent liver transplantation. Multivariate regression analysis showed that clinical stability was significantly associated with older age (P < .001), the absence of diabetes (P = .04) and of oesophageal varices (P < .001), serum albumin >3.5 gr/dL (P = .01) and gamma globulin <1.8 gr/dL (P = .01). HCC development was significantly associated with younger age (P = .01) and serum gamma globulin values ≥1.8 gr/dL (P < .001). C-P score progression was associated with oesophageal varices (P < .001), lower serum albumin (P = .03) and cholesterol (P = .01) values, and hypergammaglobulinemia (P = .02). Death was associated with younger age (P < .001) and hypergammaglobulinemia (P = .01). Multivariate Cox regression analysis and Kaplan-Meier's survival test confirmed that gammaglobulinemia ≥1.8 g/dL was a significant predictor of death (P < .02, and P < .01 respectively). CONCLUSIONS: Hypergammaglobulinemia identifies C-P class A cirrhotic patients at higher risk of disease progression, HCC development and death.

NS3 Variability in Hepatitis C Virus Genotype 1A Isolates from Liver Tissue and Serum Samples of Treatment-Naïve Patients with Chronic Hepatitis C.

BACKGROUND: Hepatitis C virus (HCV) NS3 resistance-associated substitutions (RASs) reduce HCV susceptibility to protease inhibitors. Little is known about NS3 RASs in viral isolates from the liver of chronic hepatitis C (CHC) patients infected with HCV genotype-1a (G1a). AIM: The objective of this work was to study NS3 variability in isolates from the serum and liver of HCV-G1a-infected patients naïve to direct-acting antivirals (DAAs). METHODS: NS3 variability of HCV-G1a isolates from the serum and liver of 11 naïve CHC patients, and from sera of an additional 20 naïve CHC patients, was investigated by next-generation sequencing. RESULTS: At a cutoff of 1%, NS3 RASs were detected in all the samples examined. At a cutoff of 15%, they were found in 54.5% (6/11) and 27.3% (3/11) of the paired liver and serum samples, respectively, and in 22.5% (7/31) of the overall serum samples examined. Twenty-six out of thirty-one (84%) patients showed NS3 variants with multiple RASs. Phylogenetic analysis showed that NS3 sequences clustered within 2 clades, with 10/31 (32.2%) patients infected by clade I, 15/31 (48.8%) by clade II, and 6/31 (19.3%) by both clades. CONCLUSIONS: Though the number of patients examined was limited, NS3 variants with RASs appear to be major components of both intrahepatic and circulating viral quasispecies populations in DAA-naïve patients.

Clinical outcomes with long-term sorafenib treatment of patients with hepatocellular carcinoma: a multicenter real-life study.

AIM: This multicenter field-practice study evaluates outcomes of long-term sorafenib in hepatocellular carcinoma (HCC) patients. METHODS: Consecutive HCC patients on sorafenib were enrolled. We evaluated those receiving sorafenib for ≥12 months. RESULTS: Out of 800 patients on sorafenib, 81 (10%) received long-term treatment. Median duration of treatment was 22.7 months (range: 12.3-92.6). Only 21 (26%) reported grade 3/4 adverse events. Complete response was reported in 11 patients (14%). Median overall survival was 34.8 months (95% CI: 29.9-44.3). Only baseline Child-Pugh class was associated with survival. CONCLUSION: Sorafenib could result in long-term control of HCC in a relevant proportion of patients. Given the availability of regorafenib in the second-line setting, an earlier introduction of systemic therapy may be considered according to clinical indications.

Atrial fibrillation in patients with cirrhosis.

BACKGROUND & AIMS: Few information is available regarding atrial fibrillation in cirrhotic patients. The aim of this study was to investigate the occurrence and clinical impact of atrial fibrillation in these patients. METHODS: Three hundred and thirty-five cirrhotic patients (219 males; mean age 65 ± 10.85 years; 196 Child-Pugh class A, 104 class B and 35 class C) were consecutively analysed and followed up for 24 months. Electrocardiograms were available for all patients before starting the study, at basaltime and during the follow-up. Echocardiography was performed in individuals with atrial fibrillation and in 100 randomly chosen patients without it. RESULTS: Atrial fibrillation was observed in 21/335 cirrhotics (mean age 75 ± 7 years, 13 male), six of whom had permanent and 15 had paroxysmal atrial fibrillation. At univariate analysis, atrial fibrillation significantly correlated with older age, history of coronary heart disease, Child-Pugh score, serum albumin, hepatic encephalopathy, treatment with furosemide, QTc prolongation, atrial section areas, increased PAPs and thickness of interventricular septum. Age [odd ratio 1.12, 95% CI (1.05-1.2), P = 0.001], history of coronary heart disease [odd ratio 4.93, 95% CI (1.04-23.54), P = 0.04] and PAPs [odd ratio 1.12, 95% CI (1.02-1.2), P = 0.01] maintained statistical significance at multivariate analysis. Fifty-one of the 335 patients died during the follow-up. At Cox regression analysis, advanced Child-Pugh score [hazard ratio 1.546, 95% CI (1.357-1.762), P = 0.037] and increased heart rate [hazard ratio 1.117, 95% CI (1.021-1.223), P = 0.016] were significantly associated with mortality which was independent of atrial fibrillation occurrence. CONCLUSIONS: Cirrhosis is not a predisposing factor of atrial fibrillation, which in turn has no impact on mortality in cirrhotic patients.

The calm before the storm: a report from the International Liver Cancer Association Congress 2015--part 1.

International Liver Cancer Association Congress 2015, Paris, France, 4-6 September 2015 Since its creation 9 years ago, in 2007, the International Liver Cancer Association has focused on the multidisciplinary approach to liver cancer due to advances in hepatology science and care worldwide. In its 2015 annual conference, held on 4-6 September in Paris, France, the most recent progresses in the basic biology, management and treatment of liver cancer have been presented. This report, divided into two parts, introduces and critically reviews some of the most intriguing topics discussed at the meeting.

The calm before the storm: a report from the International Liver Cancer Association Congress 2015 - part 2.

International Liver Cancer Association Congress 2015, Paris, France, 4-6 September 2015 Since its creation 9 years ago, in 2007, the International Liver Cancer Association has focused on the multidisciplinary approach to liver cancer due to advances in hepatology science and care worldwide. In its 2015 annual conference, held on 4-6 September in Paris, France, the most recent progresses in the basic biology, management and treatment of liver cancer have been presented. This report, divided into two parts, introduces and critically reviews some of the most intriguing topics discussed at the meeting.

Hepatitis B virus (HBV) DNA integration in patients with occult HBV infection and hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatitis B virus (HBV) DNA integration in the host genome is a major mechanism responsible for the etiopathogenetic role exerted by HBV in hepatocellular carcinoma (HCC) development. Extensive analyses evaluating viral integration in HBV surface antigen (HBsAg) negative patients with occult HBV infection (OBI) have not yet been performed. The aim of this study was to investigate and characterize HBV DNA integration in HCC tissues from OBI patients. METHODS: Tumour DNA extracts from 69 HCC patients (49 HBsAg-negative with occult infection diagnosed by HBV DNA detection in tumour tissues; 10 HBsAg-positive and 10 HBsAg-negative/OBI-negative as control groups) were examined by Alu-PCR technique to reveal HBV DNA integration into the host genome. The molecular characterization of the virus-genome junctions was performed by cloning and sequencing analyses. RESULTS: Integrated HBV DNA was detected in 37/49 (75.5%) OBI-positive HCC samples, in 8/10 (80%) HBsAg-positive and in 0/10 OBI-negative HCC samples. Nine of 37 (24.3%) integrated viral sequences from OBI-positive cases were inside human genome coding regions and in the remaining cases the localization at intergenic level was frequently adjacent to coding genes. Concerning viral integrants in OBI cases, X gene sequences were found in 14 cases, preS/S sequences in 13, Core sequences in 7, and Polymerase gene sequences in three cases. CONCLUSIONS: In analogy to what occurs in HBsAg-positive cases, HBV DNA integration is highly prevalent in OBI-related HCCs, it mainly involves X and preS/S viral genomic regions and it frequently occurs at the level of regulatory and functional genes.

[Therapeutic decisions and treatment with sorafenib in hepatocellular carcinoma: final analysis of GIDEON study in Italy]. / Scelte terapeutiche e trattamento con sorafenib nell'epatocarcinoma: analisi finale dello studio GIDEON in Italia.

INTRODUCTION: Sorafenib, an oral multikinase inhibitor, is the only targeted agent approved for the treatment of patients with hepatocellular carcinoma (HCC) after demonstration to increase overall survival compared to placebo in two randomized phase III study. GIDEON (Global Investigation of therapeutic DEcisions in HCC and Of its treatment with sorafeNib) is the largest, global, non-interventional, prospective study of patients with uHCC (n>3200) treated with sorafenib in real-life clinical practice conditions. Here we report the final analysis of safety and efficacy in the Italian cohort of patients. METHODS: Patients with unresectable HCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib, are eligible for inclusion. Patients demographics disease characteristics and treatment history were recorded at baseline visit. Sorafenib dose, concomitant medications, performance status, liver function, adverse events and efficacy (survival and response rate) were collected throughout the study. RESULTS: In the Italian cohort of the GIDEON study 278 patients were included in 36 centers. The global rate of adverse events was 81%. Drug-related events accounted for 67%, mostly of grade 1 and 2, and only 8% were classified as serious. The most common were diarrhea (24%), fatigue (23%), dermatological (14%), rash/exfoliation (10%), hypertension (9%), hemorrage/bleeding of gastrointestinal tract (6%). Overall survival was 14.4 months and time to progression 6.2 months. Objective responses were observed in 14 patients (5%) with 3 complete responses (1%). Stable diseases of at least 6 weeks were observed in 113 patients (41%) with a 30% of disease control rate. DISCUSSION: The safety profile of sorafenib in terms of rate and type of adverse events is similar to that emerged in the global international GIDEON study as well as in the pivotal registration studies.

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.

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.

Hepatitis B virus DNA integration in tumour tissue of a non-cirrhotic HFE-haemochromatosis patient with hepatocellular carcinoma.

Co-existence of multiple causes of liver injury increases the risk of hepatocellular carcinoma (HCC) development. HCC usually develops in patients with cirrhosis although it may also occur in individuals with no or mild liver disease, in particular in cases with hepatitis B virus (HBV) infection. Here we report the case of a 43year-old man with HFE-haemochromatosis, seronegative for hepatitis B and C infections, who developed HCC in the absence of severe liver damage. Both tumoural and non-tumoural liver DNA extracts were tested by nested-PCR and primers specific for four different HBV genomic regions in order to evaluate the presence of occult HBV infection. Only X gene sequences were detected in tumour (but not in non-tumour) DNA extracts. HBV-Alu PCR showed a HBV integration involving a 5'-deleted X gene with an intact enhancer-II/basal-core promoter region. The viral-host junction sequencing revealed that this integrant was located upstream of the partitioning-defective-6-homolog-gamma gene (PARD6G) and real time-PCR quantification demonstrated that PARD6G was overexpressed in tumour compared to non-tumour liver tissues. In conclusion, the combination of HFE-haemochromatosis and occult HBV infection in this patient might have led to a sequel of cellular events that determined the development of HCC even in the absence of cirrhosis.