Prognostic factors influencing outcomes in hepatocellular carcinoma patients undergoing selective internal radiation therapy.

Selective internal radiation therapy (SIRT) has emerged as a viable endovascular treatment strategy for hepatocellular carcinoma (HCC). According to the Barcelona Clinic Liver Cancer (BCLC) classification, SIRT is currently recommended for early- and intermediate-stage HCC that is unsuitable for alternative locoregional therapies. Additionally, SIRT remains a recommended treatment for patients with advanced-stage HCC and portal vein thrombosis (PVT) without extrahepatic metastasis. Several studies have shown that SIRT is a versatile and promising treatment with a wide range of applications. Consequently, given its favourable characteristics in various scenarios, SIRT could be an encouraging treatment option for patients with HCC across different BCLC stages. Over the past decade, an increasing number of studies have focused on better understanding the prognostic factors associated with SIRT to identify patients who derive the most benefit from this treatment or to refine the optimal technical procedures of SIRT. Several variables can influence treatment decisions, with a growing emphasis on a personalised approach. This review, based on the literature, will focus on the prognostic factors associated with the effectiveness of radioembolization and related complications. By comprehensively analysing these factors, we aimed to provide a clearer understanding of how to optimise the use of SIRT in managing HCC patients, thereby enhancing outcomes across various clinical scenarios.

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.

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.

Mitochondrial DNA is a target of HBV integration.

Hepatitis B virus (HBV) may integrate into the genome of infected cells and contribute to hepatocarcinogenesis. However, the role of HBV integration in hepatocellular carcinoma (HCC) development remains unclear. In this study, we apply a high-throughput HBV integration sequencing approach that allows sensitive identification of HBV integration sites and enumeration of integration clones. We identify 3339 HBV integration sites in paired tumour and non-tumour tissue samples from 7 patients with HCC. We detect 2107 clonally expanded integrations (1817 in tumour and 290 in non-tumour tissues), and a significant enrichment of clonal HBV integrations in mitochondrial DNA (mtDNA) preferentially occurring in the oxidative phosphorylation genes (OXPHOS) and D-loop region. We also find that HBV RNA sequences are imported into the mitochondria of hepatoma cells with the involvement of polynucleotide phosphorylase (PNPASE), and that HBV RNA might have a role in the process of HBV integration into mtDNA. Our results suggest a potential mechanism by which HBV integration may contribute to HCC development.

Hypergammaglobulinemia before Starting DAA Therapy Is A Strong Predictor of Disease Progression in Cirrhotic Patients Even after HCV Clearance.

The predictive factors of long-term clinical benefits in patients with hepatitis C virus (HCV)­related liver cirrhosis after Direct Antiviral Agents (DAA) treatment are still undefined. The aim of this study was to identify any predictors of liver failure, hepatocellular carcinoma (HCC) and/or death in patients with compensated liver cirrhosis who achieved the sustained virological response (SVR). To this purpose, 324 consecutive cirrhotic patients who started DAA treatment from 1 April 2015 to 31 December 2016 were retrospectively analyzed. All patients were followed up for a median time of 63 months (range 19−77) through clinical/biochemical/instrumental examinations performed at baseline and after stopping the DAA treatment. At the end of the evaluation, 230 (71%) individuals showed stable clinical liver disease over time, 43 (13.3%) developed HCC, and 24 (7.4%) developed hepatic decompensation without HCC. Overall, 49 (15,1%) patients died. Multivariate regression analysis showed that hepatic decompensation was significantly associated with at baseline older age, higher liver stiffness, higher spleen longitudinal size values and hypergammaglobulinemia (p = 0.003, p = 0.005, p = 0.001, p = 0.029, respectively). HCC development was significantly associated with hypergammaglobulinemia (p < 0.001). Death was associated with older age and hypergammaglobulinemia (p < 0.001 and p = 0.007, respectively). Finally, survival analysis confirmed that patients with gamma globulin levels ≥ 1.8 gr/dl had a significantly higher risk of death compared to those with gamma globulin levels < 1.8 gr/dl (p < 0.001). In conclusion, hypergammaglobulinemia before starting DAA therapy represents a strong predictor of hepatic decompensation, HCC and death in cirrhotic patients even after HCV clearance.

Occult Hepatitis B Virus Infection: An Update.

Occult hepatitis B virus (HBV) infection (OBI) refers to a condition in which replication-competent viral DNA is present in the liver (with detectable or undetectable HBV DNA in the serum) of individuals testing negative for the HBV surface antigen (HBsAg). In this peculiar phase of HBV infection, the covalently closed circular DNA (cccDNA) is in a low state of replication. Many advances have been made in clarifying the mechanisms involved in such a suppression of viral activity, which seems to be mainly related to the host's immune control and epigenetic factors. OBI is diffused worldwide, but its prevalence is highly variable among patient populations. This depends on different geographic areas, risk factors for parenteral infections, and assays used for HBsAg and HBV DNA detection. OBI has an impact in several clinical contexts: (a) it can be transmitted, causing a classic form of hepatitis B, through blood transfusion or liver transplantation; (b) it may reactivate in the case of immunosuppression, leading to the possible development of even fulminant hepatitis; (c) it may accelerate the progression of chronic liver disease due to different causes toward cirrhosis; (d) it maintains the pro-oncogenic properties of the "overt" infection, favoring the development of hepatocellular carcinoma.

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.

Rate of hepatocellular carcinoma diagnosis in cirrhotic patients with ultrasound-detected liver nodules.

Ultrasound (US) detection of liver nodules in cirrhotic patients requires further radiological examinations and often a follow-up with repeated short-term evaluations to verify the presence of hepatocellular carcinoma (HCC). Aims of the study were to assess the rate of HCC diagnosis and to identify HCC predictors in a cohort of cirrhotics followed-up after US detection of the liver nodule(s). One-hundred-eighty-eight consecutive cirrhotic patients (124 males, mean age 64.2 years) with liver nodule(s) detected by US were enrolled. All patients underwent second-level imaging [computed tomography (TC) or magnetic resonance (MR)], and those without a definite diagnosis of HCC were followed-up with TC and/or RM repeated every 3-6 months up to 18 months if HCC was not diagnosed. After 18 months, non-HCC patients came back to routine US surveillance. HCC was diagnosed in 73/188 cases (38.8%). In 66/73 patients (90.4%) HCC was identified at first radiological evaluation after US, while in the remaining seven subjects it was diagnosed at the subsequent imaging examination. Age (p = 0.001) and nodule dimension (p = 0.0001) were independent predictors of HCC at multivariate analysis. Fourty-nine/188 patients were lost at follow up after 18 months. Twenty/139 remaining patients developed HCC and 3/139 cholangiocarcinoma; 77 died between 3 and 110 months from the beginning of the study (61 for end-stage liver disease, 8 for extrahepatic causes, eight for unknown causes). Patients who developed liver cancer earlier during the follow up had the shortest overall survival. US-detected liver nodules are not neoplastic in more than half of cirrhotic patients. A definite diagnosis may be obtained at the time of the first radiologic evaluation after US in the vast majority of the cases. Patients in whom nodules are found not to be tumoral may return to the US surveillance program routinely applied to all cirrhotics.

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.

Frequency of somatic mutations in TERT promoter, TP53 and CTNNB1 genes in patients with hepatocellular carcinoma from Southern Italy.

Somatic mutations in the TERT promoter and in the TP53 and CTNNB1 genes are considered drivers for hepatocellular carcinoma (HCC) development. They show variable frequencies in different geographic areas, possibly depending on liver disease etiology and environmental factors. TP53, CTNNB1 and TERT genetic mutations were investigated in tumor and non-tumor liver tissues from 67 patients with HCC and liver tissue specimens from 41 control obese subjects from Southern Italy. Furthermore, TERT expression was assessed by reverse transcription-quantitative PCR. Neither CTNNB1 mutations or TP53 R249S substitution were detected in any case. The TP53 R72P polymorphism was found in 10/67 (14.9%) tumors, but was not found in either non-tumor tissues (P=0.001) or controls (P=0.009). TERT gene promoter mutations were found in 29/67 (43.3%) tumor tissues but were not found in either non-tumor (P<0.0001) or control liver specimens (P<0.0001). The most frequent mutation in the tumors was the known hot spot at -124 bp from the TERT ATG start site (-124G>A, 28 cases, 41.8%; P<0.0001). A new previously never reported TERT promoter mutation (at -297 bp from the ATG, -297C>T) was found in 5/67 (7.5%) tumors, in 0/67 (0%) non-tumor (P<0.0001), and in 0/41 (0%) controls (P=0.07). This mutation creates an AP2 consensus sequence, and was found alone (1 case) or in combination (4 cases) with the -124 bp mutation. The mutation at -124 and -297 bp induced a 33-fold (P<0.0001) and 40-fold increase of TERT expression levels, respectively. When both mutations were present, TERT expression levels were increased >300-fold (P=0.001). A new TERT promoter mutation was identified, which generates a de novo binding motif for AP2 transcription factors, and which significantly increases TERT promoter transcriptional activity.

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.

Free episomal and integrated HBV DNA in HBsAg-negative patients with intrahepatic cholangiocarcinoma.

There is evidence that chronic hepatitis B virus (HBV) infection is associated with an increased risk of intrahepatic cholangiocarcinoma (ICC) development, and it has been hypothesized an etiological role of HBV in the development of this tumor. Very little is known about occult HBV infection (OBI) in ICC. Aims of the study were to investigate the OBI prevalence and to characterize the HBV molecular status at intrahepatic level in OBI-positive cases with ICC. Frozen liver tumor specimens from 47 HBV surface-antigen-negative patients with ICC and 41 paired non-tumor liver tissues were tested for OBI by 4 different HBV-specific nested PCR. Covalently closed circular HBV DNA (HBV cccDNA) and viral integrations were investigated in OBI-positive cases. HBV DNA was detected in tumor and/or non-tumor specimens from 29/47 (61.7%) ICC patients. HBV cccDNA was found in tissues from 5/17 (34.5%) cases examined. HBV integration was detected in 4/10 (40%) tumor tissues tested and involved HBx and HBV-core gene sequences in 3 and 1 cases, respectively. Viral integration occurred: (a) 9,367 nucleotides upstream of the cat-eye-syndrome critical region protein-5-isoform coding sequence; (b) within the cystinosin isoform-1-precursor gene; (c) within the thromboxane-A-synthase-1 gene; (d) within the ATPase phospholipid transporting 9B gene. Occult HBV infection is highly prevalent in patients with ICC. Both free viral genomes and integrated HBV DNA can be present in these cases. These results suggest an involvement of HBV in the carcinogenic process leading to ICC development even in cases with occult infection.

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.

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.

Elective endoscopic variceal ligation is not a risk factor for bacterial infection in patients with liver cirrhosis.

BACKGROUND: Patients with cirrhosis are at high risk of bacterial infections. Invasive procedures are generally believed to increase this susceptibility. AIMS: We investigated the incidence of bacterial infections in cirrhotic patients undergoing elective endoscopic variceal ligation (EVL). METHODS: We enrolled 60 consecutive cirrhotic patients who underwent a total number of 112 elective EVL procedures. One to seven bands were applied at each session until variceal eradication. Markers of inflammation/infection and blood cultures were obtained before and 24 h after EVL. RESULTS: Aetiology of liver disease was metabolic in 27 (45%), viral in 21 (35%), alcoholic in 12 (20%) patients. Child-Pugh class A/B/C distribution was 29/26/5, respectively, 23 (38%) patients had ascites and 15 (25%) had hepatocellular carcinoma. Blood cultures were negative in all samples before EVL, whereas 3/112 (2.7%) cultures tested positive after endoscopy. Streptococcus mitis and Staphylococcus epidermidis were isolated in 1 and 2 cases, respectively. None of these three patients developed any features of clinically relevant infection, suggesting that the positive cultures were an expression of a transient bacteraemia with no clinical sequelae. CONCLUSIONS: Bacterial infection is an uncommon occurrence after elective EVL in cirrhotic patients, and antibiotic prophylaxis is not necessary in this clinical setting.

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.

Nodular-cystic eruption in course of sorafenib administration for hepatocarcinoma: An unconventional skin reaction requiring unconventional treatment.

Sorafenib is a multitargeted kinase inhibitor currently used in the treatment of advanced hepatocellular carcinoma (HCC). It is associated with a significant risk of skin toxicity, which nevertheless represents a clinical marker of good response to treatment. Hand-and-foot skin reaction, alopecia, mucositis, xerosis, skin discoloration, and nail involvement occur frequently in course of therapy. More rarely, sorafenib can target hair follicles. We report the case of a patient who developed painful inflamed nodular-cystic lesions in both pubic and axillary regions in course of treatment with sorafenib. Because of the limited therapeutic options, the patient underwent photodynamic therapy (PDT), a topical treatment which combines a photosensitizing drug applied on lesional skin and a source of light, and had no systemic side effects. At the end of the treatment period, the patient experienced progressive clinical improvement, with relief of the symptoms. PDT may be helpful to limit suffering in patients affected by recalcitrant skin toxicity of the pilosebaceous unit who are not candidates for, or not responsive to, standard therapies.

PIVKA-II is a useful tool for diagnostic characterization of ultrasound-detected liver nodules in cirrhotic patients.

Protein induced by vitamin K absence-II (PIVKA-II) is a potential screening marker for hepatocellular carcinoma (HCC). Limited data are available about its utility in discriminating neoplastic from regenerative nodules at ultrasonography (US) evaluation in cirrhotic patients. Aim of this study was to investigate the diagnostic utility of PIVKA-II in cases showing liver nodules of uncertain diagnosis at US.Ninety cirrhotics with US evidence of liver nodule(s) were enrolled. All patients underwent blood sampling within 1 week of US and were thereafter followed up. HCC was confirmed in 40/90 cases, and in all cases it was in a very early/early stage. All sera were tested for PIVKA-II and alpha-fetoprotein (AFP) at the end of follow-up. PIVKA-II at a cut off of 60 mAU/mL was significantly associated with HCC at both univariate and multivariate analysis (P = .016 and P = .032, respectively). AFP at a cut off of 6.5 ng/mL was not associated with HCC at univariate analysis (P = .246). ROC curves showed that PIVKA-II had 60% sensitivity, 88% specificity, 80% positive predictive value (PPV), and 73% negative predictive value (NPV), whereas AFP had 67% sensitivity, 68% specificity, 63% PPV, and 72% NPV. AUROC curves showed that the combination of both biomarkers increased the diagnostic accuracy for HCC (AUC 0.76; sensitivity 70%, specificity 94%, PPV 91%, and NPV 79%).In conclusion, PIVKA-II is a useful tool for the diagnostic definition of US-detected liver nodules in cirrhotic patients, and it provides high diagnostic accuracy for HCC when combined with AFP.