Search

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. [ABSTRACT FROM AUTHOR]

Introduction: Sorafenib, an oral multikinase inhibitor, is the only systemic agent proven to be effective in patients with hepatocellular carcinoma (HCC). There are no approved second line systemic therapies in patients who have had disease progression on or are not eligible to sorafenib. Case Presentation: We describe two cases of unresectable HCC that were treated with low, "metronomic" doses of capecitabine. In the first patient, capecitabine was used after sorafenib failure. In the second case, treatment with capecitabine was attempted since the patient was considered not eligible for sorafenib due to spontaneous hepatic bleeding of a large HCC lesion. Treatment was effective and well tolerated in both patients with long-lasting objective responses. Conclusions: Lacking established second-line therapy, metronomic capecitabine may be a valid alternative in the treatment of HCC patients who are judged not eligible for sorafenib or those having progression disease on sorafenib. [ABSTRACT FROM AUTHOR]

Background/Aims: Autoimmune hepatitis affects mainly women. It is subdivided into type 1 and type 2 according to the autoantibody profile and without immunosuppression usually evolves to cirrhosis and end-stage liver failure. Methods: We evaluated clinical, biochemical, immunological and genetic features and treatment response of 163 consecutive Italian patients with autoimmune hepatitis. Results: At diagnosis, type 1 autoimmune hepatitis showed more inflamed liver histology and more pronounced cholestasis, whereas type 2 was more common in children. Male and female patients shared similar clinical, biochemical and immunological features. Of 89 patients with 5-year follow-up or longer, 23 patients irrespective of presenting clinical, biochemical and immunological features achieved complete remission (normal transaminases and gammaglobulin levels) which was maintained with minimal steroid dosage; attempt at treatment withdrawal led to disease exacerbation. Complete responders had more often HLA DRB1∗0401 (p =0.011) and their risk of disease progression was lower (p <0.0001). Conclusions: Type 1 and type 2 autoimmune hepatitis is one and the same disease. Autoimmune hepatitis has similar features in male and female patients. HLA DRB1∗0401 positive patients are more likely to achieve complete remission. Continuous low-dose steroids are necessary to maintain remission, significantly reducing the risk of disease progression. [Copyright &y& Elsevier]

BACKGROUND: Population-based studies of the natural course of chronic viral liver disease that consider comorbidity factors are lacking. Using data from the Dionysos Study, we quantified the burden of chronic viral liver disease and the role of alcohol intake to morbidity and mortality in a representative sample of subjects from the general population of two communities of Northern Italy. METHODS AND FINDINGS: We followed up 139 subjects with chronic hepatitis C virus (HCV) infection and 61 with chronic hepatitis B virus (HBV) infection for a median (IQR) time of 8.4 (1.0) and 8.3 (0.9) yr, respectively. Ethanol intake was evaluated using a food-frequency questionnaire, fatty liver (FL) was diagnosed by ultrasonography, and liver cirrhosis (LC) and hepatocarcinoma (HCC) were diagnosed by liver biopsy. Exact multivariable Poisson regression was performed to identify predictors of death. The incidence and remission rates of FL were 9.0 and 29.7 in the HCV cohort and 4.0 and 30.4 per 1,000 person-years (PY) in the HBV cohort. Progression to LC and HCC was more common in the HCV than in the HBV cohort (4.5 vs 2.0 and 2.7 vs 2.0 per 1,000 PY, respectively). Ethanol intake was an independent predictor of LC in the HCV cohort [rate ratio (RR) = 4.15 (95% CI 1.02–41.2) for every increase of 30 g/day of ethanol intake at baseline] and of death rate in both cohorts [RR = 8.53 (95% CI 1.40–24.61) and 3.56 (1.34 to 26.50) for every increase of 30 g/day of ethanol intake at baseline]. CONCLUSIONS: The morbidity and mortality rate of HBV and HCV infection in the general population is lower than that reported in secondary-care populations, blood donors, or clinical series. Ethanol intake is an independent predictor of LC in subjects with chronic HCV infection and an independent predictor of death in subjects with either HCV or HBV infection. [ABSTRACT FROM AUTHOR]

• Management of sorafenib-related adverse events has changed over time. • A tailored approach with more temporary dose reductions is now more frequent. • Median treatment duration has increased overtime (5.8 vs. 4.1 months). • More importantly, overall survival has also increased (12.0 vs. 11.0 months). • Increasing survival impacts on the design of trials using sorafenib as comparator. Sorafenib is associated with multiple adverse events (AEs), potentially causing its permanent interruption. It is unknown how physicians' experience has impacted on the management of these AEs and consequently on clinical outcomes. We aimed to assess whether AE management changed over time and if these modifications impacted on treatment duration and overall survival (OS). We analysed the prospectively collected data of 338 consecutive patients who started sorafenib between January 2008 and December 2017 in 3 tertiary care centres in Italy. Patients were divided according to the starting date: Group A (2008–2012; n = 154), and Group B (2013–2017, n = 184). Baseline and follow-up data were compared. In the OS analysis, patients who received second-line treatments were censored when starting the new therapy. Baseline characteristics, AEs, and radiological response were consistent across groups. Patients in Group B received a lower median daily dose (425 vs. 568 mg/day, p < 0.001) due to more frequent dose modifications. However, treatment duration was longer (5.8 vs. 4.1 months, p = 0.021) with a trend toward a higher cumulative dose in Group B. Notably, the OS was also higher (12.0 vs. 11.0 months, p = 0.003) with a sharp increase in the 2-year survival rate (28.1 vs. 18.4%, p = 0.003) in Group B. Multivariate time-dependent Cox regression analysis confirmed later period of treatment (2013–2017) as an independent predictor of survival (HR 0.728; 95% CI 0.581–0.937; p = 0.013). Unconsidered confounders were unlikely to affect these results at the sensitivity analysis. Experience in the management of sorafenib-related AEs prolongs treatment duration and survival. This factor should be considered in the design of future randomised clinical trials including a sorafenib treatment arm, as an underestimate of sample size may derive. Sorafenib has been the standard frontline systemic treatment for hepatocellular carcinoma for over a decade. Its tolerability is limited by different adverse events, which might lead to its permanent discontinuation in a sizeable proportion of patients. After a careful analysis of potential confounders, we demonstrated that the physicians' experience in managing adverse events related to sorafenib has improved over time, with longer treatment periods and less permanent discontinuation for toxicities. More importantly, these improvements also translated into longer patient survival. Our results have relevant repercussions in clinical practice and in the design of future clinical trials. [ABSTRACT FROM AUTHOR]

Background and Aims: The present study aims to investigate the role of the prognostic nutritional index (PNI) on survival in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib., Methods: This multicentric study included a training cohort of 194 HCC patients and three external validation cohorts of 129, 76 and 265 HCC patients treated with Sorafenib, respectively. The PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). Univariate and multivariate analyses were performed to investigate the association between the covariates and the overall survival (OS)., Results: A PNI cut-off value of 31.3 was established using the ROC analysis. In the training cohort, the median OS was 14.8 months (95% CI 12-76.3) and 6.8 months (95% CI 2.7-24.6) for patients with a high (>31.3) and low (<31.3) PNI, respectively. At both the univariate and the multivariate analysis, low PNI value (p = 0.0004), a 1-unit increase of aspartate aminotransferase (p = 0.0001), and age > 70 years (p< 0.0038) were independent prognostic factors for OS. By performing the same multivariate analysis of the training cohort, the PNI <31.3 versus >31.3 was found to be an independent prognostic factor for predicting OS in all the three validation cohorts., Conclusions: PNI represents a prognostic tool in advanced HCC treated with first-line Sorafenib. It is readily available and low-cost, and it could be implemented in clinical practice in patients with HCC., Competing Interests: The authors have declared that no competing interests exist.

Background & Aims: In recent years, primary biliary cirrhosis is mostly diagnosed in patients who are asymptomatic; however, a proportion of cases still present with typical complaints such as fatigue and/or pruritus. We compared biochemical, histological and immunological features of patients with or without fatigue and/or pruritus at onset to see whether the different clinical presentation may eventually impact on disease progression., Methods: We analysed the Bologna cohort of 216 patients with primary biliary cirrhosis referred to our Centre between 1997 and 2007, according to symptomatic (fatigue and/or pruritus) or asymptomatic presentation. Clinical, biochemical, histological and immunological feature at diagnosis, response to ursodeoxycholic acid and progression of the disorder were compared after a mean follow-up of 81 ± 75 months., Results: At diagnosis, symptomatic patients were significantly more often women (98.6% vs. 87.2%, P = 0.004), younger (mean age 49 ± 12 vs. 55 ± 12 years, P = 0.003) and with more pronounced biochemical activity, as indicated by higher alkaline phosphatase (mean 2.93 ± 2 vs. 2.12, P = 0.002) and aminotransferase (mean 1.92 ± 1 vs. 1.47 ± 1.27, P = 0.014) levels, whereas histological stage and autoantibody profile were similar. Symptomatic patients were less likely to respond to ursodeoxycholic acid therapy (63% vs. 81%, P = 0.006) and developed more often cirrhosis and its complications (31% vs. 13%, P = 0.004)., Conclusions: Fatigue and/or pruritus at onset identify a subset of patients with primary biliary cirrhosis who preferentially are women, younger, with a particularly active disease, less responsive to ursodeoxycholic acid treatment, and more inclined to evolve to cirrhosis and its complications., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aim: Primary biliary cirrhosis (PBC) is frequently associated with other autoimmune diseases, including systemic sclerosis (SSc). In the last years many efforts have been dedicated to the research of widely accepted criteria for the early diagnosis of SSc. Since studies on the prevalence of early SSc in PBC patients are lacking, our aim was to investigate its hitherto unknown prevalence in a large cohort of PBC patients., Methods: We studied 80 PBC patients and 72 patients with other chronic liver diseases. Diagnostic workup included research into signs of connective tissue disease, determination of autoantibody profile, and examination of capillary abnormalities through nailfold videocapillaroscopy., Results: Ten PBC patients (12.5%) satisfied diagnostic criteria for early SSc and 5 (6.3%) had definite SSc. None of the patients in the control group were diagnosed either with early or definite SSc. No differences were observed in terms of aminotransferases, alkaline phosphatase, and liver function tests between PBC patients with and without associated SSc., Conclusions: Early SSc is significantly frequent in PBC patients. The detection of early SSc in PBC patients may lead to a prompt treatment of its complications, preventing inabilities and preserving the chance of liver transplantation.

Background: The ART score (a point score for the assessment of retreatment with transarterial chemoembolization, TACE) has been recently developed in Austria to differentiate patients who may benefit from multiple sessions of TACE for hepatocellular carcinoma (HCC) treatment. The primary aim of the study was to test the validity of the ART score in an Italian study cohort. The secondary aims were to evaluate overall survival (OS) and clinical determinants of improved survival in patients treated with multiple TACE sessions., Methods: The ART score and the clinical outcome of 51 consecutive patients with HCC submitted to multiple TACE sessions from April 2002 to December 2009 were retrospectively analyzed., Results: Median OS was 26.0 months (95% confidence interval 18.4-33.6) with 1-, 3- and 5-year survival rates of 75, 33 and 11%, respectively). Thirty-three patients had an ART score of 0-1.5 and in 18 it was ≥2.5, but in our patient series, the ART score was not found to be a predictor of survival (p = 0.173). At univariate analysis, tumor extent (uni- vs. bilobar: 34.0 vs. 9.0 months; p < 0.001), Child-Pugh score before the second TACE (A vs. B7 vs. B8-9: 26.0 vs. 16.0 vs. 5.0 months; p = 0.005) and Child-Pugh score increase between the first and second TACE (absent vs. + 1 point vs. + ≥2 points: 27.0 vs. 4.0 vs. 5.0 months; p < 0.001) were statistically related with survival. At multivariate analysis, only Child-Pugh score increase remained a significant predictor of worse survival (p = 0.001, hazard rate = 11.6)., Conclusions: The ART score was not found to work as an objective tool to guide TACE retreatment in our Italian patient series, only the Child-Pugh score increase was an independent predictor of a shorter survival.

Objectives: Some patients with primary biliary cirrhosis (PBC) have antinuclear antibodies (ANAs). These ANAs include the "multiple nuclear dots" (MND) staining pattern, targeting promyelocytic leukemia protein (PML) nuclear body (NB) components, such as "speckled 100-kD" protein (Sp100) and PML. A new PML NB protein, designated as Sp140, was identified using serum from a PBC patient. The aim of this study was to analyze the immune response against Sp140 protein in PBC patients., Methods: We studied 135 PBC patients and 157 pathological controls with type 1 autoimmune hepatitis, primary sclerosing cholangitis, and systemic lupus erythematosus. We used indirect immunofluorescence and a neuroblastoma cell line expressing Sp140 for detecting anti-Sp140 antibodies, and a commercially available immunoblot for detecting anti-Sp100 and anti-PML antibodies., Results: Anti-Sp140 antibodies were present in 20 (15%) PBC patients but not in control samples, with a higher frequency in antimitochondrial antibody (AMA)-negative cases (53 vs. 9%, P<0.0001). Anti-Sp140 antibodies were found together with anti-Sp100 antibodies in all but one case (19 of 20, 90%) and with anti-PML antibodies in 12 (60%) cases. Anti-Sp140 positivity was not associated with a specific clinical feature of PBC., Conclusions: Our study identifies Sp140 as a new, highly specific autoantigen in PBC for the first time. The very frequent coexistence of anti-Sp140, anti-Sp100 and anti-PML antibodies suggests that the NB is a multiantigenic complex in PBC and enhances the diagnostic significance of these reactivities, which are particularly useful in AMA-negative cases.

Antibodies to liver/kidney microsome type 1 occur in Italian patients with hepatitis C, but rarely develop in North American patients. Our goals were to compare the frequencies of the HLA markers associated with autoimmune expression in Italian and North American patients with chronic hepatitis C and to determine genetic bases for regional differences in antibody production. HLA B8, DR3, DR4, DR7, DR11, DR13, DQ2, and the B8-DR3-DQ2 haplotype were determined by microlymphocytotoxicity and polymerase chain reaction in 105 Italian patients (50 with microsomal antibodies), 100 North American patients (none with microsomal antibodies), and Italian and North American healthy control subjects. Italian patients with microsomal antibodies differed from North American patients without these antibodies by having a higher frequency of HLA DR7 (54% vs. 27%, P=0.002). HLA DR7 occurred more frequently in seropositive Italian patients than in seronegative counterparts (54% vs. 11% P < 0.0001), Italian healthy control subjects (54% vs. 29%, P=0.0009), and North American healthy control subjects (54% vs. 19%, P < 0.0001). The frequency of HLA DR7 was similar in North American patients and controls (27% vs. 19%, P=0.2), but it was lower than in Italian controls (19% vs. 29%, P=0.059). Seropositive Italian patients had a lower frequency of HLA DR11 than seronegative Italian patients and Italian controls (18% vs. 34%, P=0.07, and 18% vs. 35%, P=0.02, respectively). In contrast to seropositive Italian patients, North American patients had HLA DR4 (30% vs. 12%, P=0.02), HLA DR13 (29% vs. 10%, P=0.01), and the B8-DR3-DQ2 haplotype (23% vs. 6%, P=0.01) more often. Similarly, HLA DR4 and the B8-DR3-DQ2 phenotype were more frequent in North American patients than in Italian controls (30% vs. 16%, P=0.005, and 23% vs. 7%, P=0.00002, respectively). HLA DR7 is associated with the development of microsomal antibodies in Italian patients with chronic hepatitis C. The lower frequency of HLA DR7 in North America could contribute to the rarity of these antibodies in this region. HLA DR11 may be protective against the development of microsomal antibodies in Italian patients, whereas HLA DR4, HLA DR13, and the B8-DR3-DQ2 haplotype may be protective in North American patients.

Aim: Our goals were to analyze the known genetic predispositions for autoimmune hepatitis (AIH) in AIH Italian population and to compare them with North American counterparts., Methods: Human leukocyte antigens (HLA) B8, C7, DR3, DR4, DR7, DR11, DR13, DQ2 and the B8-DR3-DQ2 phenotype were determined by microlymphocytotoxicity and polymerase chain reaction in 74 Italian patients (57 with type 1 and 17 with type 2 AIH) and 149 North American patients with type 1 AIH, and in adequate controls., Results: B8-DR3-DQ2 occurred more frequently in Italian patients with type 1 AIH than in Italian controls (30% vs 7%, P<0.0001), but less frequently than in North American counterparts (30% vs 48%, P = 0.02). DR4 occurred less frequently in Italian patients with type 1 AIH (23% vs 43%, P = 0.01) and in controls (16% vs 34%, P = 0.0003) than in North American counterparts. No differences were found in alleles' frequency between type 1 and type 2 Italian AIH patients. DR11 had a frequency lower in type 1 Italian AIH patients than controls (17% vs 35%, P = 0.01)., Conclusion: HLA DR4 is not associated with AIH in Italy. The known HLA risk factors for AIH occur similarly in Italian patients with type 1 and type 2 AIH, and they are less frequent than in North American patients. B8-DR3-DQ2 is the predominant phenotype of type 1 AIH also in Italy, and HLA DR11 may be a regionally distinctive protective factor against type 1 AIH.