Search

Background & Aims There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients. Methods Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. Results Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12. Conclusions VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients. Lay summary The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%).

Purpose. To assess the ability of Cone-Beam CT (CBCT), performed during the Transcatheter Arterial Chemoembolization (TACE), in predicting the response to treatment of hepatocellular carcinoma (HCC). Materials and Methods. We evaluated fifty patients (M/F = 40/10, mean age: 66.7 years ± 8.22) with hepatocellular carcinoma (HCC), for a total of 82 nodules evaluated (mean diameter: 21.4 ± 11 mm). All patients performed a CT scan one month before and one month after TACE. After TACE is completed, a CBCT was performed to assess the degree of drug retention in the lesions. For each lesion, the major diameter, volume, and density of the vital portion were evaluated. The response to TACE was assessed using the mRECIST criteria on the CT scan carried out one month after the procedure. The receiver operating characteristic (ROC) curves were performed to assess the accuracy of the CBCT in predicting the response to treatment and to identify the cut-off points for each parameter under examination. Results. A complete response (CR) was observed in 24/50 patients (48%), a partial response (PR) in 16/50 (32%), stable disease (SD) in 8/50 (16%), and progressive disease (PD) in 2/50 (4%). Evaluation of the area under the ROC curve showed that the diameter, volume, and density of the lesion, measured with CBTC, had an accuracy of 94%, 96%, and 98%, respectively, in discriminating a complete response from a not complete response. Conclusion. CBCT is effective in predicting short-term response at 1-month follow-up of HCC treated by chemoembolization.

Objective: The aims of this study were to: a) evaluate tumor response rates using modified-Response-evaluation-criteria-in-solid-tumors (mRecist) criteria, b) evaluate safety of Degradable Starch Microspheres Trans-arterial-chemo-embolization (DSMs-TACE) for unresectable hepatocellular-carcinoma (HCC) treatment. Materials and Methods: We prospectively enrolled 24 HCC cirrhotic patients (21/3 M/F, mean age 66.3 years) to be treated with repeated DSMs-TACE procedures, performed at 4-6 week intervals on the basis of tumor response and patients tolerance. Clinical and biochemical evaluations were performed before and after each procedure. Treatment response was also assessed by Computed-tomography (CT) or Magnetic-resonance-imaging (MRI)-scan 4-6 weeks following each procedure. Results: In our experience, DSMs-TACE was both safe and effective. A total of 53 DSMs-TACE procedures were performed (2.2 per patient). No procedure-related death was observed. Complete Response (CR) was observed in 5/24 (20.8%), 4/17 (23.5%) and 5/12 (41.6%) patients after the first, second and third procedure, respectively. At the end of each treatment, all patients experienced at least a partial response. At the end of the repeated procedures, no differences between mono- or bi-lobar disease were observed in patients with CR (64.2% vs 50%; p=ns). In most cases, treatment discontinuation was due to worsening liver function. Conclusion: DSMs-TACE is a valid, well-tolerated alternative treatment to Lipiodol-TACE or DEB-TACE, as it has demonstrated to achieve a relatively high percentage of complete tumor necrosis. CR rates were similar between patients with mono- or bi-lobar disease indicating the possibility of carrying-out repeated procedure in a safe and effective way in both types of patients.

To evaluate safety and efficacy of degradable starch microspheres (DSMs) TACE in a large clinical cohort of patients with unresectable HCC. This is a single-center consecutive patients cohort study. The study was approved by local institutional ethics committee. Written informed consent was obtained. From December 2013 to March 2018, 137 cirrhotic patients with unresectable HCC were enrolled. For DSMs-TACE, a mixture of 4 mL of DSMs, 6 mL of non-ionic contrast and doxorubicin at a dose of 50 mg/m2 were used. Primary end point was long-term outcome, in terms of time to progression (TTP) and overall survival (OS). Secondary endpoints were: safety, liver toxicity, 1-month percentage of tumor necrosis according to the modified RECIST criteria. Two hundred and sixty-seven DSMs-TACE were performed in 137 HCC patients (33 patients in BCLC stage A, 84 patients in BCLC stage B, and 20 in stage C). Patients had a mean nodule number of 3.5 ± 1.2 (SD). Major complications were observed in 6.8% of cases. Post-embolization syndrome was common (101 patients 73.7%). According to mRecist criteria, a high objective response rate was obtained even after just one treatment (84.3% of patients showed complete response or partial response). The median TTP and OS after DSMs-TACE were 12 months and 36 months, respectively. OS at 6 months, 1 year, 2 and 3 years was 98%, 81.3%, 57.9%, 34.9%, respectively. DSMs-TACE is a safe and effective therapy for patients with HCC, allowing to obtain a good rate of OS with excellent local tumor control.

The study was undertaken in order to provide a snapshot from real clinical practice of virological presentation and outcome of patients developing immunosuppression-driven HBV reactivation. Seventy patients with HBV reactivation were included (66.2% treated with rituximab, 10% with corticosteroids and 23.8% with other immunosuppressive drugs). Following HBV reactivation, patients received anti-HBV treatment for a median (IQR) follow-up of 31(13-47) months. At baseline-screening, 72.9% of patients were HBsAg-negative and 27.1% HBsAg-positive. About 71.4% had a diagnosis of biochemical reactivation [median (IQR) HBV DNA and ALT: 6.9 (5.4-7.8) log IU/mL and 359 (102-775) U/L]. Moreover, 10% of patients died from hepatic failure. Antiviral prophylaxis was documented in 57.9% and 15.7% of HBsAg-positive and HBsAg-negative patients at baseline-screening (median [IQR] prophylaxis duration: 24[15-33] and 25[17-36] months, respectively). Notably, HBV reactivation occurred 2-24 months after completing the recommended course of anti-HBV prophylaxis in 35.3% of patients. By analysing treatment outcome, the cumulative probability of ALT normalization and of virological suppression was 97% and 69%, respectively. Nevertheless, in patients negative to HBsAg at baseline-screening, only 27% returned to HBsAg-negative status during prolonged follow-up, suggesting the establishment of chronic infection. In conclusion, most patients received a diagnosis of HBV reactivation accompanied by high ALT and 10% died for hepatic failure, supporting the importance of strict monitoring for an early HBV reactivation diagnosis. Furthermore, HBV reactivation correlates with high risk of HBV chronicity in patients negative for HBsAg at baseline-screening, converting a silent into a chronic infection, requiring long-term antiviral treatment. Finally, a relevant proportion of patients experienced HBV reactivation after completing the recommended course of anti-HBV prophylaxis, suggesting the need to reconsider proper duration of prophylaxis particularly in profound immunosuppression.

We aimed to investigate HBx genetic elements correlated with hepatitis B virus (HBV) -related hepatocellular carcinoma (HCC) and their impact on (a) HBV replicative efficiency, (b) HBx binding to circular covalently closed DNA (cccDNA), (c) apoptosis and cell-cycle progression, and (d) HBx structural stability.This study included 123 individuals chronically infected with HBV: 27 with HCC (77.9% (21/27) genotype D; 22.1% (6/27) genotype A) and 96 without HCC (75% (72/96) genotype D; 25.0% (24/96) genotype A). HepG2 cells were transfected by wild-type or mutated linear HBV genome to assess pre-genomic RNA (pgRNA) and core-associated HBV-DNA levels, HBx-binding onto cccDNA by chromatin immunoprecipitation-based quantitative assay, and rate of apoptosis and cell-cycle progression by cytofluorimetry.F30V was the only HBx mutation correlated with HCC (18.5% (5/27) in HCC patients versus 1.0% (1/96) in non-HCC patients, p 0.002); a result confirmed by multivariate analysis. In vitro, F30V determined a 40% and 60% reduction in pgRNA and core-associated HBV-DNA compared with wild-type (p0.05), in parallel with a significant decrease of HBx binding to cccDNA and decreased HBx stability. F30V also decreased the percentage of apoptotic cells compared with wild-type (14.8 ± 6.8% versus 19.1 ± 10.1%, p0.01, without affecting cell-cycle progression) and increased the probability of HBx-Ser-31 being phosphorylated by PI3K-Akt kinase (known to promote anti-apoptotic activity).F30V was closely correlated with HBV-induced HCC in vivo, reduced HBV replicative efficiency by affecting HBx-binding to cccDNA and increased anti-apoptotic HBx activity in vitro. This suggests that F30V (although hampering HBV's replicative capacity) may promote hepatocyte survival, so potentially allowing persistent production of viral progeny and initiating HBV-driven hepatocarcinogenesis. Investigation of viral genetic markers associated with HCC is crucial to identify those patients at higher risk of HCC, who hence deserve intensive liver monitoring and/or early anti-HBV therapy.

Background and aims Blood lysosomal acid lipase (LAL) is reduced in non-alcoholic steatohepatitis, which is the major cause of cryptogenic cirrhosis (CC); few data on LAL activity in CC do exist. We investigated LAL activity in a cohort of patients with liver cirrhosis. Methods This is a multicentre cohort study including 274 patients with liver cirrhosis of different aetiology from 19 centres of Internal Medicine, Gastroenterology and Hepatology distributed throughout Italy. Blood LAL activity (nmol/spot/h) was measured with dried blood spot extracts using Lalistat 2. Results Overall, 133 patients had CC, and 141 patients had cirrhosis by other causes (61 viral, 53 alcoholic, 20 alcoholic + viral, 7 autoimmune). Mean age was 64.2 ± 13.4 years, and 28.5% were women. Patients with CC were older compared to other aetiology-cirrhosis, with a lower Child-Turcotte-Pugh (CTP, p=0.003) and MELD (p=0.009) score, and a higher prevalence of cardio-metabolic risk factors and previous ischemic events. In the whole cohort, median LAL activity value was 0.58 nmol/spot/h, 0.49 and 0.65 in the groups of CC and known-aetiology cirrhosis, respectively (p=0.002). The difference remained significant after adjustment for white blood cells count (p=0.001). Multivariable linear regression analysis showed that CC (vs. known aetiology, Beta = −0.144, p=0.018), platelet count (Beta = 0.398, p < 0.001) and CTP score (Beta = −0.133, p=0.022) were associated with log-LAL activity. Similar results were found using MELD as covariate. Conclusions We found a marked reduction of LAL activity in patients with cryptogenic cirrhosis compared to the other known aetiologies. A prospective study will clarify the role of LAL in chronic liver diseases.

// Romina Salpini 1, * , Matteo Surdo 1, * , Nadia Warner 2 , Maria Francesca Cortese 1 , Danny Colledge 2 , Sally Soppe 2 , Maria Concetta Bellocchi 1 , Daniele Armenia 1 , Luca Carioti 1 , Fabio Continenza 3 , Domenico Di Carlo 1 , Patrizia Saccomandi 1 , Carmen Mirabelli 1, 4 , Michela Pollicita 1 , Roberta Longo 5 , Sara Romano 5 , Giuseppina Cappiello 5 , Alberto Spano 5 , Pascale Trimoulet 6 , Herve Fleury 6 , Jacopo Vecchiet 7 , Nerio Iapadre 8 , Angelo Barlattani 9 , Ada Bertoli 1 , Terenzio Mari 10 , Caterina Pasquazzi 11 , Gabriele Missale 12 , Cesare Sarrecchia 13 , Elisa Orecchini 14 , Alessandro Michienzi 14 , Massimo Andreoni 13 , Simona Francioso 15 , Mario Angelico 15 , Jens Verheyen 16 , Francesca Ceccherini-Silberstein 1 , Stephen Locarnini 2 , Carlo Federico Perno 1 , Valentina Svicher 1 1 Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata” Rome, Italy 2 Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia 3 Laboratory of Monitoring Antiviral Drugs, National Institute for Infectious Diseases (INMI) “Lazzaro Spallanzani” Rome, Italy 4 Institut Pasteur, Unite de Biologie des Virus Enteriques, Paris, France 5 Unit of Microbiology, “S. Pertini Hospital”, Rome, Italy 6 Laboratoire de Microbiologie Fondamentale et Pathogenicite, Hopital Pellegrin Tripode, Bordeaux, France 7 Department of Medicine and Aging Sciences, “SS Annunziata” Hospital, Chieti, Italy 8 Infectious Diseases Unit, “S Salvatore” Hospital, L'Aquila, Italy 9 Hepatology Unit, “S Giacomo” Hospital, Rome, Italy 10 Hepatology Unit, “Regina Margherita” Hospital, Rome, Italy 11 Hepato-Infectivology Unit, “S Andrea” Hospital, Rome, Italy 12 Hospital of Parma, Parma, Italy 13 Tor Vergata University Hospital, Infectious Diseases Unit, Rome, Italy 14 Department of Biomedicine and Prevention, University of Rome “Tor Vergata” Rome, Italy 15 Tor Vergata University Hospital, Hepatology Unit, Rome, Italy 16 Institute of Virology, University Hospital, University of Duisburg-Essen, Essen, Germany * These authors have contributed equally to this work Correspondence to: Carlo Federico Perno, email: cf.perno@uniroma2.it Valentina Svicher, email: valentina.svicher@uniroma2.it Keywords: hepatitis B, hepatocellular carcinoma, hepatitis B surface antigen, HBsAg mutations, cell proliferation Received: November 25, 2016 Accepted: December 27, 2016 Published: February 01, 2017 ABSTRACT Background: An impaired HBsAg-secretion can increase HBV oncogenic-properties. Here, we investigate genetic-determinants in HBsAg correlated with HBV-induced hepatocellular carcinoma (HCC), and their impact on HBsAg-secretion and cell-proliferation. Methods: This study included 128 chronically HBV-infected patients: 23 with HCC (73.9% D; 26.1% A HBV-genotype), and 105 without cirrhosis/HCC (72.4% D, 27.6% A) as reference-group. The impact of mutations on HBsAg-secretion was assessed by measuring the ratio [secreted/intracellular HBsAg] until day 5 post-transfection. The impact of mutations on cell-cycle advancement was assessed by flow-cytometry. Results: Two HBsAg mutations significantly correlated with HCC: P203Q (17.4% [4/23] in HCC vs 1.0% [1/105] in non-HCC, P=0.004); S210R (34.8% [8/23] in HCC vs 3.8% [4/105] in non-HCC, P

Liver elasticity as assessed by real-time elastography (RTE) has been shown to be correlated to liver fibrosis in various chronic liver diseases. The aim of our study was to assess the RTE performance in the evaluation of liver fibrosis in nonalcoholic steatohepatitis (NASH), as well as the histopathologic variables determining the eventual discordance between the RTE-predicted and the biopsy-proven fibrosis. Fifty-two consecutive biopsy proven NASH patients and 20 controls were studied. Liver tissue elasticity measurements were performed using the Hitachi EUB-8500 sonographer and the EUP-L52 Linear (3-7 MHz) probe. RTE liver tissue mean elasticity (TME) values were calculated and correlated to the histologic fibrosis, activity and steatosis scores. A decrease in TME was observed with increasing fibrosis (r = -0.75). Similarly, TME varied together consistently with steatosis (r = -0.3). In contrast, TME did not show any correlation with the severity of inflammation. Multiple regression analysis showed that fibrosis was the only variable able to significantly (p < 0.0001) modify TME values. The diagnostic accuracy of TME measurement for F > 0 evaluated by AUC-ROC analysis was 0.86. The diagnostic accuracy of TME measurement for F >= 2 was 0.92. We suggest that RTE could be used as a complementary imaging method to evaluate liver fibrosis in NASH patients. Future studies of larger patient cohorts are necessary for the validation of the technique.

Risk of hepatocellular carcinoma (HCC) in hepatitis C virus cirrhotic patients treated with direct-acting antiviral agents (DAA) is still debating. We investigated it in a large cohort. The cohort comprised 1045 cirrhotic patients who completed treatment with DAA, with a median follow-up of 17.3 months after end of treatment (EOT), including 943 patients without history of HCC and 102 previously treated for HCC. The majority were men (59.9%), with compensated cirrhosis (88.8%), genotype 1b (44.7%). Univariate, multivariate analysis and Kaplan-Meier curves were performed to detect predictors of HCC in patients with and without reduction in alpha-fetoprotein (AFP) during treatment. SVR12 was 95.6%. HCC developed in 95 (9.9%), including 54 of 943 (5.7%) occurrent and 41 of 102 (39%) recurrent tumours. De novo were more often unifocal (P = 0.01) and curable (P = 0.03). AFP decreased from 16.1 ± 36.2 mg/dL (baseline) to 11.4 ± 55 mg/dL (EOT). At univariate analysis, predictors were a previous HCC, older age, higher model for end-stage liver disease, prolonged INR, lower platelets, baseline and EOT AFP, virological failure and no reduction in AFP during treatment. Kaplan-Meier curves showed lower incidence of HCC in patients showing any reduction in AFP (P = 0.001). Those with AFP

A 63-year-old man with chronic hepatitis C and persistently normal alanine aminotransferase levels was treated with peginterferon alpha-2a (180 microg weekly) and ribavirin (800 mg daily). Hepatitis C virus-ribonucleic acid was negative at week 4. After 12 weeks of therapy, haemoglobin levels had decreased by 3.5mg/dL, and he developed a syncope episode with electrocardiographic signs of myocardial ischaemia. Antiviral treatment was stopped and the ischaemia-like electrocardiographic changes resolved completely within 2 months. Eight months later, because of the previous rapid virological response and patient motivation, he was treated again with peginterferon and ribavirin. Baseline and weekly electrocardiographic recordings were obtained during treatment. At week 4 hepatitis C virus-ribonucleic acid was negative. At week 8, when the haemoglobin levels had decreased by 3.4 mg/dL, the patient developed the same ischaemia-like changes that occurred during the previous treatment. Antiviral therapy was stopped and the electrocardiographic ischaemia-like changes disappeared after 1 month. The patient neither had a history of previous cardiovascular diseases, nor evidence of current disease at myocardial scintigraphy. However, a coronary microvessel spasm, possibly related to drug-toxicity and/or anaemia could not be excluded. This case indicates the need of strict electrocardiographic monitoring in elderly patients undergoing treatment with peginterferon and ribavirin.

ObjectiveThe objective of this study was to compare the efficacy of anti-hepatitis C virus (anti-HCV) treatment schedules on the basis of an early virological response (EVR), defined as undetectable serum HCV-RNA (

To assess the diagnostic performance of magnetic resonance imaging (MRI) with gadoxetic acid in the identification of hepatocellular carcinoma (HCC) nodules by comparison with histological findings. In a cohort of patients suffering from cirrhosis of various etiologies (chronic hepatitis C virus (HCV) or hepatitis B virus (HBV), alcohol abuse, cryptogenic forms), we selected 17 patients affected by HCC who were eligible for liver transplantation on the basis of a computed-tomography (CT) total-body examination. Such patients also underwent an MRI examination under basal conditions, and with four dynamic phases, as well as a hepatobiliary phase acquired after at least 20 min and recognized by the excretion of contrast agent into the bile duct, following intravenous administration of 0.05 mol/kg of gadoxetic acid (gadoxetate disodium, Primovist®; Bayer, Osaka, Japan). The MRI images were then evaluated in a double-blinded experimental setup by two radiologists experienced in imaging of the liver. The diagnosis of HCC was made in the presence of nodular lesions that showed typical or atypical enhancement patterns. The liver was subsequently explanted (on average 47.4 days after MRI evaluation), dissected into 1-cm samples, and histologically evaluated according to the classification of Edmondson–Steiner. At the histopathological examination, 46 nodules were identified, on average 2.7 nodules for each patient. Of these, 37 were hepatocellular carcinomas, 3 were characterized by histologically unrecognizable complete necrosis, and 6 showed high-grade dysplasia. MRI with hepatospecific contrast medium showed inter-observer average values of sensitivity, specificity, and diagnostic accuracy of 94.6, 90, and 93.6 %, respectively. In one case, a nodule was not identified by MRI with gadoxetic acid, even in the hepatospecific phase (false negative (FN)). This result could be implicated to the long time interval between the analysis and the explant (88 days). In another case, there was an overdiagnosis of a HCC with a typical nodular pattern (false positive (FP)), but which most likely should have been attributed to a previous echinococcus cyst. MRI analysis, in combination with the study of the hepatobiliary phase, also showed a greater sensitivity, the same specificity, and a greater diagnostic accuracy compared to MRI evaluated only in the dynamic phases (with an average percentage between the two operators, respectively, of 75.7, 90, and 78 %). MRI with gadoxetic acid shows a diagnostic accuracy superior to contrast-enhanced MRI, allowing for the diagnosis of additional lesions, and it could be considered as an imaging method to carry out a more appropriate management of waiting lists for liver transplants.

Summary Background : An early virological response to interferon-α treatment is a strong predictor of sustained response, but it has never been exploited to stratify patients in clinical trials. Aim : To evaluate the efficacy of amantadine plus interferon-α compared with interferon-α alone in naive patients with chronic hepatitis C who were randomized on the basis of the early virological response to interferon-α. Methods : One hundred and eighty-one patients received recombinant interferon-α2a (3 MU three times weekly) for 2 months and 164 were evaluated for early (i.e. month 2) virological response. Hepatitis C virus (HCV) RNA-negative patients (n = 66) were randomized to receive 3 MU of interferon-α three times weekly, with or without amantadine (200 mg/day); HCV RNA-positive patients (n = 98) were randomized to receive 6 MU of interferon-α three times weekly, with or without amantadine (200 mg/day). HCV RNA-positive patients at 6 months discontinued treatment, and all others completed 12 months. Results : At month 6, HCV RNA-negative patients made up 54.2% of the interferon + amantadine group and 42.0% of the monotherapy group (P = 0.07). At month 12, HCV RNA-negative patients made up 38.5% of the interferon + amantadine group and 28.4% of the monotherapy group (N.S.). The sustained virological response rates were 21.6% and 20.9%, respectively (N.S.). Conclusion : The addition of amantadine does not enhance the sustained virological response to interferon-α in naive patients with chronic hepatitis C; however, an additive effect of amantadine occurs in the first 6 months, mainly in patients without an early response to monotherapy. Early response to interferon-α is a strong predictor of sustained virological response.

Insulin resistant metabolic syndrome is a major clinical disorder including hyperlipidaemia, hypertension, impaired glucose tolerance and/or type 2 diabetes and central obesity, which are well established cardiovascular risk factors. We report the case of a 61-year-old woman who developed severe hypercholesterolaemia and hypertriglyceridaemia after liver transplantation. In her forties she had hypertension, mixed hyperlipidaemia, mild hyperglycaemia and moderate abdominal obesity, suggesting the presence of the metabolic syndrome. She had liver enzyme elevation and severe steatosis and hepatomegaly at ultrasonography. At age 52, cryptogenic liver cirrhosis was diagnosed and rapidly progressing liver failure developed. In 1992 she underwent liver transplantation. Seven years after transplant the patient had abdominal obesity, high blood pressure, marked hypercholesterolaemia, hypertriglyceridaemia and moderate elevation of alanine aminotransferase. She also had impaired glucose tolerance and markedly increased basal and post-glucose load plasma insulin levels. Steatohepatitis was demonstrated by serial liver biopsies. This is the first case that reports the recurrence of the metabolic syndrome following liver transplantation. We postulate that metabolic syndrome may have promoted fatty liver and subsequent progression to end stage liver disease. We also stress the need for careful management of the metabolic syndrome in order to decrease the long-term risk for cardiovascular disease.

In 2011, our regional district adopted an experimental system for fast referral (within 72 h) by general practitioners to several outpatient specialist evaluations including hepatology. The aim of this study was to assess the characteristics and appropriateness of urgent hepatology visits.Retrospective study.Hospital-based study in Italy.A total of 192 subjects referred to our outpatient hepatology clinic classified as 'urgent' were compared with 397 patients evaluated with standard referral. A comparison with 200 patients visited just before the adoption of the new system was also included.Patients' features and appropriateness of referral in urgent and non-urgent groups using the new system.Increase in liver enzymes was the main factor that leads to specialist hepatology consultation and was more frequent in the urgent group (37% vs. 27.1%, P0.001). Liver malignancies were identified in 2.6% of patients in the urgent group, whereas this percentage was 10 times lower in the non-urgent group (P = 0.01). Urgent patients required inpatient admission more frequently compared with non-urgent patients (4.2% vs. 0.5%; P = 0.003). Inappropriate referral was recorded in 41% of cases in the urgent group (no reason for urgency 27%; condition not attributable to liver 13.5%). In the non-urgent group, consultations were inappropriate in 20.1% of cases (condition not attributable to liver). In comparison with the old system, the new one allocated85% of patients with serious illness to urgent group.This strategy is helpful in selecting patients with more serious hepatic conditions. Appropriateness of referral represents a crucial issue.

To evaluate the downstaging rates in hepatitis C virus-patients with hepatocellular carcinoma (HCC), treated with degradable starch microspheres transcatheter arterial chemoembolization (DSM-TACE), to reach new-Milan-criteria (nMC) for transplantation.This study was approved by the Ethics Committee of our institution. From September 2013 to March 2014 eight patients (5 men and 3 women) with liver cirrhosis and multinodular HCC, that did not meet nMC at baseline, were enrolled in this study. Patients who received any other type of treatment such as termal ablation or percutaneous ethanol injection were excluded. DSM-TACE was performed in all patients using EmboCept(®) S and doxorubicin. Baseline and follow-up computed tomography or magnetic resonance imaging was assessed measuring the longest enhancing axial dimension of each tumor according to the modified Response Evaluation Criteria In Solid Tumors measurements, and medical records were reviewed.DSM-TACE was successfully performed in all patients without major complication. We treated 35 lesions (mean 4.3 per patient). Six of eight patients (75%) had their HCC downstaged to meet nMC. Every patient whose disease was downstaged eventually underwent transplantation. The six patients who received transplant were still living at the time of this writing, without recurrence of HCC. Baseline age (P = 0.25), Model for End-stage Liver Disease score (P = 0. 77), and α-fetoprotein level (P = 1.00) were similar between patients with and without downstaged HCC.DSM-TACE represents a safely and effective treatment option with similar safety and efficacy of conventional chemoembolization and could be successfully performed also for downstaging disease in patients without nMC, allowing them to reach liver transplantation.

Recent studies in vitro and in animals have suggested that ribavirin may potentiate the antihepatitis C virus (HCV) activity of interferon-alpha (IFN-alpha) by up-modulating the production of T cell-derived cytokines, such as interleukin (IL)-2 and IFN-gamma, which play a key role in the cellular immune response against HCV. To study the immune-modulatory mechanisms of ribavirin further, cytokine production by activated T cells and circulating cytokine levels were studied by FACS analysis and ELISA testing in 25 patients with chronic hepatitis C unresponsive to IFN-alpha, before and after treatment with either ribavirin plus IFN-alpha or IFN-alpha alone. After 16 weeks of treatment, both the expression of IFN-gamma by activated T cells and the blood levels of IFN-gamma, were significantly reduced with respect to pretreatment values in patients treated with ribavirin and IFN-alpha but not in those undergoing treatment with IFN-alpha alone. The expression of IFN-gamma was significantly lower in patients that gained normal ALT levels with respect to those that did not. No modification of the expression of IL-2, IL-4 and IL-10 was found before and after treatment in either group of patients. In conclusion, the results of this study do not support up-modulation of IFN-gamma and IL-2 production as the mechanism by which ribavirin potentiates IFN-alpha anti HCV activity. In addition, our findings suggest that ribavirin may exert an anti-inflammatory effect and may help reducing IFN-gamma-driven T cell activation and liver damage.

Background Rapid and early virological responses to peginterferon-alpha and ribavirin are predictive of sustained virological response (SVR) in hepatitis C virus (HCV) infection. We aimed at finding a simple rule to determine the shortest duration of dual therapy for all HCV genotypes, obtained by multiplying time to Initial Viral Response, IVR (first undetectable HCV-RNA) by 4 (Tailored Therapy-4, or TT4). Method 267 naive HCV-infected patients with compensated liver disease were randomized (2:1) to the TT4 (n = 180) or current standard-of-care (SoC, n = 87) and received peginterferon-alpha plus ribavirin. Patients with HCV-RNA decrease ≤2 log10 at week 12 or detectable HCV-RNA at week 24 discontinued treatment. Results Both groups had comparable baseline characteristics, SVR rates were similar in the whole population (60.6% vs. 60.9%) and within each genotype subgroup (G1: 46.6% vs. 55.6%; G2: 90.2% vs. 94.4%; G3: 74.1% vs. 58.3%; G4: 45.8% vs. 33.3%). Relapse rate was higher in G1-TT4 than G1-SoC. Treatment duration in SVR patients was shorter in TT4 compared to SoC, both overall [25 ± 15 vs. 36 ± 12.1 weeks], and for subgroups: G1 [35.3 ± 16.7 vs. 47.3 ± 2.6 weeks], G2 [18.3 ± 7.5 vs. 24 ± 2.8 weeks], G3 [15.2 ± 8.7 vs. 22.8 ± 3 weeks] and G4 [26.9 ± 13 vs. 48 weeks]. Conclusions In HCV-naive patients, TT4-rule treatment yields similar SVR rates compared to SoC but with shorter treatment duration and remarkable cost reduction.

Summary Background Rapid virological response (RVR) is the best predictor of sustained response to standard HCV treatment. Aim To evaluate predictive factors of RVR. Methods Sixty-five patients (mean age 52.6 ± 13.8; 37 genotype-1, and 28 genotypes-2/3) were consecutively treated with pegIFN-alpha2a or 2b once weekly plus daily ribavirin based on body weight for 24 or 48 weeks, according to genotype. RVR was defined as undetectable HCV-RNA at week 4. Results Twenty-seven percent of patients achieved RVR in genotypes 1 and 60.7% in genotypes 2/3 (P

R. Salpini1, M. Surdo1, N. Warner2, M.F. Cortese1, C. Mirabelli 1,3, D. Colledge2, S. Soppe2, P. Saccomandi1, M. Pollicita1, R. Longo4, S. Romano4, G. Cappiello4, A. Spano4, P. Trimoulet5, H. Fleury5, J. Vecchiet6, N. Iapadre7, A. Barlattani8, A. Bertoli 1, T. Mari9, C. Pasquazzi10, G. Missale11, C. Sarrecchia12, E. Orecchini13, A. Michienzi13, M. Andreoni12, S. Francioso14, M. Angelico14, F. Ceccherini-Silberstein1, S. Locarnini2, C.F. Perno1, V. Svicher1 1 Department of Experimental Medicine, University of Rome “Tor Vergata” Rome, Italy 2 Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia 3 Institut Pasteur, Unite de Biologie des virus enteriques, 25 rue du Dr Roux, 75015 Paris, France 4 S. Pertini Hospital”, Rome, Italy 5 Hopital Pellegrin Tripode, Bordeaux, France 6 SS Annunziata” Hospital, Chieti, Italy 7 S Salvatore” Hospital, L’Aquila, Italy 8 “S Giacomo” Hospital, Rome, Italy 9 “Regina Margherita” Hospital, Rome, Italy 10 “S Andrea” Hospital, Rome, Italy 11 Hospital of Parma, Parma, Italy 12 Tor Vergata University Hospital, Infectious Diseases Unit, Rome, Italy 13 Department of Biomedicine and Prevention, University of Rome “Tor Vergata” Rome, Italy 14 Tor Vergata University Hospital, Hepatology Unit, Rome, Italy