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Hepatitis C virus (HCV) is able to bypass the immune system modulating innate and adaptive immune response and blocking T helper 1 (Th1) cell production. Because the human leukocyte antigen (HLA)-G molecule has immunomodulatory properties inhibiting the function and production of natural killer and cytotoxic lymphocyte T cells, as well as promoting shift from Th1 toward Th2 response, we hypothesized its involvement in susceptibility to HCV infection.Considering that HLA-G mRNA expression has been reported to be under genetic control, an association study was conducted analyzing 800 base pairs upstream the ATG at the 5'upstream regulator region (URR) and 850 base pairs from ATG to exon 3 and the 3'untranslated region (UTR) of HLA-G gene in Italian HCV-positive patients and uninfected controls.Four 5'URR polymorphisms (-725CGT, -509CG, -400GA and -398GA), 7 polymorphisms at coding region (+15GA, +36GA, +243GA, insC506, 531GC, delA615 and 685GA), the +644GT polymorphism, and 1 haplotype (TTGTTCCIGAC) showed different frequency distributions between HCV patients and uninfected controls.The results from our study suggest a possible involvement of HLA-G in the risk modulation toward HCV infection.

Summary. 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.

The subthalamic nucleus (STN) has generally been considered as a rely station within frontal-subcortical motor control circuitry. The function of the STN in the current model of the basal ganglia organization was developed from animal model and neurodegenerative diseases with hypo- and hyperkinetic movement disorders: therefore, the STN represents a relay in the so-called "indirect" pathway of the parallel basal ganglia-thalamocortical circuits. STN excitatory efferents reinforce the inhibition of basal ganglia output nuclei, the internal globus pallidus (GPi) and the reticular substantia nigra (SNr) on thalamo-frontal neurons. A "direct" striato-pallidal pathway opposes the STN by normally inhibiting basal ganglia outflow, facilitating thalamo-frontal drive. Starting from the clinical observations to motor improvement after deep brain stimulation of the STN, we extend the discussion to the possible cognitive and attention role of the DBS-STN technique.

Recent studies had indicated the importance of the stem cells (SC) in systemic and solid cancers, including in primary liver cancers (PLC). The SC can contribute in the tumor-stromal cross talk in the cancer microenvironment. However their flexibility in the progression and the spread of the PLC is still unclear. In this study, we isolated and characterized a cells population with SC characteristic from paired neoplastic and non-neoplastic tissues from a total 15 patients of hepatocellular carcinoma (HCC, n=10), cholangiocarcinoma (CC, n=3) and non-tumoral liver (n=2). The cells were maintained in selective media and characterized by flow cytometry, RT-PCR, anchorage-independent assay and in vitro cells-directed trans-differentiation using inducer media. In vivo xenograft assay was performed by subcutaneous and orthotopic inoculation of primary cells from HCC and CC in male adult athymic nude and NOD/SCID mice, respectively. Isolated cells were negative for the expression of CD34, CD45, CD117 and CD133, but positive for CD90 and CD44. They expressed mesenchymal SC and pluripotency factors and had the ability to clone after low density plating in 3D matrix. After induction into insulin-secreting cells, they showed gene up-regulations of pancreatic cells markers somatostatin and gastric inhibitory protein, showing potency to trans-differentiate to endodermal lineage. Under adipogenic stimulation, they differentiate into adipocytes as confirmed by lipid droplets accumulation in the cytoplasm and high expression of adipocytes regulator PPARG, detected by nile red lipid staining and RT-PCR, respectively. Under osteogenic condition, the cells became positive of alkaline phosphatase staining and showed up-regulation of bone specific genes such as bone sialoprotein and osteopontin. In vivo assay in nude mice, alpha fetoprotein and albumin in primary cells were noticed 4 months after injection, albeit no visible tumor nodules were detected. Interestingly, by orthotopic injection in NOD/SCID mice, tumor nodules in the liver and tumor metastasis on lung were observed, indicating the capacity of the SC to enter into circulation. Further analysis on the xenograft cells showed a mixed population between human and mouse cells as confirmed by RT-PCR and DNA sequencing. The expression of liverspecific markers were also identified in metastatic site. Our data provide clear evidence of the plasticity of the SC-like cells isolated from HCC and CC in the process of hepatocarcinogenesis and metastasis. Their trans-differentiation flexibility may 804A AASLD ABSTRACTS HEPATOLOGY, October, 2012 induce a switch from normal to cancerous microenvironment. It supports the importance of the presence of the SC in human PLC. Disclosures: The following people have nothing to disclose: Caecilia H. Sukowati, Beatrice Anfuso, Lory S. Crocé, Claudio Tiribelli

Page 1 of 9 (page number not for citation purposes) BMC Gastroenterology Research article Open Access Systematic review and meta-analysis on the adverse events of rimonabant treatment: Considerations for its potential use in hepatology Norberto C Chavez-Tapia*1, Felix I Tellez-Avila2, Giorgio Bedogni1, Lory S Crocè1,3, Flora Masutti1 and Claudio Tiribelli1,3 Address: 1Centro Studi Fegato (CSF) - Liver Research Center, Bldg Q - AREA Science Park-Basovizza Campus, Italy, 2Department of Gastroenterology Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México and 3Department ACADEM, University of Trieste, Italy Email: Norberto C Chavez-Tapia* - khavez@gmail.com; Felix I Tellez-Avila - felixtelleza@gmail.com; Giorgio Bedogni - giorgiobedogni@gmail.com; Lory S Crocè - l.croce@csf.units.it; Flora Masutti - fmasutti@csf.units.it; Claudio Tiribelli - ctliver@csf.units.it * Corresponding author Abstract Background: The cannabinoid-1 receptor blockers have been proposed in the management of obesity and obesity-related liver diseases (fatty liver as NAFLD or NASH). Due to increasing number of patients to be potentially treated and the need to assess the advantage of this treatment in terms of risk/benefit, we analyze the side events reported during the treatment with rimonabant by a systematic review and meta-analysis of all randomized controlled studies. Methods: All published randomized controlled trials using rimonabant versus placebo in adult subjects were retrieved. Relative risks (RR) with 95% confidence interval for relevant adverse events and number needed to harm was calculated. Results: Nine trials (n = 9635) were considered. Rimonabant 20 mg was associated with an increased risk of adverse event (RR 1.35; 95%CI 1.17-1.56), increased discontinuation rate (RR 1.79; 95%CI 1.35-2.38), psychiatric (RR 2.35; 95%CI 1.66-3.34), and nervous system adverse events (RR 2.35; 95%CI 1.49-3.70). The number needed to harm for psychiatric adverse events is 30. Conclusion: Rimonabant is associated with an increased risk of adverse events. Despite of an increasing interest for its use on fatty liver, the security profile and efficacy it is needs to be carefully assessed before its recommendation. At present the use of rimonabant on fatty liver cannot be recommended.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection is often associated with severe forms of liver disease. However, comprehensive studies are lacking, and scant information is available regarding the virological behavior over time in coinfected patients. This study enrolled 133 untreated HBV/HCV-positive patients (male/female = 102/31; median age 51 years [range: 22-83 years]) who were longitudinally followed up for 1 year with bimonthly evaluation of HBV/HCV viremia levels and liver biochemistry. Thirty of these patients had triple infection with hepatitis Delta virus (HDV), while 103 patients were HDV-negative. In the HDV-negative group, active infection with both HBV and HCV was revealed in 24 cases, inactive infection by both viruses was seen in 15 cases, active HBV/ inactive HCV was seen in 15 cases, and inactive HBV/active HCV was seen in 49 cases. However, 32 subjects (31%) presented dynamic virological profiles characterized by fluctuation of HBV and/or HCV viremia levels that at different time points were over or under the cutoff limits. Consequently, a correct diagnosis could be performed in these subjects only by serially repeating the virological tests 1 year apart. Similarly, 15 of the 30 HDV-positive subjects showed active HBV and/or HCV infection, with fluctuating virological patterns in 8 cases. In conclusion, this study showed that the virological patterns in HBV/HCV coinfection are widely divergent and have dynamic profiles. A careful longitudinal evaluation of the viremia levels of both viruses is essential for making a correct diagnosis and tailoring the appropriate therapeutic schedule in coinfected patients. Copyright © 2005 by the American Association for the Study of Liver Diseases.

Although a lot of novel information and data on the epidemiology of hepatitis C virus (HCV) infection are available worldwide, the majority of these information are often fragmentary and sometimes contradictory. This review tries to highlight all the data available on the prevalence (i.e. the number of cases present in a known population), the risk factors, the natural history and the incidence (i.e. the number of new cases that occur every year) of HCV infection in the world, and particularly in Italy.

The potential role of transfusion-transmitted virus (TTV) infection in determining liver damage is poorly understood and no information exists about TTV replication within hepatocytes. In this study, we assess TTV in situ PCR in liver tissue. Twenty-one patients with different degrees of liver damage were studied by both serum TTV-DNA detection and in situ TTV PCR analysis and extractive PCR in liver biopsy paraffin sections (FFPE). Extractive PCR and in situ PCR detected TTV-DNA both in serum and liver tissue of five patients. The presence of TTV in serum matched with that found in the liver and TTV sequences were never found independently in liver or serum. Four out of five TTV-DNA-positive patients have not other known cause of liver damage while in one a coinfection from HCV was observed. Our data indicate that in situ PCR appears to be a reliable tool for the detection of TTV-DNA in FFPE, and may help detecting unknown origin of liver damage.

Background: Although hepatic steatosis is seen with increasing frequency in clinical practice, its prevalence and risk factors are unknown. Objective: To investigate the prevalence of and risk factors for hepatic steatosis, such as alcohol consumption and obesity. Design: Cross-sectional, observational study. Setting: Participants in the Dionysos Study. Patients: 257 participants assigned to one of four categories (67 controls, 66 obese persons, 69 heavy drinkers, and 55 obese heavy drinkers). Measurements: Ethanol intake, assessed by a validated questionnaire and expressed as daily (g/d) and lifetime (kg) consumption, and body mass, expressed as body mass index. Biochemical tests of liver and metabolic function and hepatic ultrasonography were done. Results: The prevalence of steatosis was increased in heavy drinkers (46.4% [95% CI, 34% to 59%]) and obese persons (75.8% [CI, 63% to 85%]) compared with controls (16.4% [CI, 8% to 25%]). Steatosis was found in 94.5% (CI, 85% to 99%) of obese heavy drinkers. Compared with controls, the risk for steatosis was higher by 2.8-fold (CI, 1.4-fold to 7.1 -fold) in heavy drinkers, 4.6-fold (CI, 2.5-fold to 11.0-fold) in obese persons, and 5.8-fold (Cl, 3.2-fold to 12.3-fold) in persons who were obese and drank heavily. In heavy drinkers, obesity increased the risk for steatosis by twofold (CI, 1.5-fold to 3.0-fold) (P< 0.001), but heavy drinking was associated with only a 1.3-fold (Cl, 1.02-fold to 1.6-fold) increase in risk in obese persons (P = 0.0053). Elevated alanine aminotransferase and triglyceride levels are the most reliable markers of steatosis. Conclusions: Steatosis is frequently encountered in healthy persons and is almost always present in obese persons who drink more than 60 g of alcohol per day. Steatosis is more strongly associated with obesity than with heavy drinking, suggesting a greater role of overweight than alcohol consumption in accumulation of fat in the liver.

Background - The severity, clinical course, and risk of hepatitis C virus (HCV) related chronic liver disease are still rather poorly defined. Aims - To investigate the prevalence, risk factors, and severity of HCV related liver disease in the general population, and investigate whether infection with a specific genotype is associated with an increased risk of cirrhosis or hepatocellular carcinoma. Methods - HCV RNA determination by polymerase chain reaction (PCR) and HCV genotyping were performed in all anti-HCV positive subjects belonging to the Dionysos study (6917 subjects). Diagnosis of cirrhosis and hepatocellular carcinoma was established by liver biopsy in all cases. All the data were analysed by univariate and multivariate statistics in all the cohort. To investigate the natural history of HCV infection, anti-HCV positive subjects were followed up every six months for three years with liver function tests and ultrasonograms. Results - The overall prevalence of HCV RNA positivity was 2.3%. Positivity increased progressively with age, and was higher in women (ratio of men to women = 0.7). Genotypes 1b and 2a were the most frequent (42 and 24% of HCV RNA positive patients), with a prevalence of 1 and 0.6% respectively. Intravenous drug use, blood transfusions received before 1990, history of previous hepatitis among the cohabiting, and history of animal (mainly dogs) bites were significantly (p

Background/Aims Though hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors in the world, the optimal therapeutic strategy is still poorly defined. This is mainly due to geographic differences in HCC which may affect the validity of treatment regimens in differents areas of the world. The aim of the present study was to analyze the natural course of the disease as well as to assess the efficacy of different therapeutical schemes in HCC observed in Ljubljana (Slovenia) and Trieste (Italy), two cities in Western Europe situated close to each other. Methods: During the period from January 1988 to December 1993, 224 consecutive patients (132 in Trieste and 92 in Ljubljana) with HCC were enrolled in the study. Patients were treated with the following 3 schemes: surgery 39 (17.4%), transcatheter chemoembolization (TACE) 116 (51.8%), and no treatment 69 (30.8%). The tumor was classified by Okuda staging and the liver disease by Child-Pugh score. Patients were followed up for 12-60 months, with an average of 40 months. The response rate to TACE and recurrence following surgery were evaluated. Comparative analysis of survival between different treatment groups was performed. Results: The natural course of the disease, and other characteristics of the HCC, showed a typical Western type of tumor. Liver disease was scored as Child A in 58%, Child B in 30% and Child C in 12%, and the tumor was staged as Okuda I in 52%, Okuda II in 37% and Okuda III in 11%, respectively, Treatment with TACE was followed by an objective response in 27%, with a median survival of 31 months. Surgery was followed by a recurrence rate of 77% within 19.5 months and median survival of 49 months. The overall median survival of nontreated patients was 8 months. Survival in each group of patients differed significantly between all three consecutive stages of Okuda (p

Objective: To evaluate the frequency of p53 tumour suppressor gene and H- and K-ras oncogene mutations in both neoplastic and distant cirrhotic non-neoplastic tissue in Italian patients with hepatocellular carcinoma (HCC). Patients: Ten men and four women (mean age 62 +/-7 years) with HCC associated with cirrhosis, who underwent resection. More than half the patients had a lesion over 3 cm in diameter and in 12 cases carcinoma was well differentiated. Methods: Exons 4 to 9 of p53 and codons 12, 13 and 61 of the H- and K-ras genes were analyzed by the polymerase chain reaction-single strand conformation polymorphism method in both neoplastic and non-adjacent cirrhotic tissue and in cell lines harbouring known mutations as positive controls. Results: No aberrant migrating fragments were observed in tumoral and cirrhotic non-neoplastic tissue. Conclusion: Our findings suggest that p53 mutation is a rare occurrence in HCC, at least in countries with a low incidence of this cancer. They also confirm that H- and K-ras mutations are infrequent in HCC and play a minimal role in hepatocarcinogenesis.

In 1990, a case-control study was conducted in Italy to investigate the possible association between HCV infection and hepatocellular carcinoma (HCC). Serum samples from 65 subjects with newly diagnosed hepatocellular carcinoma and 99 hospital control subjects were tested for the presence of anti-HCV by second-generation ELISA test; positive sera were assayed by RIBA anti-HCV second-generation test. In addition, samples were tested for hepatitis B surface antigen (HBsAg), antibodies to the hepatitis B core antigen (anti-HBc), and antibodies to HBsAg (anti-HBs). The presence of HCV and/or HBsAg serologic markers was significantly associated with hepatocellular carcinoma risk: the relative risk (RR) of HCC was 21.3 (95% CI = 8.8-51.5) for anti-HCV positivity in the absence of HBsAg; the relative risk of HCC was 13.3 (95% CI = 5.5-32.2) for the presence of HBsAg in the absence of anti-HCV. A higher risk (77.0) was observed when both markers were present. These findings indicate that HCV and HBsAg are independent risk factors for HCC. The results of multivariate analysis showed that the adjusted RR linking anti-HCV and HCC was 26.9 (95% CI = 9.9-72.5), the adjusted RR linking HBsAg and HCC was 11.4 (95% CI = 3.1-41.4), whereas no association (RR 1.5; 95% CI = 0.6-3.6) was found to link HCC with anti-HBc and/or anti-HBs positivity. Through the computation of population attributable risk we estimate that 25% of HCC cases occurring in Italy could be attributed to anti-HCV positivity alone and 20% to HBsAg carrier state alone.(ABSTRACT TRUNCATED AT 250 WORDS)

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