Introduction: Deleterious mutations associated with an increased risk of cancer are prevalent in the general population and remain undetected in the vast majority of patients until cancer develops. Hereditary cancer assessment is an important part of patient evaluation, especially upon initial presentation to a clinician. Customarily, specialists focus on family history specific to their specialty. Gynecologists and breast surgeons query patients about family history of breast and ovarian cancer (ie HBOC syndrome) while gastroenterologists & colorectal surgeons focus on Lynch syndrome. Recently, we broadened our cancer risk assessment in our GI population by utilizing the more broad NCCN guidelines rather than focusing on GI criteria. Methods: We employed a digital survey on a tablet using NCCN guidelines. The patients were presented with the tablet prior to being seen by the physician. If the survey indicated that the patient was at increased risk for hereditary cancer, further evaluation and possible testing was offered. Results: 2,239 patients were screened: 639 patients (29%) = high risk, 76% met HBOC criteria, 12% met Lynch criteria, and 12% both; 381 interested in genetic evaluation (60%), 374 were tested (98%): 27 were positive for deleterious mutations: 9 APC low penetrance (7 of 9 Ashkenazi Jewish - elevated colon cancer risk), 6 Monoallelic MUTYH, 3 ATM, 2 APC, 2 BRCA1, 2 BRCA2, 1 CHEK2, 1 PMS2, 1 RAD51D. 26/27 mutations (96%) with GI-related cancer risk - 3 single-site testing=24 mutations via panel testing & 23 (95.8%) with GI-related cancer risk. 14/23 (61%) had HBOC-related indications vs. 9 (39%) with Lynch indications. Overall, 18 mutations (67%) are GI-related genes (monoallelic MUTYH, APC low penetrance, APC & PMS2) - 2 were single-site testing, ie 16 mutations were identified by panel testing. 8/16 (50%) = HBOC-related indications & 8 (50%) were Lynch indications Conclusion: In an attempt to identify individuals with an increased risk of hereditary cancer in our practice, we expanded our assessment based on overall risk by utilizing NCCN guidelines rather than focused GI criteria. We detected 27 previously unidentified mutations in our population of 2239 screened patients. Expanding the survey questions to include HBOC risks and using panel testing, resulted in a 2.5 fold increase in the detection of GI related mutations. This experience suggests that hereditary risk assessment should address overall cancer risk and not be limited to focused assessment.

Antibiotics for presumed small intestinal bacterial overgrowth have been shown to improve irritable bowel syndrome symptoms in at least 40 % of subjects. A lactulose breath test for small intestinal bacterial overgrowth has been used to select patients who will respond. However, its predictive value, using the classic definition of a positive lactulose breath test, has been disappointing.

BACKGROUND AND STUDY AIMS:This was an observational, non-interventional, multicenter, phase IV study, in patients with genotype 1/4/5/6 chronic hepatitis C (CHC). The primary objectives were to evaluate SVR in patients with no or minimal fibrosis (METAVIR F0-F1) versus well established fibrosis (F2-F4), and to estimate response on Weeks 12, 24 and 48 on treatment in previously untreated patients with genotypes 1/4/5/6 CHC.PATIENTS AND METHODS:538 patients treated with pegylated interferon alfa 2b 1.5 mcg/kg in combination with ribavirin 800-1200 mg/day were enrolled in 55 sites in Belgium and Luxembourg, 505 being considered for the analysis. 40% of the patients were female and 60% male, the average age was 47.5 years, 10.5% were 65 or older.RESULTS:SVR was observed in 35% of the patients, EVR in 68%, of which pEVR in 33% and cEVR in 35%. SVR was observed in 43% of the low fibrosis group (F0, F1) and 30% of the high fibrosis group (F2, F3, F4) (p = 0.005). SVR rates were 34% for genotype 1, 37% for genotype 4, and 47% for genotype 5 (NS). Multivariate analysis showed that EVR and baseline METAVIR score are independent prognostic factors for SVR.CONCLUSIONS:This trial confirms that fibrosis stage and early viral response are the most important key-factors to predict sustained response, suggesting that the earlier patients are treated, the better the outcome. Non-invasive techniques enable us to closely monitor progression of fibrosis, allowing a better selection of patients for antiviral treatment in the DAA-era.

AIM:To compare responses to therapy of Black African (BA) and non-Black African (non- BA) patients with hepatitis C virus genotype 4 (HCV-4) residing in Belgium.METHODS:In this retrospective multicenter study, 473 patients with HCV-4 were selected from databases at 7 Belgian centers; 209 treatment-naive patients (154 BA) had received treatment with peg-interferon (peg-IFN) plus ribavirin (RBV) and were included in the study.RESULTS:There was a greater percentage of female patients in the BA group than in the non- BA group; BA patients were also older, had a greater body mass index, and more frequently had abnormal glucose metabolism. The route of contamination was more frequently unknown in BA than in non-BA patients and BA patients had more HCV-4 subtypes. There were no differences in other demographic factors between the groups. Sustained viral response (SVR) and complete early viral response rates were significantly lower and relapse rates significantly higher in BA than in non-BA patients. There were no differences between groups in rates of dose modification or in drug tolerance.CONCLUSION:In our cohort, treatment-naive BA patients with HCV-4 who were treated with peg-IFN and ribavirin had a much lower SVR rate than treatment-naive non-BA patients with HCV-4 who were treated with peg-IFN and ribavirin, and a higher relapse rate, possibly related to a weaker response to interferon-based therapy. Treatment may need to be adapted in this population.

Boceprevir (BOC) added to peginterferon alfa-2b (PegIFN) and ribavirin (RBV) significantly increases sustained virologic response (SVR) rates over PegIFN/RBV alone in previously untreated adults with chronic hepatitis C genotype 1. We evaluate the relationship of incident anemia with triple therapy. A total of 1,097 patients received a 4-week lead-in of PegIFN/RBV followed by: (1) placebo plus PegIFN/RBV for 44 weeks (PR48); (2) BOC plus PegIFN/RBV using response-guided therapy (BOC/RGT); and (3) BOC plus PegIFN/RBV for 44 weeks (BOC/PR48). The management of anemia (hemoglobin [Hb] <10 g/dL) included RBV dose reduction and/or erythropoietin (EPO) use. A total of 1,080 patients had 1 Hb measurement during treatment. The incidence of anemia was 50% in the BOC arms combined (363/726) and 31% in the PR48 arm (108/354, P < 0.001). Among BOC recipients, lower baseline Hb and creatinine clearance were associated with incident anemia. In the BOC-containing arms, anemia was managed by the site investigators as follows: EPO without RBV dose reduction, 38%; RBV dose reduction without EPO, 8%; EPO with RBV dose reduction, 40%; and neither RBV dose reduction nor EPO, 14%. SVR rates were not significantly affected by management strategy (70%-74%), and overall patients with anemia had higher rates of SVR than those who did not develop anemia (58%). Serious and life-threatening adverse events (AEs) and discontinuations due to AEs among BOC-treated patients did not differ by EPO use. Conclusion: With BOC/PR therapy, SVR rates in patients with incident anemia were higher than nonanemic patients and did not vary significantly according to the investigator-selected approach for anemia management. Prospective studies are needed to confirm this observation. (HEPATOLOGY 2013)

ABSTRACT HCV core antigen (Ag) and HCV RNA levels were evaluated in matched liver biopsy samples and sera from 22 patients with hepatitis C infection by using the quantitative Architect HCV Ag immunoassay and a real-time RT-qPCR assay, respectively. The data showed a strong correlation between liver and serum compartments of HCV Ag levels (r = 0.80) and HCV RNA levels (r = 0.87). In summary, the serum HCV Ag and RNA levels reflect the intrahepatic values.

PRESENTATIONSand randomized (1:1:1) to receive placebo (A); GS-9450, 10 mg QD (B); or GS-9450, 40 mg QD (C) for 24 weeks.The primary outcome was pre-specified histologic response (≥2-point decrease in Knodell necroinflammation score with no worsening in fibrosis score) between study groups from pre-treatment and Week 24 liver biopsies.Results: 307 subjects were randomized and treated [n = 103 (A), 101 (B), and 103 (C)].70% were male, 81% were Caucasian, mean age was 53, mean baseline (BL) ALT was 107 IU/mL, mean BL HAI and fibrosis scores were 8.0 and 2.8, and 9% were cirrhotic.Median ALT in GS-9450 groups improved at Week 4, with normalization in 46%, and was maintained through Week 20 in a majority.Adverse events led to treatment discontinuation in 1.9% (A), 5.0% (B) and 4.9% (C) of patients.During treatment, Grade 3 or 4 treatment emergent (TE) ALT elevations occurred in 6.8% (A), 5.0% (B), and 7.8% (C) of subjects.Notably, three subjects receiving GS-9450 developed marked simultaneous marked simultaneous ALT (7, 8, 28 × BL) and bilirubin (4.3, 6.8, 11.0 mg/dL) elevation by Week 8-12, and two others developed marked marked ALT elevation alone (11, 18 ×BL), resulting in study termination by the sponsor for possible drug-induced livery injury (DILI).Two placebo recipients also developed simultaneous elevation of ALT (2, 3 ×BL) and bilirubin (1.9, 3.3 mg/dL).50% of study subjects received study medication through Week 20, and 87 paired liver biopsies were obtained.Histologic improvement by pre-defined criteria occurred in 10/27 (37%), 5/28 (18%) and 5/32 (16%) of Group A, B, and C subjects, respectively.Conclusions: GS-9450 induced ALT improvement in patients with chronic HCV infection previously failing PEG/RBV, but was associated with presumptive DILI.The histology data do not support the concept of therapeutic caspase inhibition in chronic HCV infection.

Background: Liver allocation in Eurotransplant (ET) is based on the MELD score. Interlaboratory MELD score differences in INR and creatinine determination have been reported. The clinical implication of this observation has not been demonstrated.Methods: MELD scores were calculated in 66 patients with liver cirrhosis using bilirubin, creatinine, and INR analyzed in six liver transplant centers. Based on allocation results of ET, patients transplanted from December 2006 to June 2007 were divided according to MELD score in four groups. For each group, the influence of the match MELD on the probability of receiving a transplant was studied (Cox proportional hazards model).Results: Laboratory-dependent significant differences in MELD score were demonstrated. Cox proportional hazards model showed a significant association between MELD score and the probability of organ allocation. The unadjusted hazard ratio for receiving a liver transplant was significantly different between group 2 and group 4 (group 2: MELD 19-24; group 4: MELD > 30).Conclusion: Laboratory-dependent significant differences in MELD score were observed between the six transplant centers. We demonstrated a significant association between the MELD score and the probability of organ allocation. The observed interlaboratory variation might yield a significant difference in organ allocation in patients with high MELD scores.

b. Child-Pugh class A; c. performance status 0; d. tumor progressing after loco-regional therapies (resection, ablation, chemoembolization).Study period: 01

INTRODUCTION:Non-alcoholic Fatty Liver Disease (NAFLD) is increasingly recognised as a source of liver related morbidity and mortality. Hard data on epidemiology and natural history are scarce. AIM:To study demographic and metabolic characteristics of the NAFLD patients seen by Belgian hepatologists. METHODS:Belgian hepatologists filled in a questionnaire for every newly diagnosed NAFLD patient between January 1st and December 31st 2004. Liver biopsy was advised if ALT > 1.5 x ULN and if 3/5 of the criteria for the metabolic syndrome (MS) (ATPI-II) were present, but was not mandatory. Biopsy was scored using the Brunt classification. RESULTS:230 patients were prospectively included in 9 centres; 54% were males; mean age was 49.4 +/- 13.9 y; mean BMI was 30.6 +/- 4.6 kg/m2. The MS was present in 53%. In 16% formerly undiagnosed diabetes was discovered. 51% had a liver biopsy: 25% met the criteria, 26% did not. Grading did not differ between patients with or without MS. Staging was significantly more severe in patients with MS (2.43 +/- 1.25 vs. 1.73 +/- 1.18, p < 0.001). A subgroup of patients with GGT > 5 x ULN were significantly older (55.9 vs. 47.64 y, p = 0.02), more frequently diabetic (53% vs. 23%, p = 0.01) and had more advanced fibrosis (3.42 vs. 1.08, p = 0.008). ALT levels were variable. CONCLUSIONS:The MS is highly prevalent in Belgian NAFLD patients and is associated with more severe disease. Mild to moderate fibrosis is frequent, and the proposed criteria for liver biopsy are not accurate in selecting these patients. Patients with elevated GGT constitute a subgroup with more advanced disease.

BACKGROUND:Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.METHODS:We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.RESULTS:A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.CONCLUSIONS:The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.).

To assess liver fibrosis, we evaluated automated serum hyaluronic acid (HA) measurement alone or included in the Hepascore in 130 patients with different chronic liver diseases (CLD). We confronted HA with Fibrotest, and, when available, with transient elastography (Fibroscan) and liver biopsy used for liver fibrosis diagnosis. HA was the only biomarker showing difference between "advanced fibrosis" and "cirrhosis", Hepascore and Fibrotest being significantly different only between the groups "cirrhosis" and "lack of fibrosis" defined by Fibroscan or by biopsy. For cirrhosis, HA less than 65 ng/mL correctly identified non-cirrhotic patients in 96% of the cases while HA greater than 175 ng/mL correctly identified cirrhotic patients in 81% of the cases. For fibrosis, the cut-off of 115 ng/mL showed a positive predictive value of 90%. Here we demonstrate that HA alone or included in Hepascore reveals a good ability to detect all stages of CLD, especially to exclude cirrhosis from advanced fibrosis. HA assay might be used to evaluate liver fibrosis in complement to other non-invasive diagnostic markers. (C) 2011 Elsevier Masson SAS. All rights reserved.

Background and Aims: Insulin resistance (IR) plays an important role in various chronic liver diseases.In alcoholic liver disease (ALD), BMI and blood glucose have been identified as risk factors for fibrosis.However, the impact of IR in ALD is currently unknown.The aim of our study was to evaluate the relationship between IR and histological damage, portal hypertension and severity of liver disease in ALD.Patients and Methods: From April 2009 to September 2010, 103 consecutive patients with excessive alcohol intake (>40 g/day) undergoing transjugular liver biopsy for suspected liver disease were included in the study.IR was evaluated by homeostasis model assessment of insulin resistance (HOMA-IR).Patients with a history of diabetes or other cause of liver disease were excluded.Results: 103 patients (64% males, mean age 53.45±9.79years, mean BMI 25.41±5.38kg/m 2 , 69% with cirrhosis, 12% died within 6 months 40% had histological alcoholic hepatitis [AH], median MELD score 12.09 [7.99-20.18],median hepatic venous pressure gradient [HPVG] 13 [6-18] mmHg, median HOMA-IR 2.76 [1.33-5.29])were included with a median follow-up of 3 months.HOMA-IR showed a significant correlation with HVPG (r = 0.29 p = 0.004), BMI (r = 0.37, p < 0.001), INR (r = 0.20, p = 0.049) and platelets (r = -0.43,p < 0.001).Conversely, HOMA-IR was not correlated with steatosis, the presence and severity of AH or with the MELD score.A ROC curve analysis (AUC = 0.67, p = 0.005) showed that the optimal HOMA-IR cut-off to identify patients at risk of cirrhosis was 2.69 (sensitivity = 0.60, specificity = 0.69, positive and negative predictive value were 0.81 and 0.44 respectively).After adjustment for age, gender, BMI and presence of AH, HOMA-IR above 2.69 remained an independent predictor of cirrhosis (OR = 3.43, 95% CI = 1.97-10.96,p = 0.038).Moreover, this threshold was associated to a higher risk of 6 months' mortality (p = 0.043).Conclusions: In ALD, IR is correlated with the severity of portal hypertension.Furthermore, IR predicts 6 months' mortality and is independently associated to cirrhosis.IR may represent both a new predictor of severity and a new therapeutic target in ALD.

BACKGROUND AND STUDY AIMS:Large international clinical trials conducted in the past 5 years rapidly improved the treatment of chronic hepatitis C; however, it is unclear whether the advances seen in clinical trials are being paralleled by similar improvements in routine clinical practice. PegIntrust is a Belgian community-based trial evaluating the sustained virological response.PATIENTS AND METHODS:Observational study of 219 patients receiving pegylated interferon alfa-2b (1.5 microg/kg/wk) and weight-based ribavirin (800-1200 mg/day) for 48 weeks. Primary study end point was sustained virological response (SVR), defined as undetectable HCV RNA 6 months after the completion of treatment.RESULTS:In total, 108 patients (49.3 %) had undetectable HCV RNA at the end of therapy, 91 (41.6%) attaining SVR. Of the 111 patients without an end-of-treatment response, 28 were non-responders, and 21 had virological breakthrough. In total, 134 patients attained early virological response (EVR); 88 (65.7%) of those patients attained SVR. In contrast, 82 (96.5 %) of the 85 patients who did not attain EVR also did not attain SVR. Age, fibrosis score and baseline viral load were identified as important predictors of treatment outcome. The most frequently reported serious adverse events resulting in treatment discontinuation were anemia (n = 10), fatigue/asthenia/malaise (n = 6) and fever (n = 3).CONCLUSION:Our data indicate that treatment of chronic hepatitis C with PEG-IFN alfa-2b plus weight-based ribavirin results in favourable treatment outcomes in a Belgian cohort of patients treated in community-based clinical practice.

BACKGROUND/AIMS A large multicenter trial to compare the efficacy of peginterferon alfa-2a with interferon alfa-2a, in combination with ribavirin, in chronic hepatitis C patients. Efficacy data for prior relapsers are reported because treatment recommendations for this patient population are not well defined. PATIENTS AND METHODS This study was a multicenter, prospective, randomized clinical trial. The primary efficacy endpoint was sustained virologic response in naive patients (n = 348) and relapsers (n = 95). RESULTS Sustained virologic response rates were similar in naïve patients and relapsers, both for non-pegylated and pegylated interferon (respectively 27 and 26% and 54 and 43%). Pegylated interferon given for 48 weeks did not improved the relapse rate: 15.9 and 27.3% for non-pegylated and 16.7 and 30.4% for pegylated interferon, naïve vs relapsers respectively. Stepwise logistic regression analysis revealed a significant association between slow response (detectable HCV RNA at week 12 and undetectable at week 24) and relapse in patients with an end-of-treatment response (55% versus 13% respectively; p = 0.02; odds ratio = 6.07). CONCLUSIONS This trial confirms the value of using peginterferon alfa-2a in both naïve and relapsed patients and provides support for a more tailored approach to treatment for relapsers and particulary for patients with a slow viral response.

Conclusions:1.This group of compensated liver cirrhosis did not present increased IP, increased endotoxaemia, or altered duodenal histology.2. Presence of portal hypertension was not related to increased IP. 3. Cirrhotics presented higher levels of circulating interleukins, not explained by increased IP or by increased endotoxaemia.