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Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor. Currently, liver transplantation may be the optimal treatment for HCC in cirrhotic patients. Patient selection is currently based on tumor size. We developed a program to offer liver transplantation to selected patients with HCC outside of traditional criteria.Retrospective review for patients transplanted with HCC between April 2008 and June 2017. Patients were grouped by tumor size according to Milan, University of California San Francisco (UCSF), and outside UCSF criteria. Patient demographics, laboratory values, and outcomes were compared. Patients radiographically outside Milan criteria were selected based on tumor control with locoregional therapy (LRT) and 9 months of stability from LRT. α-fetoprotein values were not exclusionary.Two hundred twenty HCC patients were transplanted, 138 inside Milan, 23 inside UCSF, and 59 beyond UCSF criteria. Patient survival was equivalent at 1, 3, or 5 years despite pathologic tumor size. Waiting time to transplantation was not significantly different at an average of 344 days. In patients outside UCSF, tumor recurrence was equivalent to Milan and UCSF criteria recipients who waited9 months from LRT. Although tumor recurrence was more likely in outside of UCSF patients (3% versus 9% versus 15%; P = 0.02), recurrence-free survival only trended toward significance among the groups (P = 0.053).Selective patients outside of traditional size criteria can be effectively transplanted with equivalent survival to patients with smaller tumors, even when pathologic tumor burden is considered. Tumor stability over time can be used to help select patients for transplantation.

In patients with portal hypertension, ectopic varices can develop at any site along the gastrointestinal tract outside the classically described gastroesophageal location. Like esophageal variceal hemorrhage, bleeding from ectopic varices can be life-threatening. Diagnosis and treatment of ectopic varices can be challenging; to date, no effective treatment algorithm has been described. A systematic teamwork approach to diagnosing and treatment of ectopic varices is required to successfully manage hemorrhage from ectopic varices.

Data outside of clinical trials with direct-acting antiviral regimens with or without ribavirin as treatment of chronic hepatitis C virus in solid organ transplant recipients are limited. Liver transplant (LT), kidney transplant (KT), and dual liver kidney (DLK) transplant recipients from the Hepatitis C Therapeutic Registry and Research Network database, a multicenter, longitudinal clinical care treatment cohort, treated with direct-acting antiviral regimens between January 1, 2014, and February 15, 2016, were included to assess safety and efficacy. Included were 443 posttransplant patients (KT = 60, LT = 347, DLK = 36); 42% had cirrhosis, and 54% had failed prior antiviral therapy. Most had genotype (GT) 1 (87% with 52% GT1a, 27% GT1b, and 8% GT1 no subtype) and were treated with sofosbuvir (SOF)/ledipasvir ± ribavirin (85%) followed by SOF + daclatasvir ± ribavirin (9%) and ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (6%). Rates of sustained virologic response (SVR) at 12 weeks were available on 412 patients, and 395 patients (95.9%) achieved SVR at 12 weeks: 96.6%, 94.5%, and 90.9% among LT, KT, and DLK transplant recipients, respectively. Ribavirin did not influence SVR rates and was more often used in those with higher BMI, higher estimated glomerular filtration rate and lower creatinine. Female gender, baseline albumin ≥3.5 g/dL, baseline total bilirubin ≤1.2 mg/dL, absence of cirrhosis, and hepatic decompensation predicted SVR at 12 weeks. Six episodes of acute rejection (n = 2 KT, 4 LT) occurred, during hepatitis C virus treatment in 4 and after cessation of treatment in 2. Conclusion In a large prospective observational cohort study, direct-acting antiviral therapy with SOF/ledipasvir, ombitasvir/paritaprevir/ritonavir + dasabuvir, and SOF plus daclatasvir was efficacious and safe in LT, KT, and DLK transplant recipients; ribavirin did not influence SVR, and graft rejection was rare. (Hepatology 2017;66:1090-1101).

SummaryBackground Chronic hepatitis C virus therapy in patients with advanced liver disease remains a clinical challenge. HCV-TARGET collects data in patients treated at tertiary academic and community centres. Aim To assess efficacy of all-oral HCV therapy in advanced liver disease. Methods Between December 2013 and October 2014, 240 patients with a MELD score of ≥10 initiated HCV treatment with an all-oral regimen. Data from the 220 patients who completed 12-week follow-up were analysed. Results Genotype 1 (GT1) patients had higher sustained virological response (SVR) when treated with sofosbuvir plus simeprevir ± ribavirin than with sofosbuvir plus ribavirin (66–74% vs. 54%); GT1b vs GT1a (84% vs. 64%). SVR for GT2 was 72% with sofosbuvir plus ribavirin, while GT3 patients had a substantially lower response (35%). A decrease in MELD score was not clearly related to SVR over the short course of follow-up although some had improvements in MELD score, serum bilirubin and albumin. A predictor of virological response was albumin level while negative predictors were elevated bilirubin level and GT1a. Most patients with GT1 were treated with approximately 12-week duration of sofosbuvir and simeprevir ± ribavirin therapy while GT2 and GT3 patients were treated with approximately 12 and 24 weeks of sofosbuvir plus ribavirin respectively. Conclusions All-oral therapies are effective among patients with advanced liver disease with high levels of success in GT2 and GT1b, and may serve to reduce the severity of liver disease after SVR. Treatment for GT3 patients remains an unmet need. Clinical trial number: NCT01474811

Objective Due to a high efficacy in clinical trials, sofosbuvir (SOF) and ribavirin (RBV) for 12 or 16 weeks is recommended for treatment of patients with HCV genotype (GT) 2 infection. We investigated safety and effectiveness of these regimens for GT2 in HCV-TARGET participants. Design HCV-TARGET, an international, prospective observational study evaluates clinical practice data on novel antiviral therapies at 44 academic and 17 community medical centres in North America and Europe. Clinical data were centrally abstracted from medical records. Selection of treatment regimen and duration was the investigator9s choice. The primary efficacy outcome was sustained virological response 12 weeks after therapy (SVR12). Results Between December 2013 and April 2015, 321 patients completed 12 weeks (n=283) or 16 weeks (n=38) of treatment with SOF and RBV. Prior treatment experience and cirrhosis was more frequent among patients in the 16-week regimen compared with 12 weeks (52.6% vs 27.6% and 63.2% vs 21.9%, respectively). Overall, SVR12 was 88.2%. The SVR12 in patients without cirrhosis was 91.0% and 92.9% for 12 or 16 weeks of therapy, respectively. In patients with cirrhosis treated for 12 or 16 weeks, SVR12 was 79.0% and 83%. In the multivariate analysis, liver cirrhosis, lower serum albumin and RBV dose at baseline were significantly associated with SVR12. Common adverse events (AEs) included fatigue, anaemia, nausea, headache, insomnia, rash and flu-like symptoms. Discontinuation due to AEs occurred in 2.8%. Conclusions In this clinical practice setting, SOF and RBV was safe and effective for treatment of patients with HCV GT2 infection. Trial registration number NCT01474811.

In selected patients, locoregional therapy (LRT) has been successful in downstaging advanced hepatocellular carcinoma (HCC) so that the conventional criteria for liver transplantation (LT) can be met. However, the factors that predict successful treatment are largely unidentified. To determine these factors, we analyzed our experience with multimodal LRT in downstaging advanced HCC before LT in a retrospective cohort study. Thirty-two patients with advanced HCC exceeding conventional and expanded criteria for LT underwent therapy, but only those patients whose tumors were successfully downstaged were considered for LT. Eighteen patients (56%) had their tumors successfully downstaged; 14 patients (44%) did not. No intergroup differences existed with respect to patient characteristics or the types and number of treatments. However, mean alpha-fetoprotein levels were significantly higher in the non-downstaged group than in the downstaged group (P < 0.048), and significantly more patients in the non-downstaged group had infiltrative tumors (P = 0.0001). The median survival time was 42 and 7 months for the downstaged and non-downstaged groups, respectively (P = 0.0006). Fourteen patients (43.3%) underwent LT. After a median follow-up period of 35 months (range, 1.5-50 months) after LT, 2 patients (14.2%) developed tumor recurrence. The Kaplan-Meier survival rates after LT were 92% at 1 year and 75% at 2 years. The noninfiltrative expanding tumor type was the sole predictor of successful downstaging and improved outcome on univariate and multivariate analyses. Our study suggests that, in patients with advanced HCC, morphological characteristics of the tumor may predict a good response to downstaging and an improved outcome after LT.

Background & Aims The interferon-free regimen of simeprevir plus sofosbuvir was recommended by professional guidelines for certain patients with hepatitis C virus (HCV) genotype 1 infection based on the findings of a phase 2 trial. We aimed to evaluate the safety and efficacy of this regimen in clinical practice settings in North America. Methods We collected demographic, clinical, and virologic data, as well as reports of adverse outcomes, from sequential participants in HCV-TARGET—a prospective observational cohort study of patients undergoing HCV treatment in routine clinical care settings. From January through October 2014, there were 836 patients with HCV genotype 1 infection who began 12 weeks of treatment with simeprevir plus sofosbuvir (treatment duration of up to 16 weeks); 169 of these patients received ribavirin. Most patients were male (61%), Caucasian (76%), or black (13%); 59% had cirrhosis. Most patients had failed prior treatment with peginterferon and ribavirin without (46%) or with telaprevir or boceprevir (12%). The primary outcome was sustained virologic response (SVR), defined as the level of HCV RNA below quantification at least 64 days after the end of treatment (beginning of week 12 after treatment—a 2-week window). Logistic regression models with inverse probability weights were constructed to adjust for baseline covariates and potential selection bias. Results The overall SVR rate was 84% (675 of 802 patients, 95% confidence interval, 81%–87%). Model-adjusted estimates indicate patients with cirrhosis, prior decompensation, and previous protease inhibitor treatments were less likely to achieve an SVR. The addition of ribavirin had no detectable effects on SVR. The most common adverse events were fatigue, headache, nausea, rash, and insomnia. Serious adverse events and treatment discontinuation occurred in only 5% and 3% of participants, respectively. Conclusions In a large prospective observational cohort study, a 12-week regimen of simeprevir plus sofosbuvir was associated with high rates of SVR and infrequent treatment discontinuation. ClinicalTrials.gov: NCT01474811.

Aspergillus infection remains a significant and deadly complication after liver transplantation (LT). We sought to determine whether the antifungal prophylactic use of voriconazole reduces the incidence of invasive aspergillosis (IA) in high-risk LT recipients without prohibitively increasing cost. During the study era (April 2008 to April 2014), 339 deceased donor LTs were performed. Of those patients, 174 high-risk recipients were administered antifungal prophylaxis with voriconazole. The median biological Model for End-Stage Liver Disease score at the time of LT was 33 (range, 18-49) with 56% requiring continuous renal replacement therapy and 50% requiring ventilatory support immediately before transplantation. Diagnosis of IA was stratified as proven, probable, or possible according to previously published definitions. No IA was documented in patients receiving voriconazole prophylaxis. At 90 days after LT, the institutional cost of prophylaxis was $5324 or 5.6% of the predicted cost associated with post-LT aspergillosis. There was no documentation of resistant strains isolated from any recipient who received voriconazole. In conclusion, these data suggest that voriconazole prophylaxis is safe, clinically effective, and cost-effective in high-risk LT recipients.

International audience; BACKGROUND & AIMS:Boceprevir with peginterferon/ribavirin (BOC/PR) leads to significantly higher sustained virological response (SVR) rates in patients with chronic hepatitis C and partial response or relapse after prior treatment with peginterferon/ribavirin. We studied the efficacy of BOC/PR in patients with prior treatment failure, including those with a null response (2 weeks after end-of-treatment in the prior study received PR for 4 weeks before adding boceprevir.RESULTS:Of 168 patients enrolled, four discontinued from the PR lead-in and 164 received BOC/PR. Baseline viral load was >800,000 IU/ml in 77% of patients; 62% had HCV genotype 1a, and 10% were cirrhotic. In the ITT analysis (all 168 patients), SVR was achieved in 20 (38%) of 52 patients with prior null response, 57 (67%) of 85 with prior partial response, and 27 (93%) of 29 with prior relapse. In the mITT analysis (164 BOC/PR-treated patients), SVR rates were 41% (20/49), 67% (57/85), and 96% (27/28), respectively. SVR was achieved by 48% of patients with

Background: The diagnosis and management of biliary tract disorders in certain cases may be incomplete without direct visualization of the bile ducts. Methods: We report our experience of 61 choledochoscopies (33 women, 27 men, mean age 44.6 years). Twenty patients had previously undergone orthotopic liver transplantation. All except two choledochoscopies were performed via the transpapillary route. Indications included suspected large bile duct stones in 18 patients, anastomotic strictures in 16, abnormal cholangiograms in 5, elevated liver function tests in 7, suspected cholangiocarcinoma in 4, occluded biliary metallic stent in 4, hemobilia in 4, primary sclerosing cholangitis in 2 and ischemic bile duct injury in 1 patient. Results: Choledochoscopy confirmed the anticipated diagnosis in 36 of 61 (59%) patients. Importantly, it provided additional unsuspected diagnostic information in 18 of the 61 (29.5%) patients. In addition, for patients in whom standard cholangiography was deemed abnormal, choledochoscopy demonstrated normal results in 7 (11.4%) patients. Fifty-two choledochoscopies were performed with therapeutic intentions, and the procedure was helpful in providing targeted treatment in 27 (44.2%) patients. Conclusions: Choledochoscopy is a safe and useful endoscopic modality that can provide specific diagnoses and direct treatment in various biliary tract diseases. The additional information provided by choledochoscopy may change overall patient management and outcome. (Gastrointest Endosc 1999;50:67-73.)

Our aim was to evaluate the response to intraluminal gas in irritable bowel syndrome and to determine whether this response was consequent upon disordered motility or altered perception. We evaluated 10 patients who satisfied the clinical criteria for the diagnosis of irritable bowel syndrome and 10 healthy controls. An eight-lumen perfused catheter assembly was positioned to monitor motor activity in the duodenum and proximal jejunum; a separate side port in the distal duodenum permitted gas infusion. Subjects recorded symptoms of abdominal pain, bloating, and nausea throughout the study, using a visual analog scale. Following an overnight fast and a 60-min basal recording period in the fasted state, subjects ate a standard meal; 60 min later, “sham” gas was administered for 20 min, followed by the actual infusion of nitrogen gas at 40 ml/min. Subjects were randomized to receive atropine (7 µg/kg) or placebo intravenously during the period of actual gas infusion. Patients with irritable bowel syndrome described more pain (score, mean±se, control versus irritable bowel: 0.22±0.16 vs 1.65±0.5,P

Hepatocellular carcinoma (HCC) is increasing in incidence, resulting in approximately 35% of orthotopic liver transplantation (OLT) performed each year. Sorafenib (SOR) is a multi-kinase inhibitor that is approved for the treatment of unresectable HCC. Concerns have been raised regarding the safety of SOR in patients undergoing major surgery. We retrospectively reviewed 79 consecutive patients with HCC receiving OLT. Patient data were compared for those who received SOR pre-OLT with those who did not. SOR was continued until time of transplant. During this time period, 15 patients received SOR pre-OLT and 64 did not. The two groups were similar with regards to demographic and clinical data. SOR patients were more likely to have larger tumors, more tumor nodules, and be outside of Milan criteria. The rate of recurrence of HCC was not different between the groups (13% in SOR group, 11% in no-SOR group). Surgical complications were not increased in patients receiving SOR prior to OLT. Survival rate was also similar between the two groups (median follow-up 19.7 months). In this small cohort of patients, use of SOR prior to liver transplantation does not confer an increased risk of surgical complications, even when continued until the day of surgery.

Methods: Three hundred HCV patients and 860 family members were studied. All family members were screened for HCV antibodies by ELISA. Positive cases were examined using Real-Time PCR to confirm the presence of HCV-RNA. Seventy five patients of 300 were treated using SOC treatment. Molecular study of IL-28B gene was done to all patients and their families using PCR and restriction enzyme analysis. Results: IL-28B gene (rs12979860) polymorphism in patients was 27.43%, 55.43% and 17.14% for C/C, C/T and T/T genotypes respectively, in non infected family members was 37.38%, 44.05% and 18.57% for C/C, C/T and T/T respectively. There was significant increase as regard CC genotype in non-infected family members than patients. Of the treated 75 patients, 36 achieved SVR (48%). Better response to treatment was found in CC genotype (75%) than CT (48%) and TT (28.5%). Conclusions: CC genotype for IL-28B gene has better response to treatment and may have a protective role against HCV infection as it detected significantly in non infected family members of HCV patients. Acknowledgement: Project was funded by Science, Technology Development Fund (STDF), Egypt, Grant No. 1687.

Background Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. However, these regimens have not been adequately compared. Methods At 118 sites, patients who had HCV genotype 1 infection and who had not previously been treated were randomly assigned to undergo 48 weeks of treatment with one of three regimens: peginterferon alfa-2b at a standard dose of 1.5 μg per kilogram of body weight per week or a low dose of 1.0 μg per kilogram per week, plus ribavirin at a dose of 800 to 1400 mg per day, or peginterferon alfa-2a at a dose of 180 μg per week plus ribavirin at a dose of 1000 to 1200 mg per day. We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the standard-dose peginterferon alfa2b regimen and the peginterferon alfa-2a regimen. Results Among 3070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P = 0.20 for standarddose vs. low-dose peginterferon alfa-2b; P = 0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8% (95% confidence interval [CI], −2.3 to 6.0) between standard-dose and low-dose peg interferon alfa-2b and −1.1% (95% CI, −5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5% (95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0% (95% CI, 16.4 to 23.6) for lowdose peginterferon alfa-2b, and 31.5% (95% CI, 27.9 to 35.2) for peginterferon alfa2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively. Conclusions In patients infected with HCV genotype 1, the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferon– ribavirin regimens or between the two doses of peginterferon alfa-2b. (ClinicalTrials. gov number, NCT00081770.)

Liver biopsy is an important diagnostic tool in the management of patients following orthotopic liver transplant. We evaluated complications following percutaneous liver biopsy in a group of liver transplant patients who had Roux-en-Y choledochojejunostomies fashioned as part of their biliary reconstruction during liver transplantation. Complications were divided into two major groups: septic complications (including fever, symptomatic bacteremia, cholangitis, infected hematoma and hypotension related to sepsis) and bleeding (defined as hypotension requiring volume expansion greater than 500 cm3 or blood transfusion, hemothorax, intrahepatic or peritoneal hemorrhage and hemobilia occurring within 1 wk of liver biopsy). One hundred ninety-two biopsies were performed in 46 patients with choledochojejunostomies, and 118 biopsies were carried out in an age- and sex-matched control group of patients with choledochocholedochostomy biliary anastomosis. There were no septic complications in the choledochojejunostomy patients and one (0.32%) septic complication in the choledochocholedochostomy patients (NS). Eight bleeding complications occurred (2.6%) in eight patients (8.3%). Five (2.6%) occurred in five (10.8%) of the choledochojejunostomy patients, vs. three (2.5%) in three (6.5%) choledochocholedochostomy patients (NS). None of the bleeding complications required surgical intervention or was fatal. We conclude that liver biopsy in posttransplant patients with Roux-en-Y choledochojejunostomies is a safe procedure and that the incidences of complications were similar in our two groups. The negligible incidence of septic complications in the choledochojejunostomy patients does not appear to warrant the administration of prophylactic antibiotics, as has been previously suggested.

1University Henri Poincare of Nancy, Vandoeuvre-les-Nancy, France; 2South Florida Center of Gastroenterology, Wellington, FL; 3Northwestern Feinberg School of Medicine, Chicago, IL; 4Henry Ford Hospital, Detroit, MI; 5Alamo Medical Research, San Antonio, TX; 6University of British Columbia and Vancouver General Hospital, Vancouver, BC, Canada; 7Liver Specialists of Texas, Houston, TX; 8Virginia Commonwealth University School of Medicine, Richmond, VA; 9Mt. Vernon Endoscopy Center, Alexandria, VA; 10Weill Cornell Medical College, New York, NY; 11Universite Denis Diderot-Paris, Paris; 12Hopital Beaujon, Clichy, France; 13Duke University School of Medicine, Durham, NC; 14Cedars-Sinai Medical Center, Los Angeles, CA; 15Merck Sharp & Dohme Corp, Whitehouse Station, NJ; 16Baylor College of Medicine, Houston, TX

Our aim was to evaluate gastric emptying and orocecal transit in patients with end-stage liver disease and portal hypertension undergoing evaluation for liver transplantation. Although gastric emptying half-times for both liquid and solid emptying were similar in patients with chronic liver disease and control subjects, orocecal transit, as measured by a scintigraphic technique, was significantly prolonged in the patients with liver disease (transit time, minutes, mean +/- SEM, patients versus controls: 127 +/- 10.5 versus 80 +/- 9.5, P < .003). Serum levels of progesterone and estradiol were similar in patients and controls. We conclude that small intestinal transit is delayed in patients with advanced liver disease and portal hypertension and may contribute to gastrointestinal symptoms and promote sepsis of enteric origin in this patient population.