Ombitasvir/paritaprevir/ritonavir & dasabuvir ± ribavirin following protease inhibitors failure - a prospective multi-centre trial.

BACKGROUND: Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with first generation protease inhibitors (PI) + peg-interferon (pegIFN) and ribavirin (RBV) achieved sustained virologic response (SVR) rates of 65-75% but was associated with multiple side effects. The aim of this study was to evaluate safety and efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (3D) ± RBV in HCV genotype 1 patients that failed previous treatment with first generation PIs. METHODS: An investigator-initiated, open-label, multi-centre clinical trial. HCV Genotype 1 patients who were previously null/partial responders or relapsers to telaprevir, boceprevir or simepravir+pegIFN/RBV and met eligibility criteria were included. 3D ± RBV were administrated for 12 or 24 weeks according to label. The primary outcome was antiviral response (SVR12); Secondary outcomes were patient reported outcomes, adverse events and resistance associated variants. RESULTS: Thirty-nine patients initiated treatment according to study protocol (59% men, age 54.0 ± 8.7 years, BMI 28.7 ± 4.5 kg/m2). Thirty-seven (94.9%) completed the study. Thirty-five patients had genotype 1b (9 cirrhotics) and 4 had genotype 1a (2 cirrhotics). Intention-to-treat SVR12 was 92.3% and per-protocol SVR12 was 97.3%. The rate of advanced fibrosis (FibroScan® score F3-4) declined from 46.2 to 25.7% (P = 0.045). Abnormal ALT levels declined from 84.6 to 8.6% (P < 0.001). Seven patients (17.9%) experienced serious adverse events (3 Psychiatric admissions, 1 pneumonia, 1 ankle fracture, 2 palpitations), and 12 patients (30.8%) experienced self-reported adverse events, mostly weakness. CONCLUSION: 3D ± RBV is safe and effective in achieving SVR among patients with HCV genotype 1 who failed previous first-generation PI treatment. TRIAL REGISTRATION: NCT02646111 (submitted to ClinicalTrials.gov, December 28, 2015).

68Ga-PSMA is a novel PET-CT tracer for imaging of hepatocellular carcinoma: A prospective pilot study.

Background:68Ga-Prostate Specific Membrane Antigen (68Ga-PSMA), a positron emission tomography (PET) tracer that was recently introduce for imaging of prostate cancer, may accumulate in other solid tumors including Hepatocellular Carcinoma (HCC). The aim of the study was to assess the potential role of 68Ga-PSMA PET-Computed Tomography (CT) for imaging of HCC. Material and Methods: A prospective pilot study in seven patients with HCC with 41 liver lesions: 37 suspected malignant lesions (tumor lesions) and 4 regenerative nodules. For each liver lesion, uptake of 68Ga-PSMA and 18F-FDG uptake were measured [standard uptake value (SUV) and lesion-to-liver background ratios (TBR-SUV)], and correlated with dynamic characteristics (HU and TBR-HU) obtained on contrast enhanced CT data. Immunohistochemistry staining of PSMA in the tumor tissue was analyzed in samples obtained from 5 patients with HCC and compared to control samples from 3 patients with prostate cancer. Results: Thirty-six of the 37 tumor lesions and none of the regenerative nodules showed increased 68Ga-PSMA uptake while only 10 lesions were 18F-FDG avid. Based on contrast enhancement, tumor lesions were categorized into 27 homogeneously enhancing lesions, nine lesions with "mosaic" enhancement composed of enhancing and non-enhancing regions in the same lesion and a single non-enhancing lesion, the latter being the only non-68Ga-PSMA avid lesion. Using the Mann-Whitney test, 68Ga-PSMA uptake was found significantly higher in enhancing tumor areas compared to non-enhancing areas and in contrast, 18F-FDG uptake was higher in non-enhancing areas, P<0.001 for both. 68Ga-PSMA uptake (TBR SUVmax) was found to correlate with vascularity (TBR-HU) (Spearman r=0.866, p<0.001). Immunohistochemistry showed intense intra-tumoral microvessel staining for PSMA in HCC, in contrast with cytoplasmic and membranous staining, mainly in the luminal border, in prostate cancer samples. In two of the study patients 68Ga-PSMA PET-CT identified unexpected extrahepatic metastases. Four regenerative liver nodules showed no increased uptake of either of the PET tracers. Conclusion:68Ga-PSMA PET-CT is superior to 18F-FDG PET-CT in imaging patients with HCC. HCC lesions are more commonly hypervascular taking up 68Ga-PSMA in tumoral micro-vessels. 68Ga-PSMA PET-CT is a potential novel modality for imaging patients with HCC.

Resection vs Transplant Listing for Hepatocellular Carcinoma: An Intention-to-Treat Analysis.

BACKGROUND: Liver transplantation (LT) and liver resection (LR) are curative treatment options for patients with hepatocellular carcinoma within the Milan criteria. Severe organ shortage dictates the preference for LR. Our aim was to provide an intention-to-treat retrospective comparison of survival between patients who were placed on waiting lists for LT and those who underwent LR. METHODS: The medical records of patients with hepatocellular carcinoma within the Milan criteria treated by LR or listed for LT between 2007 and 2016 were reviewed. We performed intention-to-treat analyses of overall survival and recurrence. RESULTS: There were 54 patients on the waiting list for LT, and 30 of them underwent LR. Thirteen of the 54 patients (24%) were not transplanted because of disease-related mortality or tumor progression. The median waiting time to transplantation was 304 days. The 90-day mortality was higher in transplanted patients (9.8% vs 3.3%, P = .003). Intention-to-treat survival was similar for the LT and LR groups (5-year survival, 47.8% vs 55%, respectively, P = .185). There was a trend toward improved 5-year disease-free survival for listed patients (56.2% vs 26.3% for patients undergoing LR, P = .15). CONCLUSION: Intention-to-treat survival is similar in patients undergoing LR and those on waiting lists for LT. There is a 24% risk to drop from the transplant list. The higher perioperative mortality among patients undergoing LT is balanced by a higher tumor recurrence rate after LR.

High frequency of multiclass HCV resistance-associated mutations in patients failing direct-acting antivirals: real-life data.

BACKGROUND: Direct-acting antiviral (DAA) therapy has dramatically increased sustained virological response rates in HCV-infected patients. However, resistance-associated substitutions (RAS) interfering with NS3- and NS5A-targeted therapy, still emerge. This real-life study analysed the type and frequency of RAS in rare cases of patients failing DAA regimens in 12 clinical centres in Israel. METHODS: Blood samples and clinical data from 49 patients who failed various DAAs were collected. RAS identified in the NS3 and NS5A regions by population (Sanger) and next-generation sequencing (NGS) were compared by treatment regimen and HCV subtypes. RESULTS: The majority (71.4%, 35/49) of patients were infected with the genotype (GT)1b strain, while 12.2% (6/49) carried GT1a and 14.3% GT3a/b (7), GT4a (1) and GT1b/GT3a. RAS were identified in 85.7% (42/49) of failures, of which 90.5% (38/42) were clinically relevant RAS (known to be associated with a specific GT and DAA in patients failing therapy or those with more than twofold change in in vitro replicon assays). The most abundant RAS were 168A/E/Q/G/N/V (32.6%, 16/49) identified in NS3, and 93H/N (61.2%, 30/49), 31I/M/V (34.7%, 17/49) and 30R/H/K (12.2%, 6/49), identified in NS5A. Significantly more clinically relevant RAS were identified in NS5A (82.2%, 37/45) than in NS3 (35.7%, 10/28; P<0.01). While RAS were identified in all GT1a, GT3b and GT4a failures (100%, 10/10), only 71.8% (28/39) of GT1b or GT3a failures had RAS (P=0.09). In four cases, NGS identified additional clinically relevant RAS and in one patient, NGS deciphered coexistence of GT3a and GT1b infections. CONCLUSIONS: Our findings, together with additional real-life data, will contribute to the optimization of retreatment in DAA failure, when cost-related and suboptimal regimens must be employed.

Role of colonoscopy in patients with persistent acute diverticulitis.

AIM: To identify patients with persistent acute diverticulitis who might benefit from an early colonoscopy during their first hospitalization. METHODS: All patients hospitalized between July 2000 and December 2006 for acute diverticulitis who underwent colonoscopy were included in the study. Patients were followed during hospitalization and after discharge. Patients were considered to have a persistent course of acute diverticulitis if symptoms continued after 1 wk of conventional treatment with IV antibiotics, or if symptoms recurred within 2 mo after discharge. Patients were considered to benefit from an early colonoscopy if the colonoscopy was therapeutic or if it changed a patient's outcome. RESULTS: Three hundred and six patients were hospitalized between July 2000 and December 2006 with the diagnosis of acute diverticulitis. Two hundred and twenty four of these were included in the study group. Twenty three patients (10.3%) fulfilled the criteria for a persistent course of acute diverticulitis. Of them, four patients (17.4%) clearly benefited from an early colonoscopy; these patients' clinical course is described. None of the patients with a regular non-persistent course demonstrated any benefit from colonoscopy. CONCLUSION: Early colonoscopy detected other significant pathology, which accounted for the clinical presentation in 17% of patients with persistent acute diverticulitis. Therefore, we believe an early colonoscopy should be considered in all patients with a persistent clinical course.

Diverticulitis in the young patient--is it different ?

AIM: To prospectively study the incidence and the natural history of acute diverticulitis in young patients. METHODS: A total of 207 patients hospitalized at our hospital between January 2000 to February 2005 with the diagnosis of acute diverticulitis were included. Their demographic characteristics, medical history, physical, radiographic and endoscopic findings as well as therapy were recorded. Patients were followed every 6 mo for the first year and later annually. RESULTS: The mean patients' age was 61 (range 27-92) years. Twenty-five patients (12%) were younger than 45 years. Acute diverticulitis was significantly more prevalent among male in the young age group as compared to the older age group (19/25, 76% vs 61/182, 33%, respectively, P = 0.0001). Complications occurred more often in the young age group; 32% vs 13%, (P = 0.002). During follow-up, 6 patients (28%) remained asymptomatic in the young age group as compared to 87 patients (55%) in the older age group (P = 0.024). As a result, sigmoidectomies were performed twice as often in the young age group (38% vs 13%, P = 0.002). CONCLUSION: Diverticulitis in young patients has a male predominance, a more aggressive course with a higher rate of complications and a higher recurrence rate. An earlier surgical approach might be considered in young patients with acute diverticulitis.

Adoptive transfer of NK 1.1+ lymphocytes in immune-mediated colitis: a pro-inflammatory or a tolerizing subgroup of cells?

UNLABELLED: T lymphocytes expressing NK1.1 marker (NKT) have been suggested to play crucial roles in immune modulation. AIM: To determine the role of NK1.1+ cells in induction and maintenance of pro-inflammatory and/or tolerizing responses. METHODS: Colitis was induced in C57/B6 donor mice by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS). Donor mice received five oral doses of colonic proteins extracted from TNBS-colitis colonic wall. Depletion of NK1.1+ lymphocytes was performed before lymphocyte harvesting. Splenocytes were harvested and separated into T-cell subpopulations, and transplanted into recipient mice before intracolonic instillation of TNBS. Standard clinical, macroscopic, and microscopic scores, and intracellular staining, flow cytometry, and cytotoxicity assays were performed. RESULTS: The adoptive transfer of CD4+ and NK1.1+ cells harvested from tolerized mice markedly ameliorated the colitis in recipient mice. In contrast, the adoptive transfer of CD8+ and double negative lymphocytes failed to transfer the tolerance. Recipients of splenocytes from tolerized mice exhibited an increase in CD4+ IL4+/CD4+ IFNgamma+ ratio. In contrast, recipients of splenocytes from NK1.1-depleted-tolerized mice exhibited severe colitis with a significant decrease of the CD4+ IL4+/CD4+ IFNgamma+ ratio. However adoptive transfer of splenocytes from non-tolerized NKT-depleted mice led to an alleviation of colitis with a relative increase of the CD4+ IL4+/CD4+ IFNgamma+ ratio. CONCLUSIONS: NK1.1+ lymphocytes play a critical role in immune regulation. They may be accountable for an alteration of the inflammatory response and the CD4+ IL4+/CD4+ IFNgamma ratio immune-mediated colitis and in peripheral tolerance induction.

Treatment of hepatocellular carcinoma: Steps forward but still a long way to go.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third cause of tumor associated deaths worldwide. HCC incidence rates are increasing in many parts of the world including developing and developed countries. Potentially curative treatments for HCC are resection and liver transplantation, but these are only suitable for patients with small tumors, meeting strict pre-defined criteria, or well-compensated liver disease. Early diagnosis of HCC can be achieved by surveillance of at-risk populations. For patients with non-resectable disease treatments modalities include loco-ablative and systemic therapies. In this review we focus on treatment options in HCC and their allocation. Although significant research is in progress, to this date, the results are unsatisfactory with limited long-term survival. In the fight against this deadly disease, there is still a long way to go.

Early expression of interferon gamma following oral antigen administration is associated with peripheral tolerance induction.

Oral tolerance is the induction of immune hyporesponsiveness to orally administered antigens. It was described in association with a decrease in interferon gamma (IFNgamma) production by activated T cells. To determine the role of IFNgamma and IL10 in immunemodulation via oral tolerization. Colitis was induced by intracolonic instillation of trinitrobenzene sulfonic acid. Treated mice received five oral doses of colitis-extracted proteins (CEPs) every other day, starting immediately after colitis induction. Control mice received similar doses of bovine serum albumin. Colitis was assessed in both groups by standard clinical, micro- and macroscopic scores. IFNgamma and IL10 expression in splenic lymphocytes from both groups was tested by RT-PCR immediately after oral feeding, 1, 4, 8, 12, and 24 h thereafter and then every 24 h for 2 weeks. Feeding of CEPs markedly ameliorated experimental colitis. These mice gained weight and showed markedly improved macro- and microscopic parameters of colitis. Tolerized mice exhibited IFNgamma expression in splenic lymphocytes starting immediately following oral CEP immunization and up to 14 d thereafter. IL10 was expressed starting 1 h after CEP feeding and during the first 48 h thereafter. In contrast, non-tolerized control mice manifested IFNgamma expression starting on day 6 and had no IL10 expression. Early induction of IFNgamma expression by oral antigen may be associated with systemic tolerance in the experimental colitis setting. In contrast, late expression of IFNgamma is associated with a pro-inflammatory response in non-tolerized controls.

Clinical manifestations of pyoderma gangrenosum associated with inflammatory bowel disease.

BACKGROUND: Pyoderma gangrenosum is an uncommon ulcerative cutaneous condition associated with inflammatory bowel disease. PG occurs rarely in IBD patients and there are insufficient data on the clinical manifestations of this disease with IBD. OBJECTIVE: To determine the incidence, clinical manifestations and treatment of PG in patients with IBD and the connection to IBD, its activity and extent. METHODS: All patients hospitalized with IBD at a university hospital during a 20 year period were evaluated for the occurrence of PG. RESULTS: Of 986 patients hospitalized for IBD 6 suffered from PG (0.6% incidence). Their average age was 37 with equal sex distribution and equal distribution of Crohn's disease and ulcerative colitis. PG appeared 6.5 years on average after diagnosis of IBD in all patients. The development of PG correlated with significant clinical exacerbation of IBD, the majority having active colitis at the onset of the PG. Extraintestinal manifestations of IBD occurred in half the patients (sacroillitis, peripheral arthritis and erythema nodosum). Pathergy was not elicited in any patients. Four patients had multiple skin lesions, frequently on the lower extremities. Diagnosis was made by skin biopsy in four patients. There was little correlation between amelioration of IBD and the skin lesions. Treatment consisted of high dose steroids and immunomodulatory drugs (cyclosporine, azathioprine and dapsone) in conjunction with topical treatment. CONCLUSIONS: PG is a rare extra-intestinal manifestation of IBD that coincides with the exacerbation of the intestinal disease but does not always respond to treatment of the bowel disease.

Autoimmune hepatitis in southern Israel: a 15-year multicenter study.

OBJECTIVE: In this study we aimed to assess the incidence, prevalence and clinical outcomes of patients with autoimmune hepatitis (AIH) in southern Israel. METHODS: Case-finding methods and population-based administrative data were used to evaluate the epidemiology and prognostic factors of AIH from 1995 to 2010. RESULTS: During the study period, the average annual prevalence and incidence of AIH in southern Israel were 11.0/100000 and 0.67/100000, respectively. We identified 100 AIH cases with a mean age of 47.9 years, including 95 women and five men. Type 1 AIH was found in 77 cases, and liver fibrosis and cirrhosis were found in 73.4% and 22.3% of all patients who underwent liver biopsy. In all, 98 patients were treated with a combination of steroids and azathioprine or steroids alone (prednisone and azathioprine in 71, budesonide and azathioprine in 11, prednisone or budesonide alone in six and ten, respectively). Complete remission was recorded in 56 patients, whereas partial response or failure of treatment was noted in 42 patients. In multivariate analysis the independent predictors of remission were the degree of liver fibrosis (mild vs bridging fibrosis (F3) and cirrhosis [F4]) (P=0.003) and level of albumin (P=0.031). The estimated 1-year and 10-year survival for AIH were 96.5% and 89.7%, respectively. CONCLUSIONS: The prevalence of AIH in Israel is quite similar to that of other European Caucasian populations, with a relatively long-term good prognosis, despite a low rate of response to immunosuppressive therapy.

Increasing the infliximab dose is beneficial in Crohn's disease patients who responded to a lower dose and relapsed.

BACKGROUND: Relapse after an initial response to infliximab therapy poses a problem for maintenance treatment. AIM: To assess the effects of increasing the infliximab dosage in Crohn's disease (CD) patients who initially responded but flared during maintenance therapy. METHODS: This was an observational study. Twelve CD patients with both inflammatory and fistulizing manifestations were included. All patients initially responded to 5 mg/kg of infliximab, relapsed during maintenance therapy, and were treated with 10 mg/kg. The Harvey-Bradshaw index, the fistula activity, and steroid use were assessed before and after treatment with the increased dose of infliximab. RESULTS: The mean Harvey-Bradshaw index score after flare-up during treatment with 5 mg/kg of infliximab was 13.5+/-3.7. Treatment with 10 mg/kg, in a mean of 3.3 infusions, decreased the activity score to a mean of 8.8+/-2.5. Two patients were weaned off prednisone, and a reduced dose was possible in the other steroid-treated patients. CONCLUSIONS: Increasing the infliximab dose may be beneficial in CD patients who initially responded to therapy, but relapsed during maintenance with the lower dosage.

Malignancy after liver transplantation in patients with premalignant conditions.

GOALS: Liver transplant recipients are at increased risk of developing nonhepatic malignant tumors. The aim of the current study was to evaluate the role of premalignant states, not associated with the liver disease prior to transplantation, in the development of posttransplantation malignancy. STUDY: One hundred seventy-five patients who had undergone liver transplantation were retrospectively evaluated for the development of malignant conditions. Each of the patients who developed malignancy following transplantation was evaluated for the presence of premalignant conditions before transplantation. RESULTS: Post-liver transplantation malignancy was identified in 13 patients (7.4%). Five patients developed non-Hodgkin lymphoma: four had posttransplantation lymphoproliferative diseases, and one had B cell lymphoma of the stomach. Eight patients developed solid tumors. In five of these patients, evidence of a premalignant state was identified: ulcerative colitis was diagnosed in 1 patient with carcinoma of the colon; colonic polyp, 1 patient with carcinoma of the colon; Barrett esophagus, 1 patient with esophageal carcinoma; Caroli disease, 1 patient with anaplastic cholangiocarcinoma; and cervical atypia, 1 patient with carcinoma of the cervix. CONCLUSIONS: Premalignant conditions existing before transplantation, which are not associated with the primary liver disease, are major risk factors for posttransplantation malignancy. Screening for premalignant conditions should be included in pretransplantation evaluation. Liver transplant patients with evidence of a premalignant state should be followed after transplantation for detection of malignancy.