Intraductal endoscopic radiofrequency ablation for the treatment of hilar non-resectable malignant bile duct obstruction

AIM: To evaluate the safety and technical success of endoscopic radiofrequency ablation(RFA) for palliative treatment of malignant hilar bile duct obstruction. METHODS: In this study, a recently CE and FDA-approved endoscopic RFA catheter was first tested in an ex vivo pig liver model to study the effect of electrosurgical variables on the extent of the area of induced necrosis. Subsequently, a retrospective analysis was conducted of all patients treated with endoscopic RFA for malignant biliary obstruction at our center between February 2012 and April 2013. All patients received an additional plastic stent implantation into the biliary tree following RFA. RESULTS: In the pig model, ablation time of 60-90 seconds using the bipolar soft coagulation mode at 8-10 watts with an effect of 8 was found to be the most feasible setting. Twelve patients(5 females, 7 males; mean age, 70 years) underwent 19 endoscopic RFA(range, 1-5) sessions. Deployment of RFA was successful in all patients. Systemic chemotherapy was administered in four patients. We observed biliary bleeding 4-6 wk after the intervention in three cases and two of these patients died: in one patient, spontaneous hemobilia occurred, whereas bleeding started during stent extraction in the other. In the third patient, bleeding was stopped by insertion of a non-covered self-expanding metal stent. Another three patients developed cholangitis during follow-up. Seven patients died during follow-up and median survival was 6.4 mo(95%CI: 0.05-12.7) from the time of the first RFA. CONCLUSION: Endoscopic RFA is an easy to perform and technically highly successful procedure. However, hemobilia possibly associated with RFA occurred in three of our patients. Therefore, larger prospective studies are needed to further evaluate the safety and efficacy of this promising new method.

Influence of antibiotic-regimens on intensive-care unit-mortality and liver-cirrhosis as risk factor

AIM: To assess the rate of infection, appropriateness of antimicrobial-therapy and mortality on intensive care unit(ICU). Special focus was drawn on patients with liver cirrhosis.METHODS: The study was approved by the local ethical committee. All patients admitted to the Internal Medicine-ICU between April 1, 2007 and December 31, 2009 were included. Data were extracted retrospectively from all patients using patient charts and electronic documentations on infection, microbiological laboratory reports, diagnosis and therapy. Due to the large hepatology department and liver transplantation center, special interest was on the subgroup of patients with liver cirrhosis. The primary statistical-endpoint was the evaluation of the influence of appropriate versusinappropriate antimicrobial-therapy on in-hospitalmortality.RESULTS: Charts of 1979 patients were available. The overall infection-rate was 53%. Multiresistantbacteria were present in 23% of patients with infection and were associated with increased mortality(p < 0.000001). patients with infection had significantly increased in-hospital-mortality(34% vs 17%, p < 0.000001). Only 9% of patients with infection received inappropriate initial antimicrobial-therapy, no influence on mortality was observed. Independent risk-factors for in-hospital-mortality were the presence of septicshock, prior chemotherapy for malignoma and infection with pseudomonas spp. Infection and mortality-rate among 175 patients with liver-cirrhosis was significantly higher than in patients without liver-cirrhosis. Infection increased mortality 2.24-fold in patients with cirrhosis. patients with liver cirrhosis were at an increased risk to receive inappropriate initial antimicrobial therapy.CONCLUSION: The results of the present study report the successful implementation of early-goal-directed therapy. Liver cirrhosis patients are at increased risk of infection, mortality and to receive inappropriate therapy. Increasing burden are multiresistant-bacteria.

Assessment of hemostatic profile in patients with mild to advanced liver cirrhosis

BACKGROUND Hemostasis of patients suffering from liver cirrhosis is challenging due to both,pro-and anticoagulatory disorders leading to hemostatic alterations with distinct abnormalities of coagulation.Pathological changes in conventional coagulation analysis and platelet count are common manifestations of decreased liver synthesis of coagulation factors and reduced platelet count in these patients.However,conventional coagulation analysis and platelet count do not reflect invivo coagulation status or platelet function.The purpose of this present observational study was therefore to assess the haemostatic profile including plasmatic coagulation using thrombelastometry and impedance aggregometry for platelet function in patients suffering from liver cirrhosis.AIM To assess the hemostatic profile of cirrhotic patients according to model for endstage liver disease(MELD)score.METHODS Our study included both in-and outpatients suffering from liver cirrhosis attending the out-and inpatient care of the department of hepatology.Demographic and biochemical data as well as medical history including cause of liver cirrhosis,end stage kidney failure and medication with anticoagulants were recorded.To assess the hemostatic profile,platelet function was analyzed by multiple electrode aggregometry(MEA)using Multiplate^■(ADP-,ASPI-and TRAP-test)and thrombelastometry using ROTEM^■(EXTEM,INTEM,FIBTEM).Data were compared using Mann-Whitney U-or χ^2-test.Spearman correlation was performed to analyze the association between MELD Score and results of thrombelastometry and MEA.RESULTS A total of 68 patients attending the out-and inpatient care suffering from liver cirrhosis were screened.Of these,50 patients were included and assigned to groups according to MELD score 6 to 11(n=25)or≥17(n=25).Baseline patient characteristics revealed significant differences for MELD score(8 vs 22,P<0.0001)and underlying laboratory parameters(international normalized ratio,bilirubine,creatinine)as well as fibrinogen level(275 mg/dL vs 209 mg/dL,P=0.006)and aPTT(30 s vs 35 s,P=0.047).MEA showed a moderately impaired platelet function(medians:AUCADP=43U,AUCASPI=71U,AUCTRAP=92U)but no significant differences between both groups.Thrombelastometry using ROTEM?(EXTEM,INTEM,FIBTEM)revealed values within normal range in both groups.No significant correlation was observed between MELD score and results of MEA/thrombelastometry.CONCLUSION Our data demonstrate a partially impaired hemostatic profile in liver cirrhosis patients unrelated to MELD score.An individual assessment of a potential coagulopathy should therefore be considered.

SEMS vs cSEMS in duodenal and small bowel obstruction:High risk of migration in the covered stent group

AIM:To compare clinical success and complications of uncovered self-expanding metal stents(SEMS)vs covered SEMS(cSEMS)in obstruction of the small bowel.METHODS:Technical success,complications and outcome of endoscopic SEMS or cSEMS placement in tumor related obstruction of the duodenum or jejunum were retrospectively assessed.The primary end points were rates of stent migration and overgrowth.Secondary end points were the effect of concomitant biliary drainage on migration rate and overall survival.The data was analyzed according to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.RESULTS:Thirty-two SEMS were implanted in 20 patients.In all patients,endoscopic stent implantation was successful.Stent migration was observed in 9 of16 cSEMS(56%)in comparison to 0/16 SEMS(0%)implantations(P=0.002).Stent overgrowth did not significantly differ between the two stent types(SEMS:3/16,19%;cSEMS:2/16,13%).One cSEMS dislodged and had to be recovered from the jejunum by way of laparotomy.Time until migration between SEMS and cSEMS in patients with and without concomitant biliary stents did not significantly differ(HR=1.530,95%CI0.731-6.306;P=0.556).The mean follow-up was 57±71 d(range:1-275 d).CONCLUSION:SEMS and cSEMS placement is safe in small bowel tumor obstruction.However,cSEMS is accompanied with a high rate of migration in comparison to uncovered SEMS.

FibroSURE^(TM) and FibroScan~ in relation to treatment response in chronic hepatitis C virus

AIM:To compare histological endpoint assessment using noninvasive alternatives to biopsy during treatment in a chronic hepatitis C virus(HCV)cohort.METHODS:Patients with chronic HCV were randomized to receive interferon-based therapy for 24(genotypes 2/3)or 48(genotype 1)wk.FibroSURE～TM(FS)was assessed at baseline and at week-12 post-treatment follow-up.Baseline biopsy for METAVIR was assessed by a single pathologist.FibroScan～ transient elastogra-phy(TE)was performed during treatment in a patient subset.RESULTS:Two thousand and sixty patients(n = 253 in Asia)were classif ied as METAVIR F0-1(n = 1682)or F2-4(n = 378).For F2-4,FS(n = 2055)had sensitiv-ity and specif icity of 0.87 and 0.61,respectively,with area under the receiver-operating curve of 0.82;corre-sponding values for TE(n = 214)and combined FS/TE(n = 209)were 0.77,0.88 and 0.88,and 0.93,0.68 and 0.88.Overall FS/TE agreement for F2-4 was 71%(κ = 0.41)and higher in Asians vs non-Asians(κ = 0.86 vs 0.35;P < 0.001).Combined FS/TE had 97% accuracy in Asians(n = 33).Baseline FS(0.38 vs 0.51,P < 0.001)and TE(8.0 kPa vs 11.9 kPa,P = 0.006)scores were lower in patients with sustained virological response than in nonresponders,and were maintained through follow-up.CONCLUSION:FS and TE may reliably differentiate mild from moderate-advanced disease,with a potential for high diagnostic accuracy in Asians with chronic HCV.

Concise review: Interferon-free treatment of hepatitis C virus-associated cirrhosis and liver graft infection

Chronic hepatitis C is a major reason for development of cirrhosis and hepatocellular carcinoma and a leading cause for liver transplantation. The development of direct-acting antiviral agents lead to(pegylated) interferon-alfa free antiviral therapy regimens with a remarkable increase in sustained virologic response(SVR) rates and opened therapeutic options for patients with advanced cirrhosis and liver graft recipients. This concise review gives an overview about most current prospective trials and cohort analyses for treatment of patients with liver cirrhosis and liver graft recipients. In patients with compensated cirrhosis Child-Pugh-Turcotte(CTP) class A, all approved agents are safe and SVR rates do not significantly differ from patients without cirrhosis in general. In patients with decompensated cirrhosis CTP class B or C, daclastasvir, ledipasvir, velpatasvir, and sofosbuvir are approved, and SVR rates higher than 90% can be achieved. Especially for patients with a model of end stage liver disease score higher than 15 and therefore eligible for liver transplantation, data is scarce. Reported SVR rates in patients with cirrhosis CTP class C are lower compared to patients with a less severe liver disease. In liver transplant recipients with a maximum of CTP class A, SVR rates are comparable to patients without LT. Patients with decompensated graft cirrhosis should be treated on an individual basis.

Severe infection with multidrug-resistant Salmonella choleraesuis in a young patient with primary sclerosing cholangitis

Massive global spread of multidrug-resistant(MDR) Salmonella spp. expressing extended-spectrum beta-lactamase(ESBL) and additional resistance to fluoroquinolones has often been attributed to high international mobility as well as excessive use of oral antibiotics in livestock farming. However, MDR Salmonella spp. have not been mentioned as a widespread pathogen in clinical settings so far. We demonstrate the case of a 25-year-old male with primary sclerosing cholangitis who tested positive for MDR Salmonella enterica serotype Choleraesuis expressing ESBL and fluoroquinolone resistance. The pathogen was supposedly acquired during a trip to Thailand, causing severe fever, cholangitis andpancreatitis. To our knowledge, this is the first report of Salmonella enterica serotype Choleraesuis in Europe expressing such a multidrug resistance pattern. ESBL resistance of Salmonella enterica spp. should be considered in patients with obstructive biliary tract pathology and travel history in endemic countries.

Daclatasvir vs telaprevir plus peginterferon alfa/ribavirin for hepatitis C virus genotype 1

AIM: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin(peg IFN/RBV), in treatment-naive hepatitis C virus(HCV) genotype(GT) 1-infected patients.METHODS: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned(2:1) to daclatasvir vs telaprevir, stratified by IL28 B rs12979860 host genotype(CC vs non-CC), cirrhosis status(compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype(GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus peg IFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus peg IFN/RBV; those without an extended rapid virologic response(e RVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of peg IFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus peg IFN/RBV followed by 12(with e RVR) or 36(no e RVR) wk of peg IFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12(SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia(hemoglobin < 10 g/d L) and rashrelated events, through week 12, were lower with daclatasvir + peg IFN/RBV than with telaprevir + peg IFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5 A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/m L, to investigate any link between NS5 A polymorphisms associated with daclatasvir resistance and virologic outcome. RESULTS: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups(6.0% and 8.2% in the GT1 b and GT1 a groups, respectively) than in the telaprevir groups(2.2% and 3.0%). Among GT1 binfected patients, daclatasvir plus peg IFN/RBV was noninferior to telaprevir plus peg IFN/RBV for SVR12 [85%(228/268) vs 81%(109/134); difference, 4.3%(95%CI:-3.3% to 11.9%)]. Anemia(hemoglobin < 10 g/d L) was significantly less frequent with daclatasvir than with telaprevir [difference,-29.1%(95%CI:-38.8% to-19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1 ainfected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28 B non-CC and cirrhosis- factors known to affect response to peg IFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients d e m o n s t ra t e d t h a t S V R 1 2 wa s a s s o c i a t e d w i t h IL28 B host genotype(CC vs non-CC, P = 0.011) and cirrhosis status(absent vs present, P = 0.031). NS5 A polymorphisms associated with daclatasvir resistance(at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4%(229/268) in the daclatasvir group, and by 85.1%(114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2%(90/134) and 69.7%(46/66), respectively. Discontinuations(of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria. CONCLUSION: Daclatasvir plus peg IFN/RBV demonstrated noninferiority to telaprevir plus peg IFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1 binfected patients, supporting the use of daclatasvir with other direct-acting antivirals.

Eosinophilic cholangitis is a potentially underdiagnosed etiology in indeterminate biliary stricture

AIM To investigate presence and extent of eosinophilic cholangitis(EC) as well as Ig G4-related disease in patients with indeterminate biliary stricture(IBS).METHODS All patients with diagnosis of sclerosing cholangitis(SC) and histopathological samples such as biopsies or surgical specimens at University Hospital Frankfurt from 2005-2015 were included. Histopathological diagnoses as well as further clinical course were reviewed. Tissue samples of patients without definite diagnosis after complete diagnostic work-up were reviewed regardingpresence of eosinophilic infiltration and Ig G4 positive plasma cells. Eosinophilic infiltration was as well assessed in a control group of liver transplant donors and patients with primary sclerosing cholangitis.RESULTS One hundred and thirty-five patients with SC were included. In 10/135 (13.5%) patients, no potential cause of IBS could be identified after complete diagnostic work-up and further clinical course. After histopathological review, a post-hoc diagnosis of EC was established in three patients resulting in a prevalence of 2.2% (3/135) of all patients with SC as well as 30%(3/10) of patients, where no cause of IBS was identified. 2/3 patients with post-hoc diagnosis of EC underwent surgical resection with suspicion for malignancy. Diagnosis of Ig G4-related cholangitis was observed in 7/135 patients (5.1%), whereas 3 cases were discovered in post-hoc analysis. 6/7 cases with Ig G4-related cholangitis (85.7%) presented with eosinophilic infiltration in addition to Ig G4 positive plasma cells. There was no patient with eosinophilic infiltration in the control group of liver transplant donors (n=27) and patients with primary sclerosing cholangitis(n = 14).CONCLUSION EC is an underdiagnosed benign etiology of SC and IBS, which has to be considered in differential diagnosis of IBS.

Elevated plasma levels of N-terminal pro-brain natriuretic peptide in patients with chronic hepatitis C during interferon-based antiviral therapy

AIM: To investigate plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), an established marker of cardiac function, in patients with chronic hepatitis C during interferon-based antiviral therapy. METHODS: Using a sandwich immunoassay, plasma levels of NT-proBNP were determined in 48 patients with chronic hepatitis C at baseline, wk 24 and 48 during antiviral therapy and at wk 72 during follow-up.RESULTS: Plasma NT-proBNP concentrations were significantly increased (P < 0.05) at wk 24, 48 and 72 compared to the baseline values. NT-proBNP concentrations at baseline and wk 24 were closely correlated (r = 0.8; P < 0.001). At wk 24, 7 (14.6%) patients had NT-proBNP concentrations above 200 ng/L compared to 1 (2%) patient at baseline (P = 0.059). Six of these 7 patients had been treated with high-dose IFN-α induction therapy. In multiple regression analysis, NT-proBNP was not related to other clinical parameters, biochemical parameters of liver disease or virus load and response to therapy.CONCLUSION: Elevated levels of NT-proBNP during and after interferon-based antiviral therapy of chronic hepatitis C may indicate the presence of cardiac dysfunction, which may contribute to the clinical symptoms observed in patients during therapy. Plasma levels of NT-proBNP may be used as a diagnostic tool and for guiding therapy in patients during interferon-based antiviral therapy.