Torsten Voigtländer

Endoscopic closure of esophageal intrathoracic leaks: stent versus endoscopic vacuum-assisted closure, a retrospective analysis

BACKGROUND AND STUDY AIM Placement of covered self-expanding metal or plastic stents (SEMS or SEPS) is an established method for managing intrathoracic leaks. Recently, endoscopic vacuum-assisted closure (EVAC) has been described as a new effective treatment option. Our aim was to compare stent placement with EVAC for nonsurgical closure of intrathoracic anastomotic leaks. PATIENTS AND METHODS In a retrospective analysis we were able to identify 39 patients who were treated with SEMS or SEPS and 32 patients who were treated with EVAC for intrathoracic leakage. In addition to successful fistula closure, we analyzed hospital mortality, number of endoscopic interventions, incidence of stenoses, and duration of hospitalization. RESULTS In a multivariate analysis, successful wound closure was independently associated with EVAC therapy (hazard ratio 2.997, 95 % confidence interval [95 %CI] 1.568 - 5.729; P = 0.001). The overall closure rate was significantly higher in the EVAC group (84.4 %) compared with the SEMS/SEPS group (53.8 %). No difference was found for hospitalization and hospital mortality. We found significantly more strictures in the stent group (28.2 % vs. 9.4 % with EVAC, P < 0,05). CONCLUSIONS EVAC is an effective endoscopic treatment option for intrathoracic leaks and showed higher effectiveness than stent placement in our cohort.

MicroRNAs in Serum and Bile of Patients with Primary Sclerosing Cholangitis and/or Cholangiocarcinoma

Background and Aim Patients with primary sclerosing cholangitis (PSC) are at high risk for the development of cholangiocarcinoma (CC). Analysis of micro ribonucleic acid (MiRNA) patterns is an evolving research field in biliary pathophysiology with potential value in diagnosis and therapy. Our aim was to evaluate miRNA patterns in serum and bile of patients with PSC and/or CC. Methods Serum and bile from consecutive patients with PSC (n = 40 (serum), n = 52 (bile)), CC (n = 31 (serum), n = 19 (bile)) and patients with CC complicating PSC (PSC/CC) (n = 12 (bile)) were analyzed in a cross-sectional study between 2009 and 2012. As additional control serum samples from healthy individuals were analyzed (n = 12). The miRNA levels in serum and bile were determined with global miRNA profiling and subsequent miRNA-specific polymerase chain reaction-mediated validation. Results Serum analysis revealed significant differences for miR-1281 (p = 0.001), miR-126 (p = 0.001), miR-26a (p = 0.001), miR-30b (p = 0.001) and miR-122 (p = 0.034) between patients with PSC and patients with CC. All validated miRNAs were significantly lower in healthy individuals. MiR-412 (p = 0.001), miR-640 (p = 0.001), miR-1537 (p = 0.003) and miR-3189 (p = 0.001) were significantly different between patients with PSC and PSC/CC in bile. Conclusions Patients with PSC and/or CC have distinct miRNA profiles in serum and bile. Furthermore, miRNA concentrations are different in bile of patients with CC on top of PSC indicating the potential diagnostic value of these miRNAs.

Human CCR4+CCR6+Th17 Cells Suppress Autologous CD8+ T Cell Responses

The role of Th17 cells in cancer patients remains unclear and controversial. In this study, we have analyzed the phenotype of in vitro primed Th17 cells and further characterized their function on the basis of CCR4 and CCR6 expression. We show a novel function for a subset of IL-17–secreting CD4+ T cells, namely, CCR4+CCR6+Th17 cells. When cultured together, CCR4+CCR6+Th17 cells suppressed the lytic function, proliferation, and cytokine secretion of both Ag-specific and CD3/CD28/CD2-stimulated autologous CD8+ T cells. In contrast, CCR4−CCR6+ CD4+ T cells, which also secrete IL-17, did not affect the CD8+ T cells. Suppression of CD8+ T cells by CCR4+CCR6+Th17 cells was partially dependent on TGF-β, because neutralization of TGF-β in cocultures reversed their suppressor function. In addition, we also found an increase in the frequency of CCR4+CCR6+, but not CCR4−CCR6+ Th17 cells in peripheral blood of hepatocellular carcinoma patients. Our study not only underlies the importance of analysis of subsets within Th17 cells to understand their function, but also suggests Th17 cells as yet another immune evasion mechanism in hepatocellular carcinoma. This has important implications when studying the mechanisms of carcinogenesis, as well as designing effective immunotherapy protocols for patients with cancer.

Secondary sclerosing cholangitis in critically ill patients: model of end-stage liver disease score and renal function predict outcome.

Secondary sclerosing cholangitis in critically ill patients (SSC - CIP) is an underdiagnosed emerging disease. The aim of this study was to characterize clinical features and prognostic factors for mortality in SSC - CIP. This retrospective study included 54 patients who were diagnosed via endoscopic retrograde cholangiopancreatography (ERCP) after cardiothoracic surgery (n = 21), sepsis (n = 13), polytrauma (n = 11), and others (n = 9). In total, 33 patients who either died (n = 27) or needed liver transplantation (n = 6) were compared with surviving patients (n = 21). The model for end-stage liver disease (MELD) score and need for renal replacement therapy were independent risk factors for mortality. Compared with ERCP, accuracy was 30% for ultrasound and 36 % for liver biopsies. As a result of microbiological bile analysis, 28 % of patients required a change in antibiotic treatment. SSC - CIP is frequently a fatal disease. ERCP should be considered in selected patients to establish the diagnosis and hence provide useful clinical information.

MicroRNAs in the bile of patients with biliary strictures after liver transplantation

Biliary complications after liver transplantation remain a major cause of morbidity and reduced graft survival. Ischemic‐type biliary lesions (ITBLs) are common and difficult to treat. The pathophysiology of ITBLs remains unclear, and diagnostic markers are still missing. The analysis of microRNA (miRNA) profiles is an evolving field in hepatology. Our aim was to identify specific miRNA patterns in the bile of patients with ITBLs after liver transplantation. Liver transplant patients with biliary complications were included in a cross‐sectional study. Patients with ITBLs (n = 37), anastomotic strictures (ASs; n = 39), and bile duct stones (BDSs; n = 12) were compared. Patients with ITBLs were categorized by disease severity. The miRNA concentrations in bile were determined with global miRNA profiling and subsequent miRNA‐specific polymerase chain reaction–mediated validation. The concentrations of microRNA 517a (miR‐517a), miR‐892a, and miR‐106a* in bile were increased for patients with ITBLs versus patients with ASs or BDSs (P < 0.05). Categorization by ITBL severity showed higher median concentrations in patients with intrahepatic and extrahepatic strictures (P > 0.05). miR‐210, miR‐337‐5p, miR‐577, and miR‐329 displayed no statistical differences. In conclusion, miR‐517a, miR‐892a, and miR‐106a* are increased in the bile fluid of patients with ITBLs versus patients with ASs or BDSs. An analysis of miRNA profiles may be useful in the diagnosis and management of patients with ITBLs. Future studies are needed to prove the potential prognostic value of these miRNAs. Liver Transpl 20:673‐678, 2014.

Microbiological analysis of bile and its impact in critically ill patients with secondary sclerosing cholangitis

OBJECTIVES Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is an emerging disease entity with unfavourable outcome. Our aim was to analyze the microbial spectrum in bile of patients with SSC-CIP and to evaluate the potential impact on the empiric antibiotic treatment in these patients. METHODS 169 patients (72 patients with SSC-CIP and 97 patients with primary sclerosing cholangitis (PSC)) were included in a prospective observational study between 2010 and 2013. Bile was obtained during endoscopic retrograde cholangiography (ERC) and microbiologically analyzed. RESULTS Patients with SSC displayed a significantly different microbiological profile in bile. Enterococcus faecium, Pseudomonas aeruginosa and non-albicans species of Candida were more frequent in SSC compared to patients with PSC (p < 0.05). Patients with SSC showed a higher incidence of drug or multi-drug resistant organisms in bile (p = 0.001). The antimicrobial therapy was adjusted in 64% of patients due to resistance or presence of microorganisms not covered by the initial therapy regimen. CONCLUSIONS Patients with SSC-CIP have a distinct microbial profile in bile. Difficult to treat organisms are frequent and an ERC with bile fluid collection for microbiological analysis should be considered in case of insufficient antimicrobial treatment.

Endoscopic diagnosis of cholangiocarcinoma: From endoscopic retrograde cholangiography to bile proteomics

Cholangiocarcinoma (CCA) is the second most common primary liver cancer. In clinical practice, the diagnosis remains challenging and often requires endoscopic approaches. Endoscopic retrograde and percutaneous transhepatic cholangiography are the first-line endoscopic procedures for the evaluation of indeterminate bile duct strictures. Tissue acquisition via brush cytology and forceps biopsies allows the cytological and/or histological confirmation of the disease. Due to the low sensitivity of these techniques, repetitive examinations and/or alternative approaches are required. Cholangioscopy, endoscopic and intraductal ultrasound and confocal laser endomicroscopy are additional methods which can be applied for the diagnosis of CCA. Particularly, new experimental approaches like bile and urine proteomic analyses show promising results which have to be evaluated prospectively for further integration in diagnostic algorithms.

Calprotectin in bile: a disease severity marker in patients with primary sclerosing cholangitis.

Goals: Our aim was to evaluate the diagnostic potential of calprotectin in serum and bile of patients with primary sclerosing cholangitis (PSC). Background: PSC is a chronic cholestatic liver disease of unknown etiology. It is characterized by progressive inflammation and fibrosis of the bile ducts leading to biliary cirrhosis and eventually liver failure. Reliable markers for disease activity and severity are still lacking. Subunits of calprotectin, a fecal marker of inflammation in inflammatory bowel disease, have been recently identified in bile. Study: Calprotectin was measured in patients with PSC (n=56), cholangiocarcinoma (CC) complicating PSC (CC/PSC) (n=13), CC (n=30), and bile duct stones in bile (n=38) and serum (n=73) by enzyme-linked immunosorbent assay in a cross-sectional study. PSC patients were categorized by the Mayo risk score (MRS) to characterize the disease severity. Results: Calprotectin is present in bile, and the median concentration was significantly higher in PSC patients (P<0.05). Stratification of PSC patients by MRS showed significantly elevated calprotectin levels in bile in the MRS-high group (P<0.05). Calprotectin and MRS correlated significantly (P<0.05). The presence or absence of inflammatory bowel disease in PSC patients did not alter calprotectin levels in bile. Serum AP and calprotectin in bile correlated significantly (P=0.013). No significant correlation was found for other liver-related parameters. In contrast, serum calprotectin levels were significantly higher in patients with CC, but there was no association with PSC or disease activity/severity. Conclusions: Calprotectin in bile is a promising disease marker in patients with PSC with a potential prognostic value.

Angiopoietin-2 and biliary diseases: elevated serum, but not bile levels are associated with cholangiocarcinoma.

Background The diagnosis of cholangiocarcinoma (CC) is challenging especially in patients with primary sclerosing cholangitis (PSC) and often delayed due to the lack of reliable markers. Angiopoietin-2 (Angpt-2) has been employed as a biomarker of angiogenesis and might be involved in tumor neoangiogenesis. Aim To evaluate the diagnostic potential of Angpt-2 as a biomarker to detect patients with CC. Methods Bile and serum Angpt-2 levels were measured in patients with CC (n = 45), PSC (n = 74), CC complicating PSC (CC/PSC) (n = 11) and patients with bile duct stones (n = 37) in a cross sectional study. Diagnostic accuracy of Angpt-2 was compared to carbohydrate antigen 19-9 (CA19-9). Fluorescent immunohistochemistry from human CC liver tissue samples was performed to localize the origin of Angpt-2. Results Serum Angpt-2 concentration was significantly elevated in patients with CC compared to control patients (p<0.05). Diagnostic accuracy of Angpt-2 as determined by receiver operating characteristic (ROC) analysis resulted in a higher area under the curve (AUC) value compared to CA19-9 (AUC: 0.85 versus 0.77; 95% confidence interval (CI): 0.74–0.93 versus 0.65–0.87, respectively). Angpt-2 was also detectable in bile, but was not associated with the presence of CC. Immunohistochemistry revealed a strong induction of Angpt-2 expression in the tumor vasculature. Conclusions Circulating Angpt-2 in serum might be a promising protein candidate locally derived from the tumor vasculature in patients with CC. Measurement of Angpt-2 in serum may be useful for diagnosis and further clinical management of patients with CC.

Liver transplantation for critically Ill patients with secondary sclerosing cholangitis: Outcome and complications

Secondary sclerosing cholangitis in critically ill patients (SSC‐CIP) is a destructive cholangiopathy with a poor prognosis. Liver transplantation (LT) is an established therapeutic option in end‐stage liver disease but is insufficiently evaluated in patients with SSC‐CIP. Our aim was the retrospective analysis of the outcome and complications of patients with SSC‐CIP undergoing LT between 2002 and 2012. Demographic characteristics, laboratory, transplantation, and follow‐up data were compared to sex‐ and age‐matched patients undergoing LT because of other reasons. Quality of life (QoL) before and after LT was assessed in a retrospective telephone interview. LT was performed in 21 patients with SSC‐CIP. The main causes for intensive care unit admission comprised cardiothoracic surgery interventions (10/21, 48%), polytrauma (6/21, 29%), and pneumonia (3/21, 14%). Median follow‐up period after LT was 82 months (interquartile range [IQR], 37‐129) for patients with SSC‐CIP and 83 months (IQR, 55‐104) for control patients. Biopsy‐proven rejection episodes in patients with SSC‐CIP (4/21, 19%) were similar compared to control patients (12/60, 20%; P = 0.93). Cytomegalovirus infections were equal in both groups (10/21, 48% versus 25/60, 42%; P = 0.64). The 1‐, 3‐, and 5‐year survival rates of patients with SSC‐CIP versus control patients were 100% versus 98%, 86% versus 92%, and 76% versus 87%, respectively (P > 0.05). The QoL improved significantly after LT in SSC‐CIP. In conclusion, LT is a valid option for patients with SSC‐CIP with excellent long‐term outcome and improvement of QoL. Liver Transpl 21:1295‐1299, 2015.