Transjugular diagnostics in acute liver failure including measurements of hepatocentral venous biomarker gradients.

AIM: Acute liver failure (ALF) is a syndrome of severe liver injury that may need urgent liver transplantation and is associated with significant risk of death. Early outcome prediction and further possibilities to increase accuracy of prognosis scores are important. METHODS: We examined 30 patients with ALF, according to the novel criteria of the Intractable Hepato-Biliary Diseases Study Group, who underwent transjugular liver biopsy (TJLB) and investigated the relevance of histology for correct diagnosis and etiology. We assessed the suitability of necrosis (%), hepatic venous pressure gradients (HVPG), and hepatocentral venous gradients of serum biomarkers for outcome prediction. For this purpose, we calculated the difference of biomarker levels between hepatic vein (HV) and superior vena cava (SVC) blood samples. RESULTS: Histology of TJLB specimens contributed to finding the etiology in 83%. Necrosis (%) and HVPGs were not significantly different between outcome groups. In gradient measurements, caspase 3/7 activity and total cytokeratin 18 (CK-18) (M65) had significant and relevant levels different from zero. Although they were not accurate for outcome prediction, differences between outcome groups were detected in caspase activation: levels of caspase 3/7 activity in the HV and caspase-cleaved CK-18 (M30) in the SVC were significantly higher in spontaneously recovered patients. CONCLUSIONS: Our results underline the role of caspase activation in spontaneous recovery from ALF. Furthermore, the calculation of hepatocentral venous biomarker gradients could represent a new diagnostic tool whose clinical potential needs to be further investigated.

Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells.

Although NK cells are considered innate, recent studies in mice revealed the existence of a unique lineage of hepatic CD49a(+)DX5(-) NK cells with adaptive-like features. Development of this NK cell lineage is, in contrast to conventional NK cells, dependent on T-bet but not Eomes. In this study, we describe the identification of a T-bet(+)Eomes(-)CD49a(+) NK cell subset readily detectable in the human liver, but not in afferent or efferent hepatic venous or peripheral blood. Human intrahepatic CD49a(+) NK cells express killer cell Ig-like receptor and NKG2C, indicative of having undergone clonal-like expansion, are CD56(bright), and express low levels of CD16, CD57, and perforin. After stimulation, CD49a(+) NK cells express high levels of inflammatory cytokines but degranulate poorly. CD49a(+) NK cells retain their phenotype after expansion in long-term in vitro cultures. These results demonstrate the presence of a likely human counterpart of mouse intrahepatic NK cells with adaptive-like features.

[Cost assessment for endoscopic procedures in the German diagnosis-related-group (DRG) system - 5 year cost data analysis of the German Society of Gastroenterology project]. / Kosten endoskopischer Leistungen der Gastroenterologie im deutschen DRG-System ­ 5-Jahres-Kostendatenanalyse des DGVS-Projekts.

Background In the German hospital reimbursement system (G-DRG) endoscopic procedures are listed in cost center 8. For reimbursement between hospital departments and external providers outdated or incomplete catalogues (e. g. DKG-NT, GOÄ) have remained in use. We have assessed the cost for endoscopic procedures in the G-DRG-system. Methods To assess the cost of endoscopic procedures 74 hospitals, annual providers of cost-data to the Institute for the Hospital Remuneration System (InEK) made their data (2011 - 2015; §â€Š21 KHEntgG) available to the German-Society-of-Gastroenterology (DGVS) in anonymized form (4873 809 case-data-sets). Using cases with exactly one endoscopic procedure (n = 274 186) average costs over 5 years were calculated for 46 endoscopic procedure-tiers. Results Robust mean endoscopy costs ranged from 230.56 € for gastroscopy (144 666 cases), 276.23 € (n = 32 294) for a simple colonoscopy, to 844.07 € (n = 10 150) for ERCP with papillotomy and plastic stent insertion and 1602.37 € (n = 967) for ERCP with a self-expanding metal stent. Higher costs, specifically for complex procedures, were identified for University Hospitals. Discussion For the first time this catalogue for endoscopic procedure-tiers, based on §â€Š21 KHEntgG data-sets from 74 InEK-calculating hospitals, permits a realistic assessment of endoscopy costs in German hospitals. The higher costs in university hospitals are likely due to referral bias for complex cases and emergency interventions. For 46 endoscopic procedure-tiers an objective cost-allocation within the G-DRG system is now possible. By international comparison the costs of endoscopic procedures in Germany are low, due to either greater efficiency, lower personnel allocation or incomplete documentation of the real expenses.

Efficacy and safety of bovine activated factors IIa/VIIa/IXa/Xa in patients with active gastrointestinal bleeding: a proof of concept study.

BACKGROUND AND STUDY AIMS: Endoscopic treatment of active gastrointestinal bleeding often remains difficult, and considerable technical expertise is required. Our aim was to assess the efficacy and safety of endoscopic hemostasis with a liquid combination of bovine activated factors IIa/VIIa/IXa/Xa (SeraSeal). METHODS: Patients with active gastrointestinal bleeding were prospectively included. In group A, 5 mL of bovine activated factors IIa/VIIa/IXa/Xa was topically applied via catheters to the bleeding site as initial hemostasis; group B received a similar application but as rescue therapy after failure of conventional endoscopic hemostasis. RESULTS: In group A, bleeding was stopped by the agent in 15 /22 patients (68 %) and by conventional endoscopic hemostasis in 5 of the other 7, with coiling and surgery required for definitive hemostasis in 2. In group B, the addition of the agent definitively stopped bleeding in 13 /15 patients (87 %), with hemostasis in the remaining 2 achieved with fibrin glue. Rebleeding was observed in 1 patient. CONCLUSIONS: Our proof of concept study suggests that the use of bovine activated factors IIa/VIIa/IXa/Xa might be a safe and effective addition to current endoscopic hemostatic strategies, but further studies are necessary.ClinicalTrials.gov identifier: NCT02349490.

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.

Microbiological analysis of fluids in postsurgical gastroesophageal intrathoracic leaks obtained by endoscopy: a new way to optimize antibiotic therapy.

BACKGROUND/AIMS: Postsurgical gastroesophageal intrathoracic leakage is a potentially life-threatening condition that is frequently accompanied by mediastinitis and subsequent sepsis. Aspiration of fluids from intrathoracic leaks during endoscopy for microbiological analysis is rarely performed in clinical routine. The aim was to evaluate the role of routine microbiological analysis of intrathoracic leaks via endoscopy and its impact on antibiotic therapy. METHODS: This is a prospective, observational single-center study. Seventeen consecutive patients who presented for endoscopic treatment of intrathoracic leaks were included. Concomitantly, fluids from intrathoracic leaks during endoscopic intervention and blood cultures were obtained and a microbiological analysis was performed. RESULTS: Bacteria and/or fungi were detected by culture of fluid aspirated from intrathoracic leaks in 88% cases, but in none of the blood cultures. In 15 patients, microbial colonization of the leakage was detected despite previous empiric antibiotic therapy; treatment had to be adjusted in all patients according to the observed antibiotic susceptibility profile. CONCLUSIONS: The microbiological colonization of postsurgical gastroesophageal intrathoracic leaks in patients is frequent. Only the direct microbiological analysis of fluids from intrathoracic leaks, but not of blood cultures, is effective for optimizing an antibiotic therapy in such patients.

Increased T-helper 2 cytokines in bile from patients with IgG4-related cholangitis disrupt the tight junction-associated biliary epithelial cell barrier.

BACKGROUND & AIMS: IgG4-related cholangitis is a chronic inflammatory biliary disease that involves different parts of the pancreatobiliary system, but little is known about its mechanisms of pathogenesis. A T-helper (Th) 2 cell cytokine profile predominates in liver tissues from these patients. We investigated whether Th2 cytokines disrupt the barrier function of biliary epithelial cells (BECs) in patients with IgG4-related cholangitis. METHODS: We assessed the Th2 cytokine profile in bile samples and brush cytology samples from 16 patients with IgG4-related cholangitis and respective controls, and evaluated transcription of tight junction (TJ)-associated proteins in primary BECs from these patients. The effect of Th2 cytokines on TJ-mediated BEC barrier function and wound closure was examined by immunoblot, transepithelial resistance, charge-selective Na(+)/Cl(-) permeability, and 4-kDa dextran flux analyses. RESULTS: Bile samples from patients with IgG4-related cholangitis had significant increases in levels of Th2 cytokines, interleukin (IL)-4, and IL-5. IL-13 was not detected in bile samples, but polymerase chain reaction analysis of whole-brush cytology samples from patients with IgG4-related cholangitis revealed increased levels of IL-13 mRNA, compared with controls. BECs isolated from the brush cytology samples revealed decreased levels of claudin-1 and increased levels of claudin-2 mRNAs. In vitro, IL-4 and IL-13 significantly reduced TJ-associated BEC barrier function by activating claudin-2-mediated paracellular pore pathways. Th2 cytokines also impaired wound closure in BEC monolayers. CONCLUSIONS: Th2 cytokines predominate in bile samples from patients with IgG4-related cholangitis and disrupt the TJ-mediated BEC barrier in vitro. Subsequent increases in biliary leaks might contribute to the pathogenesis of chronic biliary inflammation in these patients.

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.

Safety and performance of liver biopsies in liver transplant recipients.

BACKGROUND: Liver biopsy in patients after liver transplantation (OLT) serves as a diagnostic tool to establish the cause of liver pathology. However, liver biopsy may cause life-threatening complications. Very limited information is available about complications and success rates of liver biopsies in patients after OLT. Our aim was to investigate biopsy-related complications and quality of specimen obtained by liver biopsy after OLT and to evaluate risks and benefits of this procedure. METHODS: Retrospective analysis of patients after OLT presenting for liver biopsy between January 2000 and October 2012. All patients were observed for 24 h after intervention. Twelve or more portal tracts were required for liver biopsy specimens to be considered as adequate. RESULTS: Of 703 liver biopsies were performed in 409 patients. Thirteen (1.9%) liver biopsies did not have an adequate number of portal tracts. Only 10 (1.4%) liver biopsies caused complications. Five patients suffered from pain, three patients developed post-procedural fever, and three patients had subcapsular/intercostal bleeding. One patient suffered from a vasovagal reaction. Pain was treated by analgesics; none of the patients required blood transfusion or surgery. CONCLUSIONS: Liver biopsy is a safe and adequate diagnostic tool in patients after OLT.

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.

Complication and mortality rate after percutaneous endoscopic gastrostomy are low and indication-dependent.

OBJECTIVE: Percutaneous endoscopic gastrostomy (PEG) is often used for the feeding of patients with malnutrition due to dysphagia, and despite more than 30 years experience, numerous questions on its benefit remain. This was a prospective observational study to assess the safety of PEG. MATERIAL AND METHODS: One hundred and nineteen patients mean age 63 years (21-91 years) who were admitted to the Hannover Medical School between November 2010 and March 2012 and had an indication for PEG according to the German guidelines were included. Primary endpoints were the following: reason for indication, date of in-hospital mortality after PEG insertion, death within 3 months after PEG placement, and complications. RESULTS: Most patients (54.6%) received PEG for dysphagia caused by tumors and second (29.4%) for neurologic diseases with a minor proportion of dementia (3%). About 73% of our patients had no complications at all and only 10% suffered severe effects. We saw only 1 case of aspiration, which did not lead to pneumonia. The 30-day mortality was 10%, and no patient died as a result of the PEG procedure. Significantly more patients with neurologic disorders died within 24 weeks of PEG placement than tumor patients (60% versus 27.7%, respectively, p = 0.002, n = 100). CONCLUSION: It is important to select patients receiving PEG very carefully. The patients' indications, their primary disease, and their capability for mental cooperation are essential. If these aspects are taken into account, PEG is a safe method with few mainly mild complications.

Long-term results after adult ex situ split liver transplantation since its introduction in 1987.

BACKGROUND: Split liver transplantation is still discussed controversially. Utilization of split liver grafts has been declining since a change of allocation rules for the second graft abolished incentives for German centres to perform ex situ splits. We therefore analysed our long-term experiences with the first ex situ split liver transplant series worldwide. METHODS: A total of 131 consecutive adult ex situ split liver transplants (01.12.1987-31.12.2010) were analysed retrospectively. RESULTS: Thirty-day mortality rates and 1- and 3-year patient survival rates were 13, 76.3, and 66.4 %, respectively. One- and three-year graft survival rates were 63.4 and 54.2 %, respectively. The observed 10-year survival rate was 40.6 %. Continuous improvement of survival from era 1 to 3 was observed (each era: 8 years), indicating a learning curve over 24 years of experience. Patient and graft survival were not influenced by different combinations of transplanted segments or types of biliary reconstruction (p > 0.05; Cox regression). Patients transplanted for primary sclerosing cholangitis had better survival (p = 0.021; log-rank), whereas all other indications including acute liver failure (13.6 %), acute and chronic graft failure (9.1 %) had no significant influence on survival (p > 0.05; log-rank). Biliary complications (27.4 %) had no significant influence on patient or graft survival (p > 0.05; log-rank). Hepatic artery thrombosis (13.2 %) had a significant influence on graft survival but not on patient survival (p = 0.002, >0.05, respectively; log-rank). CONCLUSIONS: Split liver transplantation can be used safely and appears to be an underutilized resource that may benefit from liberal allocation of the second graft.

Urine proteomic analysis differentiates cholangiocarcinoma from primary sclerosing cholangitis and other benign biliary disorders.

BACKGROUND: Diagnosis and curative treatment of cholangiocarcinoma (CC) often comes too late due to the lack of reliable tumour markers especially in patients with primary sclerosing cholangitis (PSC). The authors recently introduced bile proteomic analysis for CC diagnosis. Nevertheless, bile collection depends on invasive endoscopic retrograde cholangiography. The authors therefore evaluated urine proteomic analysis for non-invasive CC diagnosis. METHODS: Using capillary electrophoresis mass spectrometry the authors established a CC-specific peptide marker model based on the distribution of 42 peptides in 14 CC, 13 PSC and 14 benign biliary disorder (BBD) patients. RESULTS: In cross-sectional validation of 123 patients, the urine peptide marker model correctly classified 35 of 42 CC patients and 64 of 81 PSC and BBD patients with an area under the curve value of 0.87 (95% CI 0.80 to 0.92, p=0.0001, 83% sensitivity, 79% specificity). Evaluation of 101 normal controls resulted in 86% specificity. All 10 patients with CC on top of PSC were correctly classified. The majority of sequence-identified peptides are fragments of interstitial collagens with some of them also detected in blood indicating their extra-renal origin. Immunostaining of liver sections for matrix metallopeptidase 1 indicated increased activity of the interstitial collagenase in liver epithelial cells of CC patients. CONCLUSION: The urine test differentiates CC from PSC and other BBD and may provide a new diagnostic non-invasive tool for PSC surveillance and CC detection.

Microbiologic analysis of peri-pancreatic fluid collected during EUS in patients with pancreatitis: impact on antibiotic therapy.

BACKGROUND: Pancreatitis is a potentially life-threatening condition frequently accompanied by peri-pancreatic fluid collections (PPFC), such as pseudocysts or pancreatic necrosis. Aspiration of PPFCs during EUS interventions for microbiologic analysis is still rarely performed in clinical routine. OBJECTIVE: To evaluate the role of routine microbiologic analysis of PPFCs and its impact on antibiotic therapy in patients with pancreatitis. DESIGN: Prospective, observational, multicenter study. SETTING: Four treatment centers. PATIENTS: A total of 44 consecutive patients who presented for endoscopic treatment of PPFCs were included. INTERVENTION: Concomitantly, PPFC during intervention and concomitant blood cultures were obtained. MAIN OUTCOME MEASUREMENTS: Microbiologic examination of PPFCs and blood samples. RESULTS: Colonization of PPFCs was found in 59% of PPFC cultures, whereas all but 2 concomitant blood cultures showed no microbial growth. Risk factors for a colonization were the presence of necrosis (P = .006), acute pancreatitis (P = .033), leukocytosis (P = .001), elevated C-reactive protein levels (P = .003), fever (P = .02), turbid material (P = .031), and longer hospital stay (P = .003). In 23 patients with fluid colonization despite empiric antibiotic therapy, the treatment had to be adjusted in 18 patients (78%) according to the observed antibiotic susceptibility profile. LIMITATIONS: Contamination cannot be totally excluded. CONCLUSION: The microbiologic colonization of PPFCs in patients with pancreatitis is common. Only the direct microbiologic analysis of PPFCs, but not of blood cultures, is useful to optimize an effective antibiotic therapy in patients with pancreatitis.

Biliary cast syndrome post-liver transplantation: risk factors and outcome.

BACKGROUND: Biliary cast syndrome (BCS) is characterized by the retention of lithogenic material leading to obstructive cholangitis and subsequent liver damage. BCS after orthotopic liver transplantation (OLT) can lead to retransplantation or death. AIM: Evaluation of aetiology, risk factors and outcome of BCS after OLT. METHODS: In a retrospective single centre analysis between 2002 and 2011, all OLT patients with BCS diagnosed by endoscopic retrograde cholangiography were identified and compared with a matched control group at a 2:1 ratio. RESULTS: Thirty patients with BCS after OLT were identified (30/887, 3.4%). Seventy per cent of those patients (21/30) underwent transplantation in the Model for Endstage Liver Disease (MELD) score era. Median time to diagnosis after OLT was 255 days (IQR 107-621). Intensive care unit treatment after OLT was significantly longer in BCS patients [16 days (IQR 8-42) vs. 9 (IQR 7-17) days; P = 0.039]. In a multivariate analysis, hepatic artery stenosis (P = 0.04), biliary strictures (P = 0.032) and need for renal replacement therapy (P = 0.002) were significantly associated with BCS. Immunosuppressant regimen, operation time, cold or warm ischaemia time, graft size, acute cellular rejection and cytomegalovirus infections were not significantly different between both groups. Retransplantation rate and 12-month mortality were significantly higher with BCS (9/30, 30% vs. 4/60, 7%, P = 0.003). CONCLUSIONS: BCS is a rare, but severe complication after OLT. Patients with hepatic artery stenosis, biliary strictures or renal replacement therapy have the highest risk to develop BCS and should therefore be monitored carefully.

Screening colonoscopy in liver transplant candidates: risks and findings.

The indication for mandatory screening colonoscopies in liver transplant candidates is controversial. Since the introduction of MELD-based allocation, patients with advanced liver disease and often severe comorbidities are prioritized for liver transplantation (LT). This study evaluated safety and outcome of colonoscopy in this high-risk patient group. During a two-yr period, we performed 243 colonoscopies in potential LT candidates. Endoscopic findings were registered in a standardized form, and correlations with biochemical or clinical parameters were analyzed using Mann-Whitney U-test and chi-square test. Only 57 patients (23.5%) had an endoscopically normal colon. Main findings were polyps (45.7%), hypertensive colopathy (24.3%), diverticulosis (21%), rectal varices (19.8%), and hemorrhoids (13.6%). In 21% of all patients, the removed polyps were diagnosed as adenomas. The prevalence of neoplastic polyps increased significantly with age: 13.6% (patients <50 yr) vs. 25% (patients ≥ 50 yr) (p = 0.03). Advanced neoplasia was found only in patients older than 40 yr. No major complications were observed; post-interventional hemorrhage was observed in 1.7% and controlled by clipping or injection therapy. In conclusion, lower gastrointestinal endoscopy is safe and effective in LT candidates. Due to the age dependency of neoplastic polyps, a screening colonoscopy should be performed in LT candidates older than 40 yr or with symptoms or additional risk factors.

Antineutrophil cytoplasmic antibodies in bile are associated with disease activity in primary sclerosing cholangitis.

OBJECTIVE. Primary sclerosing cholangitis (PSC) is an autoimmune cholestatic liver disease of unknown etiology. The role of antineutrophil cytoplasmic antibodies (ANCAs) in the serum of patients with PSC remains unclear. We hypothesized that ANCA may be detectable in bile, potentially providing diagnostic and prognostic information. METHODS. Serum and bile were prospectively collected during endoscopic retrograde cholangiography (ERC) in 72 patients with PSC and other non-PSC obstructive biliary diseases. ANCA measurements were performed by indirect immunofluorescence (IIF). RESULTS. Immunoglobulin G (IgG) ANCA was detected significantly more often in the bile of PSC patients (15/39; 38%) than without (2/33; 6%) (p = 0.001). IgG ANCA in bile was associated with a ten times higher risk of PSC (p = 0.005). In addition, IgG ANCA positivity in bile was associated with the presence of dominant strictures (p = 0.03), cholangiographic severity (p = 0.004), number of ERC (p = 0.01) and interventions performed (p = 0.03). However, IgG ANCA in bile did not correlate with transplantation, cholangiocarcinoma or death. No association was observed between ANCA positivity in sera and ANA and ASCA positivity in sera or bile with the above-mentioned clinical features. CONCLUSIONS. The presence of ANCA in the bile of patients with PSC is a novel finding and highly suggestive of PSC. Biliary IgG ANCA correlates with the severity of bile duct strictures and the ensuing number of ERCs and interventions. Therefore, a positive ANCA status in bile may serve as a diagnostic and prognostic marker of the disease progression and biliary complications.

Bile proteomic profiles differentiate cholangiocarcinoma from primary sclerosing cholangitis and choledocholithiasis.

UNLABELLED: Early detection of malignant biliary tract diseases, especially cholangiocarcinoma (CC) in patients with primary sclerosing cholangitis (PSC), is very difficult and often comes too late to give the patient a therapeutic benefit. We hypothesize that bile proteomic analysis distinguishes CC from nonmalignant lesions. We used capillary electrophoresis mass spectrometry (CE-MS) to identify disease-specific peptide patterns in patients with choledocholithiasis (n = 16), PSC (n = 18), and CC (n = 16) in a training set. A model for differentiation of choledocholithiasis from PSC and CC (PSC/CC model) and another model distinguishing CC from PSC (CC model) were subsequently validated in independent cohorts (choledocholithiasis [n = 14], PSC [n = 18] and CC [n = 25]). Peptides were characterized by sequencing. Application of the PSC/CC model in the independent test cohort resulted in correct exclusion of 12/14 bile samples from patients with choledocholithiasis and identification of 40/43 patients with PSC or CC (86% specificity, 93% sensitivity). The corresponding receiver operating characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.93 (95% confidence interval [CI]: 0.82-0.98, P = 0.0001). The CC model succeeded in an accurate detection of 14/18 bile samples from patients with PSC and 21/25 samples with CC (78% specificity, 84% sensitivity) in the independent cohort, resulting in an AUC value of 0.87 (95% CI: 0.73-0.95, P = 0.0001) in ROC analysis. Eight out of 10 samples of patients with CC complicating PSC were identified. CONCLUSION: Bile proteomic analysis discriminates benign conditions from CC accurately. This method may become a diagnostic tool in future as it offers a new possibility to diagnose malignant bile duct disease and thus enables efficient therapy particularly in patients with PSC.

Implementation of proteomic biomarkers: making it work.

While large numbers of proteomic biomarkers have been described, they are generally not implemented in medical practice. We have investigated the reasons for this shortcoming, focusing on hurdles downstream of biomarker verification, and describe major obstacles and possible solutions to ease valid biomarker implementation. Some of the problems lie in suboptimal biomarker discovery and validation, especially lack of validated platforms with well-described performance characteristics to support biomarker qualification. These issues have been acknowledged and are being addressed, raising the hope that valid biomarkers may start accumulating in the foreseeable future. However, successful biomarker discovery and qualification alone does not suffice for successful implementation. Additional challenges include, among others, limited access to appropriate specimens and insufficient funding, the need to validate new biomarker utility in interventional trials, and large communication gaps between the parties involved in implementation. To address this problem, we propose an implementation roadmap. The implementation effort needs to involve a wide variety of stakeholders (clinicians, statisticians, health economists, and representatives of patient groups, health insurance, pharmaceutical companies, biobanks, and regulatory agencies). Knowledgeable panels with adequate representation of all these stakeholders may facilitate biomarker evaluation and guide implementation for the specific context of use. This approach may avoid unwarranted delays or failure to implement potentially useful biomarkers, and may expedite meaningful contributions of the biomarker community to healthcare.

Transgastrically placed endoscopic vacuum-assisted closure system as an addition to transgastric necrosectomy in necrotizing pancreatitis (with video).

BACKGROUND: Endoscopic transluminal débridement of infected pancreatic necrosis has been proved to be an important alternative to surgical débridement. Recently, endoscopic vacuum-assisted closure (EVAC) has been described as a new effective treatment option in upper intestinal anastomotic leaks. OBJECTIVE: To test whether the EVAC can be applied to transgastrically accessible infected cavities. DESIGN: Single-center case study. SETTING: Academic medical center. PATIENTS: Two patients with necrotizing pancreatitis. MAIN OUTCOME MEASUREMENT: Successful closure of leak. RESULTS: We successfully applied EVAC to treat transgastrically accessible necrotic cavities. LIMITATIONS: Small case number. CONCLUSIONS: EVAC might be an important additional endoscopic treatment option for infected pancreatic necrosis, especially if established endoscopic treatment options fail.