Andrea S. Schneider

Bile proteomic profiles differentiate cholangiocarcinoma from primary sclerosing cholangitis and choledocholithiasis

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. (HEPATOLOGY 2010;)

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.

Routine bile collection for microbiological analysis during cholangiography and its impact on the management of cholangitis.

BACKGROUND Antibiotic treatment of cholangitis is often insufficient because of inappropriate antibiotic use or bacterial resistance. OBJECTIVE To evaluate the role of routine bile collection during endoscopic retrograde cholangiography or percutaneous transhepatic cholangiography for microbiological analysis in the antibiotic management of cholangitis and to identify risk factors of bacteriobilia. DESIGN Prospective, observational, diagnostic study. SETTING Hannover Medical School, Hannover, Germany. PATIENTS AND INTERVENTION This study involved 243 consecutive patients undergoing endoscopic retrograde cholangiography/percutaneous transhepatic cholangiography for biliary complications after orthotopic liver transplantation (27%), malignancy (27%), primary sclerosing cholangitis (15%), benign strictures (11%), and choledocholithiasis (8%). MAIN OUTCOME MEASUREMENTS Microbiological examination of bile samples. RESULTS Patients with biliary stents or who were receiving repeated interventions after orthotopic liver transplantation were at increased risk of bacteriobilia (P < .05). The rate of gram-positive monomicrobial infection was higher in patients with primary sclerosing cholangitis (P < .01). In 40 examinations, patients presented with preprocedural cholangitis although they were receiving antibiotics. According to bile culture results, the antibiotic treatment was modified to a more specific therapy in 72.5% of patients. In patients who developed cholangitis after endoscopic retrograde cholangiography (27 examinations), specific antibiotic treatment was started or refined in 67% of cases, based on bile culture results. LIMITATIONS Contamination of samples during intervention cannot be totally excluded. CONCLUSION Orthotopic liver transplantation, biliary stenting, and repeated interventions are risk factors of bacteriobilia. In our patients with primary sclerosing cholangitis, gram-positive monomicrobial infections were more common. A bile sample collected during cholangiography for microbiological analysis is a simple, potentially valuable, diagnostic tool in patients with cholangitis. Each center should recognize its own patterns of infection to ensure ideal targeted therapy.

Management of major postsurgical gastroesophageal intrathoracic leaks with an endoscopic vacuum-assisted closure system

BACKGROUND Endoscopic treatment options for postsurgical intrathoracic leaks include injection of fibrin glue, clip application, and stent placement. Endoscopic vacuum-assisted closure (E-VAC) may be an effective treatment option. OBJECTIVE To demonstrate that E-VAC is an effective endoscopic treatment option for closure of major intrathoracic postsurgical leaks. DESIGN AND SETTING A prospective, single-center study at an academic medical center. PATIENTS Eight consecutive patients with major intrathoracic postsurgical leaks. INTERVENTIONS Endoscopic placement of transnasal draining tubes, armed with a size-adjusted sponge at their distal end, in the necrotic anastomotic cavities, followed by continuous suction. Sponge and drainage were changed twice weekly. Patients were followed-up for 193 +/- 137 days. MAIN OUTCOME MEASUREMENT Successful leak closure. RESULTS Successful closure of leaks was achieved in 7 of 8 patients (88%) after a mean of 23 +/- 8 days. A median of 7 endoscopic interventions was necessary. No major treatment-associated short-term or long-term (follow-up, 193 +/- 137 days) complications were noted. LIMITATIONS Small sample size, single-center study, and lack of randomization. CONCLUSION E-VAC is an effective endoscopic treatment modality for major postsurgical intrathoracic leaks. (This study is registered at Clinicaltrials.gov, identifier NCT00876551.).

Prognostic Implications of Lactate, Bilirubin, and Etiology in German Patients With Acute Liver Failure

BACKGROUND & AIMS Among the potentially helpful indicators of poor prognosis in acute liver failure (ALF) are etiology, encephalopathy grade, blood lactate, and Kings College Criteria (KCC). The accuracy of these parameters in predicting transplantation or death shows significant variation in different countries. METHODS We retrospectively analyzed 102 patients with ALF treated at our institution between 1996 and 2005. Baseline parameters, simplified acute physiology score III (SAPS-III), KCC, Model for End-Stage Liver Disease (MELD) score, and a novel score of bilirubin, lactate, and etiology (BiLE score) were compared between transplant-free survivors and patients who required liver transplantation or died, by using multivariate linear regression analysis and receiver operating characteristics (ROC). RESULTS The most common causes of ALF were indeterminate liver failure (21%), acute hepatitis B (18%), acetaminophen ingestion (16%), and Budd-Chiari syndrome (9%). Transplantation-free survival was 38%, 44% of patients underwent liver transplantation, and 18% died without transplantation. Eight-week survival was 77%. The BiLE score was the best predictor of death or need of transplantation, with 79% sensitivity and 84% specificity. ROC analysis revealed a better performance of BiLE score when compared with bilirubin, lactate, MELD score, and SAPS-III (area under the curve: 0.87 +/- 0.04, 0.73 +/- 0.51, 0.73 +/- 0.52, 0.71 +/- 0.05, and 0.68 +/- 0.59, respectively). CONCLUSIONS The simple, combined BiLE score emerged as the best predictor of poor outcome in our patient cohort and should be prospectively evaluated in other populations.

Virus-associated hemophagocytic syndrome as a major contributor to death in patients with 2009 influenza A (H1N1) infection

IntroductionVirus-associated hemophagocytic syndrome (VAHS) is a severe complication of various viral infections often resulting in multiorgan failure and death. The purpose of this study was to describe baseline characteristics, development of VAHS, related treatments and associated mortality rate of consecutive critically ill patients with confirmed 2009 influenza A (H1N1) infection and respiratory failure.MethodsWe conducted a prospective observational study of 25 critically ill patients with 2009 influenza A (H1N1) infection at a single-center intensive care unit in Germany between 5 October 2009 and 4 January 2010. Demographic data, comorbidities, diagnosis of VAHS, illness progression, treatments and survival data were collected. The primary outcome measure was the development of VAHS and related mortality. Secondary outcome variables included duration of mechanical ventilation, support of extracorporeal membrane oxygenation and duration of viral shedding.ResultsVAHS developed in 9 (36%) of 25 critically ill patients with confirmed 2009 influenza A (H1N1) infection, and 8 (89%) of them died. In contrast, the mortality rate in the remaining 16 patients without VAHS was 25% (P = 0.004 for the survival difference in patients with or without VAHS by log-rank analysis). The patients were relatively young (median age, 45 years; interquartile range (IQR), 35 to 56 years of age); however, 18 patients (72%) presented with one or more risk factors for a severe course of illness. All 25 patients received mechanical ventilation for severe acute respiratory distress syndrome and refractory hypoxemia, with a median duration of mechanical ventilation of 19 days (IQR, 13 to 26 days). An additional 17 patients (68%) required extracorporeal membrane oxygenation for a median of 10 days (IQR, 6 to 19 days).ConclusionsThe findings of this study raise the possibility that VAHS may be a frequent complication of severe 2009 influenza A (H1N1) infection and represents an important contributor to multiorgan failure and death.

Endoscopic retrograde cholangiopancreaticography prior to explorative laparotomy avoids unnecessary surgery in patients suspected for biliary atresia.

BACKGROUND/AIMS Timely diagnosis of biliary atresia (BA) requires key investigations that are less invasive but as accurate as possible. Non-invasive imaging preselects patients before explorative laparotomy is performed. The purpose of this prospective study was to evaluate the accuracy of endoscopic retrograde cholangiopancreaticography (ERCP) in these patients and to discuss its relevance to future diagnostic guidelines in neonatal jaundice. METHODS Over a 7-year period, ERCP was routinely performed in cholestatic patients less than 6 months of age suspected for an extrahepatic origin of cholestasis, most likely BA. Endoscopic diagnosis was correlated with intraoperative findings. RESULTS In 140 consecutive patients (mean age: 60 days; weight: 4 kg), ERCP excluded BA in 34 (25%) but failed in 18 newborns (13%) for technical reasons. The average procedure time was 23 min, and no severe complications occurred. Explorative laparotomy was performed in 106 patients and revealed BA in 80 cases. In this series, the sensitivity of ERCP for diagnosing biliary atresia was 92% and specificity was 73%. CONCLUSIONS In preselected patients, ERCP is not an alternative to non-invasive imaging, but it avoids unnecessary surgical procedures in almost 25% of the cases. Hence, ERCP is recommended prior to explorative laparotomy in all patients suspected for BA.

Extracorporeal membrane oxygenation instead of invasive mechanical ventilation in patients with acute respiratory distress syndrome

Dear Editor, Invasive mechanical ventilation with or without additional extracorporeal membrane oxygenation (ECMO) support represents standard treatment for patients with acute respiratory distress syndrome (ARDS). An ‘‘awake ECMO’’ strategy in order to avoid intubation and mechanical ventilation has been implemented as a bridge to lung transplantation in patients with chronic lung disease [1, 2] but has been used only occasionally in patients with ARDS [3]. We conducted a single-center, uncontrolled pilot trial designed to assess the feasibility of veno-venous ECMO in awake, non-intubated, spontaneously breathing patients with ARDS (www.clinical.govNCT01669 863 ). Patients between 18 and 75 years old presenting with moderate or severe ARDS were eligible. The main exclusion criteria were severe bleeding disorders and uncontrolled sepsis with multi-organ failure involving at least two organ systems. The Institutional Review Board (IRB) of Hannover Medical School approved and supervised the study and all patients provided written informed consent prior to ECMO insertion. Six patients with severe ARDS were enrolled as planned; four of them were immunocompromised. Patient characteristics and outcome parameters are shown in Table 1. All patients suffered from severe ARDS with PaO2/FiO2 ratios at most 100 mmHg while receiving noninvasive ventilation. Gas exchange patterns improved immediately after ECMO insertion and noninvasive ventilation could be stopped within 1 h in two patients. Three patients (patients 1, 4, and 5) were successfully weaned from ECMO after 10, 5, and 7 days, respectively, and discharged from the ICU without needing invasive mechanical ventilation. Patient 2 was also successfully weaned from ECMO support but developed respiratory failure due to an iatrogenic pneumothorax 2 days later and required intubation as a result. A protracted ICU course ensued, complicated by ventilatorassociated pneumonia and sepsis. The patient was eventually discharged from the ICU after 50 days. Patient 3 improved rapidly on ECMO support, but became increasingly agitated and confused. On the 7th day on ECMO support, he intentionally removed his jugular cannula, resulting in emergency intubation and brief cardiopulmonary resuscitation. He subsequently died 10 days later from

Liver Cell Transplantation: Basic Investigations for Safe Application in Infants and Small Children

Liver cell transplantation (LCT) is a very promising method for the use in pediatric patients. It is significantly less invasive than whole organ transplantation, but has the potential to cure or at least to substantially improve severe disorders like inborn errors of metabolism or acute liver failure. Prior to a widespread use of the technique in children, some important issues regarding safety and efficacy must be addressed. We developed a mathematical model to estimate total hepatocyte counts in relation to bodyweight to make possible more appropriate dose calculations. Different liver cell suspensions were studied at different flow rates and different catheter sizes to determine mechanical damage of cells by shear forces. At moderate flow rates, no significant loss of viability was observed even at a catheter diameter of 4.2F. Addition of heparin to the cell suspension is favored, which is in contrast to previous animal experiments. Mitochondrial function of the hepatocytes was determined with the WST-1 assay and was not substantially altered by cryopreservation. We conclude that especially with the use of small catheters, human LCT should be safe and efficient even in small infants and neonates.

Intraportal infusion of 99mtechnetium-macro-aggregrated albumin particles and hepatocytes in rabbits: assessment of shunting and portal hemodynamic changes.

Background. Partial correction of metabolic liver disease by hepatocyte transplantation requires infusion of a large number of cells into the portal vein. Uncontrolled infusion of cells leads to extrahepatic shunting. Obstruction of the sinusoidal space may result in hemodynamic changes and impairment of liver function. Methods. Catheters connected to a port were placed into the caudal mesenteric vein of rabbits. After injection of 99mtechnetium-macroaggregated albumin (99mTc-MAA) surrogates or 99mTc-MAA/hepatocyte (Hc) mixtures (1:125), shunting into the lung was scintigraphically monitored. Volume flow (mL/min) and maximum velocity of the portal vein were recorded by color-coded Doppler ultrasound during intraportal application of 2.5×107 MAA particles, 2.5×107 isolated hepatocytes, and saline solution without particles or cells. Results. 99mTc-MAA particles (2.5×107) or equivalent MAA/Hc mixtures were completely retained in the liver. With additional application of 2.5×107 particles, shunting into the lung was observed in two animals of the MAA group. All animals in the hepatocyte group have received 5×107 MAA/Hc mixtures, and three of these received 108 mixtures without shunting. Maximum velocity and volume flow increased with saline infusion. Hepatocyte suspended in the same volume blunted the increase observed in the control group, but parameters remained normal. Liver enzymes increased after hepatocyte application but returned to normal values within 5 days. Conclusions. Sinusoidal uptake capacity for hepatocyte or MAA particles varies at a wide range in normal rabbits. Scintigraphic monitoring of transplanted cells allows efficient monitoring of cell translocation into the lungs. No significant impairments of portal hemodynamics and liver function were detected.