BACKGROUNDInfection and increased systemic inflammation cause organ dysfunction and death in patients with decompensated cirrhosis. Preclinical studies provide support for an antiinflammatory role of albumin, but confirmatory large-scale clinical trials are lacking. Whether targeting a serum albumin level of 30 g per liter or greater in these patients with repeated daily infusions of 20% human albumin solution, as compared with standard care, would reduce the incidences of infection, kidney dysfunction, and death is unknown. METHODSWe conducted a randomized, multicenter, open-label, parallel-group trial involving hospitalized patients with decompensated cirrhosis who had a serum albumin level of less than 30 g per liter at enrollment. Patients were randomly assigned to receive either targeted 20% human albumin solution for up to 14 days or until discharge, whichever came first, or standard care. Treatment commenced within 3 days after admission. The composite primary end point was new infection, kidney dysfunction, or death between days 3 and 15 after the initiation of treatment. RESULTSA total of 777 patients underwent randomization, and alcohol was reported to be a cause of cirrhosis in most of these patients. A median total infusion of albumin of 200 g (interquartile range, 140 to 280) per patient was administered to the targeted albumin group (increasing the albumin level to ≥30 g per liter), as compared with a median of 20 g (interquartile range, 0 to 120) per patient administered to the standard-care group (adjusted mean difference, 143 g; 95% confidence interval [CI], 127 to 158.2). The percentage of patients with a primary end-point event did not differ significantly between the targeted albumin group (113 of 380 patients [29.7%]) and the standard-care group (120 of 397 patients [30.2%]) (adjusted odds ratio, 0.98; 95% CI, 0.71 to 1.33; P = 0.87). A time-to-event analysis in which data were censored at the time of discharge or at day 15 also showed no significant between-group difference (hazard ratio, 1.04; 95% CI, 0.81 to 1.35). More severe or life-threatening serious adverse events occurred in the albumin group than in the standard-care group. CONCLUSIONSIn patients hospitalized with decompensated cirrhosis, albumin infusions to increase the albumin level to a target of 30 g per liter or more was not more beneficial than the current standard care in the United Kingdom.

Abstract:Background: Pancreatic carcinoma is often inoperable, carries a poor prognosis and is commonly complicated by malignant biliary obstruction. Phase I/II studies have demonstrated good safety and early stent patency using endoscopic biliary radiofrequency ablation (RFA) as an adjunct to self-expanding metal stent (SEMS) insertion for biliary decompression. Aim: To analyse the clinical efficacy of endobiliary RFA. Methods: Retrospective case-control analysis of 23 patients with surgically unresectable pancreatic carcinoma and malignant biliary obstruction undergoing endoscopic RFA and SEMS insertion, and 46 controls (SEMS insertion alone) in a single tertiary care centre. Controls were stringently matched for age, sex, metastases, ASA/co-morbidities. Survival, morbidity, and stent patency rates were assessed. Thank you for considering our manuscript and for the helpful reviews.Please find enclosed a revised version of the manuscript for reconsideration, together with a detailed point by point response to the reviewer comments.We have taken independent statistical advice on the manuscript as suggested. RESPONSES TO REVIEWER COMMENTSReviewer #1: The authors present a retrospective series of 23 pts with unresectable panc ca treated with RFA and uncovered SEMS vs. 46 with uncovered alone and matched for chemo, mets, ASA, etc. It it novel data but the main premise for RFA is that it induces a coagulative necrosis -how it improves survival if it doesn't improve stent patency is not hypothesized. Stent patency was similar between the twogroups. Are the authors suggesting that RFA may be able to reduce tumor burden? Several comments to help the authors improve the submission. I do feel that the manuscript would benefit from more clarity and defined goals for its work. What are the primary and secondary endpoints for the study. These should be clearly stated in the Methods.The primary and secondary endpoints of the study are survival and stent patency/procedure safety, respectively. This has been highlighted in the methods section (cf point 13, below). Please see the response to point 14 below, re putative beneficial effects of RFA on patients with pancreatic cancer.Other comments: 1) Those patients who underwent chemo was higher in the RFA group (70% vs. 52%) but not statistically sig't. This may be a Type 2 error given the small sample size and this limitation should be clearly highlighted in the discussion. In fact, this seems to be the most plausible explanation as to the survival benefit in the RFA group unless the authors can provide other possible hypothesis.The possibility of a type 2 error is now mentioned in the relevant discussion section.2) The improved median survival of 226D vs. 124D has a CI that goes through 1. Please explain the limitations of this analysis and include in the discussion.The upper limit of the 95% CI is 1.06. This is represented in the fact that the two survival curves on Kaplan-Meier analysis cross at late time points, when the number of surviving patients is small. Our statistica...

SOC is useful for the differential diagnosis of indeterminate biliary lesions and the treatment of 'difficult' biliary stones. The adequacy of SOC-guided biopsies is related to the number of specimens obtained. Primary sclerosing cholangitis is related to failed cannulation with the SOC system, whereas general anaesthesia is related to adequate visualization.

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