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BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab for maintenance of remission in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, placebo-controlled, double-blind, phase 3 study (LAUREL) across 111 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. During open-label induction, participants received subcutaneous etrolizumab 105 mg once every 4 weeks. Participants who had clinical response at week 10 (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) proceeded into the double-blind maintenance phase and were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or matched placebo until week 62. Randomisation was stratified by baseline concomitant treatment with corticosteroids, treatment with immunosuppressants, baseline disease activity, and week 10 remission status. All participants and study site personnel were masked to treatment assignment. The primary endpoint was remission at week 62 (MCS ≤2, with individual subscores ≤1, and rectal bleeding subscore of 0) among patients with a clinical response at week 10, measured in the modified intention-to-treat population (all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02165215, and is now closed to recruitment. FINDINGS: Between Aug 12, 2014, and June 4, 2020, 658 patients were screened for eligibility and 359 were enrolled into the induction phase. 214 (60%) patients had a clinical response at week 10 and were randomly assigned to receive etrolizumab (n=108) or placebo (n=106) in the maintenance phase. 80 (74%) patients in the etrolizumab group and 42 (40%) in the placebo group completed the study through week 62. Four patients in the placebo group did not receive study treatment and were excluded from the analyses. At week 62, 32 (29·6%) of 108 patients in the etrolizumab group and 21 (20·6%) of 102 in the placebo group were in remission (adjusted treatment difference 7·7% [95% CI -4·2 to 19·2]; p=0·19). A greater proportion of patients reported one or more adverse events in the placebo group (82 [80%] of 102) than in the etrolizumab group (70 [65%] of 108); the most common adverse event in both groups was ulcerative colitis (16 [15%] patients in the etrolizumab group and 37 [36%] in the placebo group). Ten (9%) patients in the etrolizumab group and eight (8%) in the placebo group reported one or more serious adverse events. No deaths were reported in either treatment group. INTERPRETATION: No significant differences were observed between maintenance etrolizumab and placebo in the primary endpoint of remission at week 62 among patients who had a clinical response at week 10. Etrolizumab was well tolerated in this population and no new safety signals were identified. FUNDING: F Hoffmann-La Roche. ispartof: LANCET GASTROENTEROLOGY & HEPATOLOGY vol:7 issue:1 pages:28-37 ispartof: location:Netherlands status: published

Background and Aim: The BreathID®Hp urea breath test provides several advantages over other 13C breath analyzers for the detection of Helicobacter pylori. We evaluated the sensitivity and specificity of a new BreathID®Hp Lab System (Exalenz Bioscience Ltd, Israel), a 13C-urea breath test system using breath sampling bags that facilitates multiple testing in a multicenter international clinical study. Methods: A total of 257 subjects with evaluable results for urea breath test, rapid urease test, and histology were enrolled into two study groups: 189 naïve subjects were included in the pre-therapy group, and 68 subjects comprised the post-eradication therapy group. Analytical studies were conducted to evaluate the stability, reproducibility, and repeatability of the 13C-urea breath test results using a delta over baseline cut-off value of 5. Results: Among the pre-therapy subjects evaluated with the composite results from the rapid urease test and histology/immunohistochemistry, 176 results matched those of the urea breath test, resulting in an overall agreement of 98.3% with a sensitivity of 100% and specificity of 97.9%. In the post-eradication therapy cohort, the overall agreement between the urea breath test and the biopsy diagnosis was 98.5%; the sensitivity of the urea breath test in this cohort was 92.3% and the specificity was 100%. There was uniformly high overall reproducibility (99.48%) of the test results over different batches of breath sample bags, when analyzed on different days and under different storage conditions, showing stability of the breath samples in the breath collection bags Conclusion: The BreathID®Hp Lab System is a highly accurate and dependable method for the diagnosis of H. pylori infection.

BACKGROUND & AIMS: Topically applied methylene blue dye chromoendoscopy is effective in improving detection of colorectal neoplasia. When combined with a pH- and time-dependent multimatrix structure, a per-oral methylene blue formulation (MB-MMX) can be delivered directly to the colorectal mucosa. METHODS: We performed a phase 3 study of 1205 patients scheduled for colorectal cancer screening or surveillance colonoscopies (50-75 years old) at 20 sites in Europe and the United States, from December 2013 through October 2016. Patients were randomly assigned to groups given 200 mg MB-MMX, placebo, or 100 mg MB-MMX (ratio of 2:2:1). The 100-mg MB-MMX group was included for masking purposes. MB-MMX and placebo tablets were administered with a 4-L polyethylene glycol-based bowel preparation. The patients then underwent colonoscopy by an experienced endoscopist with centralized double-reading. The primary endpoint was the proportion of patients with 1 adenoma or carcinoma (adenoma detection rate [ADR]). We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for differences in detection between the 200-mg MB-MMX and placebo groups. False-positive (resection rate for non-neoplastic polyps) and adverse events were assessed as secondary endpoints. RESULTS: The ADR was higher for the MB-MMX group (273 of 485 patients, 56.29%) than the placebo group (229 of 479 patients, 47.81%) (OR 1.46; 95% CI 1.09-1.96). The proportion of patients with nonpolypoid lesions was higher in the MB-MMX group (213 of 485 patients, 43.92%) than the placebo group (168 of 479 patients, 35.07%) (OR 1.66; 95% CI 1.21-2.26). The proportion of patients with adenomas ≤5 mm was higher in the MB-MMX group (180 of 485 patients, 37.11%) than the placebo group (148 of 479 patients, 30.90%) (OR 1.36; 95% CI 1.01-1.83), but there was no difference between groups in detection of polypoid or larger lesions. The false-positive rate did not differ significantly between groups (83 [23.31%] of 356 patients with non-neoplastic lesions in the MB-MMX vs 97 [29.75%] of 326 patients with non-neoplastic lesions in the placebo group). Overall, 0.7% of patients had severe adverse events but there was no significant difference between groups. CONCLUSIONS: In a phase 3 trial of patients undergoing screening or surveillance colonoscopies, we found MB-MMX led to an absolute 8.5% increase in ADR, compared with placebo, without increasing the removal of non-neoplastic lesions. Clinicaltrials.gov no: NCT01694966. ispartof: GASTROENTEROLOGY vol:156 issue:8 pages:2198-+ ispartof: location:United States status: published

Primary prevention of colonic adenomas and cancer through dietary interventions or chemoprevention has great appeal. This article discusses primary prevention goals and promising nutritional or chemopreventive strategies. There is substantial observational evidence that diets high in total calories and fat and or low in fruits and vegetables or total fiber as well as low levels of physical activity are related to the risk of colonic neoplasia. Similar observational data indicate that diets high in specific nutrients such as antioxidant vitamins or calcium may be protective. The article describes some of the newer chemopreventive agents and reviews the data linking diet and lifestyle to colorectal cancer risk, focusing on interventions that have also been studied in prospective clinical trials. Finally the evidence supporting the role of non-steroidal anti-inflammatory drugs for the chemoprevention of CRC is reviewed and the status of several other promising newer agents that are entering human trials is summarized.

Colorectal cancer (CRC) incidence and mortality are steadily declining and CRC screening rates are increasing in the United States. Although this a very good news, several definable groups still have very low screening rates including younger (under age 50) members of high-risk CRC families. This opinion piece describes five strategies that could be incorporated into routine practice to improve identification and guideline-based screening in members of high-risk families. Routine incorporation of a simple family history screening tool and outreach to high-risk family members could substantially improve guideline-based screening in this population. Identification of CRCs and advanced adenomas in the endoscopy suite defines another group of high-risk families for similar outreach. Lynch syndrome families can be identified by testing CRCs and selected adenomas for microsatellite instability or loss of DNA repair protein expression. Finally, selective addition of aspirin to surveillance endoscopy can decrease the risk of new adenomas and CRCs. The rationale for these strategies as well as mechanisms for their implementation and evaluation in clinical practice is described.

Bilateral thumb burns on a young woman admitted to the hospital with the diagnosis of community-acquired pneumonia led us to consider the diagnosis of crack lung despite the fact that the woman denied cocaine use. Cocaine was found on a urine toxicology study, and its use was subsequently confirmed by history. The patient was treated for crack lung with complete resolution of her symptoms and radiographic findings. Inspection of the hands for burns consistent with handling cocaine pipes should prompt a consideration of crack lung in patients with pulmonary infiltrates.

Adenosine 5’-triphosphate (ATP) is a nucleoside triphosphate composed of adenine, ribose, and three phosphate groups and is the principal carrier of chemical energy within the cell. Roughly 10 molecules of ATP are in solution throughout the intracellular space in a typical cell, providing energy for a large variety of biologic reactions that are energetically unfavorable and would otherwise not occur [4]. ATP also serves as the substrate for one of the most widely used intracellular signaling molecules, adenosine 3’,5’-cyclic monophosphate (cAMP), and is ubiquitous as a mediator of protein signaling through regulatory phosphorylation. While it has long been recognized that ATP serves as the substrate for one of the most common intracellular signaling molecules, it is more recently becoming apparent that ATP and other nucleotides also serve as potent extracellular signaling molecules. In fact, autocrine release of extracellular ATP is a ubiquitous biologic and physiologic process in numerous cell types including epithelial cells, endothelial cells, smooth muscle cells, fibroblasts, circulating lymphocytes, monocytes, red blood cells, mast cells, chondrocytes, excitatory neurons, platelets, hepatocytes, pancreatic β-cells and cholangiocytes [34]. ATP and other nucleotides exert potent autocrine and paracrine effects on cellular function through activation of purinergic receptors [12, 53]. In hepatocytes and cholangiocytes, activation of purinergic receptors through agonist binding has been linked to numerous fundamental biologic processes including cell volume regulation, glucose metabolism, bile formation, secretion and ion channel activation [40, 49, 50, 54]. Despite the recent advances in knowledge of extracellular signaling through purinergic receptors, the mechanisms of cellular ATP release remain unknown. It should be recognized that while this review focuses primarily on ATP, the mechanisms for nucleotide release presented apply to uridine nucleotides and nucleotide sugars, suggesting that these nucleotides are also capable of acting as autocrine/paracrine signaling molecules [10]. Historically, two broad models of nucleotide release have been recognized: exocytotic release of nucleotides involving the mobilization of vesicles rich in ATP, and channel-mediated release of ATP through various candidate transporters and/or exchangers. The mechanisms employed by a cell for nucleotide release will depend on the specific cell model studied and its purinergic receptor distribution. Accordingly this chapter will focus on the two principal epithelial cell types that are involved in most liver diseases: hepatocytes, which constitute the liver parenchyma, and cholangiocytes, which line the lumen of the bile ducts. The emerging role of extracellular nucleotides in the regulation of cellular physiology in these cell types was reviewed by Roman et al. [47]. This chapter builds on that work by following a similar format while focusing on more recent developments in the field.

Extracellular ATP is a potent autocrine/paracrine signal that regulates a broad range of liver functions through activation of purinergic receptors. In biliary epithelium, increases in cell volume stimulate ATP release through a phosphoinositide 3-kinase (PI3-kinase)-dependent mechanism. Because PI3-kinase also regulates vesicular exocytosis, the purpose of these studies was to determine whether volume-stimulated vesicular exocytosis contributes to cellular ATP release. In a human cholangiocarcinoma cell line, exocytosis was measured by using the plasma membrane marker FM1–43, whereas ATP release was assessed by using a luciferase-luciferin assay. Under basal conditions, cholangiocytes exhibited constitutive exocytosis at a rate of 1.6%/min, and low levels of extracellular ATP were detected at 48.2 arbitrary light units. Increases in cholangiocyte cell volume induced by hypotonic exposure resulted in a 10-fold increase in the rate of exocytosis and a robust 35-fold increase in ATP release. Both vesicular exocytosis and ATP release were proportional to cell volume, and both exhibited similar regulatory properties including: 1) dependence on intact PI3-kinase, 2) attenuation by inhibition of PKC, and 3) potentiation by activation of PKC before hypotonic exposure. These findings demonstrate that increases in cholangiocyte cell volume stimulate ATP release and vesicular exocytosis through similar regulatory paradigms. Functional interactions among cell volume, PKC, and PI3-kinase modulate exocytosis, thereby regulating ATP release and purinergic signaling in cholangiocytes. It is hypothesized that PKC is involved in the recruitment of a volume-sensitive vesicular pool to a readily releasable state.