Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of Patients With Ulcerative Colitis

BACKGROUND & AIMS: Maintenance treatment with vedolizumab, a monoclonal antibody that inhibits the gut-selective α4β7 integrin, is administered intravenously. Some patients might prefer a subcutaneous formulation of vedolizumab for maintenance treatment. Subcutaneous vedolizumab was investigated as maintenance treatment in patients with moderately to severely active ulcerative colitis. METHODS: We performed a phase 3, double-blind, double-dummy trial at 141 sites in 29 countries from December 18, 2015 through August 21, 2018. Patients with moderately to severely active ulcerative colitis received open-label treatment with intravenous vedolizumab 300 mg at weeks 0 and 2. At week 6, patients with clinical response were randomly assigned maintenance treatment with subcutaneous vedolizumab 108 mg every 2 weeks, intravenous vedolizumab 300 mg every 8 weeks, or placebo. The primary end point was clinical remission at week 52, which was defined as a total Mayo score of ≤2 and no subscore >1. RESULTS: Among the randomized 216 patients, clinical remission at week 52 was achieved by 46.2%, 42.6%, and 14.3% of patients in the subcutaneous vedolizumab, intravenous vedolizumab, and placebo groups, respectively (subcutaneous vedolizumab vs placebo: Δ32.3%; 95% confidence interval, 19.7%-45.0%; P < .001). The subcutaneous vedolizumab group also had greater endoscopic improvement and durable clinical response at week 52 compared with placebo (both P < .001). The incidence of injection-site reactions was more frequent in patients given subcutaneous vedolizumab (10.4%) than intravenous vedolizumab (1.9%) or placebo (0%); these were not treatment limiting, most were mild, and none resulted in discontinuation. Subcutaneous and intravenous vedolizumab safety profiles were otherwise similar. CONCLUSIONS: Subcutaneous vedolizumab is effective as maintenance therapy in patients with moderately to severely active ulcerative colitis who had a clinical response to intravenous vedolizumab induction therapy. It has a favorable safety and tolerability profile. ClinicalTrials.gov ID: NCT02611830; EudraCT 2015-000480-14. ispartof: GASTROENTEROLOGY vol:158 issue:3 pages:562-+ ispartof: location:United States status: publishe

Association of Biomarker Cutoffs and Endoscopic Outcomes in Crohn's Disease: A Post Hoc Analysis From the CALM Study

Abstract Background CALM was a randomized phase 3 trial in patients with Crohn's disease (CD) that demonstrated improved endoscopic outcomes when treatment was escalated based on cutoffs for inflammatory biomarkers, fecal calprotectin (FC), C-reactive protein (CRP), and CD Activity Index (CDAI) remission vs CDAI response alone. The purpose of this post hoc analysis of CALM was to identify drivers of treatment escalation and evaluate the association between biomarker cutoff concentrations and endoscopic end points. Methods The proportion of patients achieving CD Endoscopic Index of Severity (CDEIS) &lt;4 and no deep ulcers 48 weeks after randomization was evaluated according to CRP &lt;5 mg/L or ≥5 mg/L and FC &lt;250 μg/g or ≥250 μg/g. Subgroup analyses were performed according to disease location, and sensitivity analyses were conducted in patients with elevated CRP and/or FC at baseline. The association between endoscopic end points and biomarker cutoffs was performed using χ 2 test. Results The proportion of patients who achieved the primary end point CDEIS &lt;4 and no deep ulcers was significantly greater for those with FC &lt;250 µg/g (74%; P &lt; 0.001), with an additive effect for CRP &lt;5 mg/L. The association of FC &lt;250 µg/g with improved endoscopic outcomes was independent of disease location, although the greatest association was observed for ileocolonic disease. Fecal calprotectin &lt;250 µg/g, CRP &lt;5 mg/L, and CDAI &lt;150 gave a sensitivity/specificity of 72%/63% and positive/negative predictive values of 86%/42% for CDEIS &lt;4 and no deep ulcers 48 weeks after randomization. Conclusion This post hoc analysis of CALM demonstrated that a cutoff of FC &lt;250 µg/g is a useful surrogate marker for mucosal healing in CD

Epidermal Growth Factor Receptor and K-RAS status in two cohorts of squamous cell carcinomas

With the availability of effective anti-EGFR therapies for various solid malignancies, such as non-cell small lung cancer, colorectal cancer and squamous cell carcinoma of the head and neck, the knowledge of EGFR and K-RAS status becomes clinically important. The aim of this study was to analyse EGFR expression, EGFR gene copy number and EGFR and K-RAS mutations in two cohorts of squamous cell carcinomas, specifically anal canal and tonsil carcinomas.Journal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Faecal calprotectin : comparative study of the Quantum Blue rapid test and an established ELISA method

Background: Faecal calprotectin is a non-invasive marker for neutrophilic intestinal inflammation. It can be used in the differential diagnosis between functional and organic bowel disease. Moreover, it correlates with endoscopic organic bowel disease activity. The objective of this study is to evaluate a recently launched quantitative immuno-chromatographic point-of-care test: Quantum Blue Calprotectin (Buhlmann Laboratories AG, Schonenbuch, Switzerland) in comparison to an established ELISA method (Buhlmann Laboratories AG). Methods: We included 142 samples, either archived (-80 degrees C) faecal extracts or fresh routine samples. Both the normal range cartridges as well as the high range cartridge from the point-of-care test were used. The ELISA was compared with the point-of-care test and the optimal the point-of-care test cut-off values were searched for using Microsoft (R) Excel 2002 and MedCalc Software version 10.0.0.0 (Mariakerke, Belgium). Results: In the method comparison a determination coefficient (R-2) of 0.89 was found. The Passing Bablok regression analysis showed a significant deviation from linearity (y = -40.8 + 1.0x). The use of a cut-off value of 30 mu g/g faeces and a grey zone of 30-110 mu g/g faeces resulted in the best agreement between the ELISA interpretation and the point-of-care test interpretation, with 89.4% (127/142) agreement and 10.6% (15/142) mismatches. Conclusions: We may conclude that the point-of-care test can serve as a reliable alternative to the time consuming ELISA in the differential diagnosis between functional and organic bowel disease. Furthermore, it seems to be reliable in the follow-up of inflammatory bowel disease patients

Application of humic substances results in consistent increases in crop yield and nutrient uptake

The effect of humic substances on yield and nutrient uptake of grass, maize, potato and spinach was investigated in six field experiments and two pot experiments in a high input cropping system. The humic substances originating from leonardite formations in Canada were applied as liquid solution to the soil (Humifirst liquid) or as a solid incorporated in mineral fertilizers (Humifirst incorporated). Formal meta-analysis of the results of all executed experiments showed that the application of humic substances had an overall positive effect on dry matter yield of the crops and this effect was statistically significant for Humifirst incorporated. In the case of permanent grassland, humic substances promoted mainly the production of the first grass cut, which has the highest grass quality among all cuts during the growing season. Tuber production on the potato field trial showed a high response on the application of humic substances. Total potato yield increased with 13 and 17% for Humifirst liquid and Humifirst incorporated, respectively. The effect of humic substances on maize yield was limited, probably due to the rather high nutrient status of both soils. Finally, the formal meta-analysis showed a consequent increase in nitrogen and phosphorus uptake of all studied crops as well. The effect on potassium and magnesium uptake was also mainly positive, while sodium and calcium uptake were not affected in most of the experiments

Further elucidation of beer flavor instability : the potential role of cysteine-bound aldehydes

The potential involvement of 2-substituted 1,3-thiazolidine-4-carboxylic acids in beer flavor stability was further investigated. The binding behavior of beer-aging aldehydes toward both cysteine and bisulfite was confirmed and compared in model solutions of varying pH values that are relevant to malting and brewing (pH 6.0, 5.2, and 4.4). It was found that binding of aldehydes increased with increasing pH, especially for binding to cysteine. Furthermore, a sample preparation approach was developed to release aldehydes from their bound-state. After binding between aldehydes and cysteine, the strong base 4-vinylpyridine (4VP) was added to the samples as a competitor of the aldehydes toward cysteine binding, and subsequent release of aldehydes was clearly observed. The same approach also resulted in a release of aldehydes from preformed bisulfite adducts. Sample treatment with 4VP was also applied to fresh pale lager beer, resulting in increased levels of free beer-aging aldehydes. Moreover, the presence of furfural-derived 1,3-thiazolidine-4-carboxylic acid in fresh pale lager beer was confirmed and quantified by a newly developed ultra-performance liquid chromatography-UV method. The insights gained in this study strengthen the hypothesis that 2-substituted 1,3-thiazolidine-4-carboxylic acids may play an important role in beer flavor stability or instability