Bret A. Lashner

Bio: Bret A. Lashner is an academic researcher from Cleveland Clinic. The author has contributed to research in topics: Ulcerative colitis & Inflammatory bowel disease. The author has an hindex of 39, co-authored 122 publications receiving 6652 citations. Previous affiliations of Bret A. Lashner include Cleveland Clinic Lerner College of Medicine.

The risk of colorectal cancer in ulcerative colitis: a meta-analysis

Abstract: BACKGROUND AND AIMS Controversy surrounds the risk of colorectal cancer (CRC) in ulcerative colitis (UC). Many studies have investigated this risk and reported widely varying rates. METHODS A literature search using Medline with the explosion of references identified 194 studies. Of these, 116 met our inclusion criteria from which the number of patients and cancers detected could be extracted. Overall pooled estimates, with 95% confidence intervals (CI), of cancer prevalence and incidence were obtained using a random effects model on either the log odds or log incidence scale, as appropriate. RESULTS The overall prevalence of CRC in any UC patient, based on 116 studies, was estimated to be 3.7% (95% CI 3.2–4.2%). Of the 116 studies, 41 reported colitis duration. From these the overall incidence rate was 3/1000 person years duration (pyd), (95% CI 2/1000 to 4/1000). The overall incidence rate for any child was 6/1000 pyd (95% CI 3/1000 to 13/1000). Of the 41 studies, 19 reported results stratified into 10 year intervals of disease duration. For the first 10 years the incidence rate was 2/1000 pyd (95% CI 1/1000 to 2/1000), for the second decade the incidence rate was estimated to be 7/1000 pyd (95% CI 4/1000 to 12/1000), and in the third decade the incidence rate was 12/1000 pyd (95% CI 7/1000 to 19/1000). These incidence rates corresponded to cumulative probabilities of 2% by 10 years, 8% by 20 years, and 18% by 30 years. The worldwide cancer incidence rates varied geographically, being 5/1000 pyd in the USA, 4/1000 pyd in the UK, and 2/1000 pyd in Scandinavia and other countries. Over time the cancer risk has increased since 1955 but this finding was not significant (p=0.8). CONCLUSIONS Using new meta-analysis techniques we determined the risk of CRC in UC by decade of disease and defined the risk in pancolitics and children. We found a non-significant increase in risk over time and estimated how risk varies with geography.

Colonic health: fermentation and short chain fatty acids.

Abstract: Interest has been recently rekindled in short chain fatty acids (SCFAs) with the emergence of prebiotics and probiotics aimed at improving colonic and systemic health Dietary carbohydrates, specifically resistant starches and dietary fiber, are substrates for fermentation that produce SCFAs, primarily acetate, propionate, and butyrate, as end products The rate and amount of SCFA production depends on the species and amounts of microflora present in the colon, the substrate source and gut transit time SCFAs are readily absorbed Butyrate is the major energy source for colonocytes Propionate is largely taken up by the liver Acetate enters the peripheral circulation to be metabolized by peripheral tissues Specific SCFA may reduce the risk of developing gastrointestinal disorders, cancer, and cardiovascular disease Acetate is the principal SCFA in the colon, and after absorption it has been shown to increase cholesterol synthesis However, propionate, a gluconeogenerator, has been shown to inhibit cholesterol synthesis Therefore, substrates that can decrease the acetate: propionate ratio may reduce serum lipids and possibly cardiovascular disease risk Butyrate has been studied for its role in nourishing the colonic mucosa and in the prevention of cancer of the colon, by promoting cell differentiation, cell-cycle arrest and apoptosis of transformed colonocytes; inhibiting the enzyme histone deacetylase and decreasing the transformation of primary to secondary bile acids as a result of colonic acidification Therefore, a greater increase in SCFA production and potentially a greater delivery of SCFA, specifically butyrate, to the distal colon may result in a protective effect Butyrate irrigation (enema) has also been suggested in the treatment of colitis More human studies are now needed, especially, given the diverse nature of carbohydrate substrates and the SCFA patterns resulting from their fermentation Short-term and long-term human studies are particularly required on SCFAs in relation to markers of cancer risk These studies will be key to the success of dietary recommendations to maximize colonic disease prevention

Review article: the role of butyrate on colonic function

Abstract: BACKGROUND: Butyrate, a short-chain fatty acid, is a main end-product of intestinal microbial fermentation of mainly dietary fibre. Butyrate is an important energy source for intestinal epithelial cells and plays a role in the maintenance of colonic homeostasis. AIM: To provide an overview on the present knowledge of the bioactivity of butyrate, emphasizing effects and possible mechanisms of action in relation to human colonic function. METHODS: A PubMed search was performed to select relevant publications using the search terms: 'butyrate, short-chain fatty acid, fibre, colon, inflammation, carcinogenesis, barrier, oxidative stress, permeability and satiety'. RESULTS: Butyrate exerts potent effects on a variety of colonic mucosal functions such as inhibition of inflammation and carcinogenesis, reinforcing various components of the colonic defence barrier and decreasing oxidative stress. In addition, butyrate may promote satiety. Two important mechanisms include the inhibition of nuclear factor kappa B activation and histone deacetylation. However, the observed effects of butyrate largely depend on concentrations and models used and human data are still limited. CONCLUSION: Although most studies point towards beneficial effects of butyrate, more human in vivo studies are needed to contribute to our current understanding of butyrate-mediated effects on colonic function in health and disease.

Vedolizumab as induction and maintenance therapy for ulcerative colitis.

Abstract: We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 pa tients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a de crease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. Results Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P 1), as compared with 15.9% of pa tients who switched to placebo (adjusted difference, 26.1 percentage points for vedoliz umab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P<0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups. Conclusions Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.)

Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease

Abstract: BackgroundUstekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. MethodsWe randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 w...