Characterization of urinary microbiome in patients with bladder cancer: Results from a single-institution, feasibility study.

OBJECTIVES: The human microbiome has been linked to the development of several malignancies, but there is scarcity of data on the microbiome of bladder cancer patients. In this study, we analyzed microbial composition and diversity among patients with and without bladder cancer. MATERIAL AND METHODS: Samples were collected from 38 urothelial carcinoma (UC) patients and 10 noncancer controls from August 2018 to May 2019. DNA was extracted and processed for 16 S ribosomal RNA sequencing. Alpha diversity community characteristics including evenness and richness as well as beta diversity metrics were obtained. Linear discriminant analysis effect size was used to identify microbial components whose sequences were more abundant. Pairwise statistics provided quantitative assessment of significant distributions among groups. RESULTS: Thirty seven total samples contained high quality sequence data for subsequent analyses and divided into 3 cohorts: control (n = 10), muscle-invasive (n = 15) and superficial UC (n = 12). Control samples had significantly higher species evenness when compared to invasive (P = 0.031) and superficial tumors (P = 0.002). In addition, higher species richness was observed in noncancer versus cancer samples (Faith phylogenetic diversity, P < 0.05). Significantly enriched taxa were found in both control (Bacteroides, Lachnoclostridium, Burkholderiaceae) and cancer samples (Bacteroides and Faecalbacterium). CONCLUSION: Significantly decreased microbial community diversity was seen in the urine of patients with bladder cancer when compared to a noncancer group. Distinct taxa were noted suggesting unique microbial communities in the urine of bladder cancer patients.

Expression of gastric pyloric mucin, MUC6, in colorectal serrated polyps.

Serrated polyps of the colorectal mucosa represent a heterogeneous and controversial taxonomic category with variation in histopathological, molecular, and immunohistochemical characteristics and with an incomplete understanding of pathogenesis. A previous study reported that the expression of gastric pyloric-type mucin, MUC6, characterized sessile serrated adenomas. We therefore evaluated the expression of MUC6 in serrated polyps identified among 2502 participants in a Phase III chemoprevention trial within the Arizona Cancer Center Colorectal Cancer Prevention Trials Program and characterized the associated histopathological features and location. We carried out immunohistochemistry for MUC6 on 146 serrated lesions and 87 conventional tubular adenomas, and assessed the percentage of cells with expression and the grade of staining intensity. In all 92 hyperplastic polyps, 43 sessile serrated adenomas, and 11 traditional serrated adenomas were included. Polyps ranged in size from 1-150 mm. The association of MUC6 staining with serrated polyp category was evaluated using classification and regression tree (CART) analysis and two-sided Fisher's exact test. A total of 53% of sessile serrated adenomas (n=23), 17% of hyperplastic polyps (n=16), and 18% of traditional serrated adenomas (n=2), but none of 87 tubular adenomas, expressed MUC6. Expression was limited to the lower crypts in all serrated polyps. The extent of positive staining ranged from 2-100% of crypt cells and was independent of the histopathological type. MUC6 expression had relatively high specificity for sessile serrated adenoma (82%) but low sensitivity (54%). In CART analysis, proximal location was found to be the best partitioning factor for MUC6, followed by classification as sessile serrated adenoma. We conclude that MUC6 expression is strongly associated with proximal location of serrated polyps, but only has modest utility as a tissue biomarker for sessile serrated adenoma.

Preclinical antitumor activity, pharmacokinetics and pharmacodynamics of imexon in mice.

Imexon, a novel pro-oxidant, thiol-binding agent, is currently in phase I/II clinical trials in patients with advanced solid tumors. The aim of this study was to characterize the preclinical pharmacology of imexon in vivo. We investigated the anticancer activity of imexon in several cancer cell lines grown as xenografts in severe combined immunodeficient mice. Imexon was active against both hematologic and solid tumor types. The maximally tolerated dose, at the selected dosing schedule, was 150 mg/kg. Using the maximally tolerated dose of imexon, we sought to identify a potential pharmacodynamic biomarker to monitor the mechanistic effect systemically. As imexon binds cellular thiols in vitro, thiol depletion by imexon in vivo was evaluated as a potential biomarker. Following a single 150 mg/kg dose of imexon by intraperitoneal injection, glutathione levels decreased by 40% at 3 h in mouse erythrocytes. In mouse plasma, imexon treatment led to a significant decrease in cystine levels 2-4 h after drug administration. Notably, by this time, free imexon plasma levels were nondetectable. By investigating the pharmacokinetics of imexon, we also found that imexon undergoes rapid clearance from plasma in a dose-independent fashion with a half-life of 12-15 min. In summary, imexon is active against several cancer types in vivo. Imexon also decreases circulating thiols and exhibits dose-independent pharmacokinetics in mice. Plasma cystine levels may represent a biomarker of imexon activity in vivo.