Urinary microbiota is associated to clinicopathological features in benign prostatic hyperplasia.

BACKGROUND: The urinary microbiota of patients with benign prostatic hyperplasia (BPH) has been associated with lower urinary tract symptoms (LUTS), however, little is known about urinary microbiota correlations with clinicopathological parameters associated with BPH. Here, we investigate associations between the urinary microbiota and clinical parameters of patients with BPH undergoing surgery. METHODS: Forty-one patients with BPH undergoing surgery were recruited from two medical centers. Catheterized urine specimens were collected and the microbiota was characterized by 16S rRNA gene sequencing. Patients were segregated into two groups according to each clinical parameter and differences in urinary microbiota diversity and composition were evaluated. RESULTS: Higher prostate weight and prostate-specific antigen (PSA) levels were associated with higher alpha diversity in the urinary microbiota of BPH patients. At the specific microbe level, we found that the greater the prostatic weight, the lower the relative abundance of Streptococcus, while the greater the PSA levels, the higher the abundance of Lactobacillus. Treatment with 5-α-reductase inhibitor was associated with overall urinary microbiota composition, in part due to a higher abundance of Corynebacterium and Anaerococcus in this group. CONCLUSIONS: We demonstrated that the urinary microbiota of BPH patients is associated with clinicopathological features, paving the way for larger studies in which causality between urinary microbiota and BPH can be appropriately explored.

Comprehensive Landscape of Cyclin Pathway Gene Alterations and Co-occurrence with FGF/FGFR Aberrations Across Urinary Tract Tumors.

BACKGROUND: Cyclin pathway gene alterations are frequent in urothelial tumors and may co-exist with other important aberrations, leading to therapeutic opportunities. We characterized the landscape of cyclin gene alterations in urothelial and non-urothelial urinary tract (UT) malignancies. PATIENTS AND METHODS: Overall, 6842 urothelial and 897 non-urothelial UT cancers were analyzed (hybrid-capture-based comprehensive genomic profile (Foundation Medicine)). Alteration frequency in cyclin-sensitizing and -resistance genes, and co-occurrence with fibroblast growth factor receptor (FGFR) gene abnormalities were evaluated. RESULTS: Cyclin-activating gene alterations were detected in 47.3% of urothelial and 37.9% of non-urothelial UT cancers. Frequency varied by histology and tumor site. CDKN2A and CDKN2B loss were the most frequent alterations in urothelial tumors (present in 38.5% and 30.4% of patients, respectively). Both genes were less frequently altered in adenocarcinomas (15.2% and 8.9%), but commonly altered in squamous cell carcinomas (74.4% and 39%). Tumors of neuroendocrine origin were relatively silent in activating cyclin alterations, but frequently displayed Rb1 alterations (86% and 83.7% of neuroendocrines and small cell carcinomas). Urachal tumors (n = 79) presented a distinct landscape of cyclin alterations relative to other UT cancers, with less frequent alterations overall. FGF/FGFR genes were altered in 34.9% of urothelial (22.1% in FGFR3), and 19.4% of non-urothelial urinary tract tumors (6.8% FGFR3). Cyclin-activating alterations frequently co-occurred with FGF/FGFR alterations but were in general mutually exclusively with cyclin resistance alterations (RB1/CCNE1). CONCLUSIONS: Cyclin pathway activating alterations are common in urinary tract tumors, but frequency varies with histology and tumors sites. Co-occurrence of cyclin and FGFR pathway alterations may inform therapeutic opportunities.

Choice of 16S Ribosomal RNA Primers Impacts Male Urinary Microbiota Profiling.

Accessibility to next-generation sequencing (NGS) technologies has enabled the profiling of microbial communities living in distinct habitats. 16S ribosomal RNA (rRNA) gene sequencing is widely used for microbiota profiling with NGS technologies. Since most used NGS platforms generate short reads, sequencing the full-length 16S rRNA gene is impractical. Therefore, choosing which 16S rRNA hypervariable region to sequence is critical in microbiota profiling studies. All nine 16S rRNA hypervariable regions are taxonomically informative, but due to variability in profiling performance for specific clades, choosing the ideal 16S rRNA hypervariable region will depend on the bacterial composition of the habitat under study. Recently, NGS allowed the identification of microbes in the urinary tract, and urinary microbiota has become an active research area. However, there is no current study evaluating the performance of different 16S rRNA hypervariable regions for male urinary microbiota profiling. We collected urine samples from male volunteers and profiled their urinary microbiota by sequencing a panel of six amplicons encompassing all nine 16S rRNA hypervariable regions. Systematic comparisons of their performance indicate V1V2 hypervariable regions better assess the taxa commonly present in male urine samples, suggesting V1V2 amplicon sequencing is more suitable for male urinary microbiota profiling. We believe our results will be helpful to guide this crucial methodological choice in future male urinary microbiota studies.

Trametinib and Hydroxychloroquine (HCQ) Combination Treatment in KRAS-Mutated Advanced Pancreatic Adenocarcinoma: Detailed Description of Two Cases.

PURPOSE: Over the last decades, cytotoxic chemotherapy has been the cornerstone of metastatic pancreatic adenocarcinoma treatment. In late-stage disease, a range of treatment regimens still offers minor benefits. Molecular profiling studies have shown that pancreatic adenocarcinoma (PDAC) is a mutation-driven tumor type, with KRAS mutations found in approximately 90% of cases, which could partially explain the resistance to chemotherapy. Preclinical data on selective targeting of a downstream point of the RAF-MEK-ERK pathway with a MEK inhibitor along with the concurrent use of an autophagy inhibitor such as hydroxychloroquine appears to be one alternative approach to overcome resistance and inhibit cell proliferation. METHODS: We herein aim to investigate the rationale of autophagy inhibitors use and describe the outcomes of patients who received this experimental treatment. RESULTS: Two patients have received this experimental regimen from January 2020 to the present date, achieving disease stabilization that is clinically meaningful, considering the chemoresistance scenario of the included patients. CONCLUSIONS: Our real-life data regarding KRAS-mutated PDAC patients who received treatment with the MEK inhibitor trametinib combined with hydroxychloroquine after experiencing disease progression are consistent with the preclinical data, pointing to the clinical benefits of this regimen.

Use of Expansion Cohorts in Phase I Trials and Probability of Success in Phase II for 381 Anticancer Drugs.

Purpose: Evaluate the association between the use of phase I expansion cohorts (ECs) and drug performance in phase II as well as time to approval by the FDA.Experimental Design: We performed a systematic search of MEDLINE for single-agent dose-finding adult oncology phase I trials published in 2006 to 2011 and subsequent phase II trials. Successful phase II trials were those that met their primary endpoints. Dates of approval were obtained from the Drugs@FDA website in April 2014. A logistic regression model was used to determine the associations between variables and success in phase II.Results: We identified 533 phase I trials evaluating 381 drugs; 112 drugs had at least one phase I trial with an expansion cohort. Phase I trials with expansion cohorts of two to 20 patients were associated with a higher rate of successful phase II trials than those with no expansion cohort [48% vs. 27%; OR, 2.1; 95% confidence interval (CI), 1.1-4.0; P = 0.037]. Phase II success rates were the same for expansion cohort with two to 20 and more than 20 patients (48% vs. 52%). Other positive associations were disease-specific trials (OR, 1.7; 95% CI, 1.0-2.9; P = 0.037), industry sponsorship (OR, 2.9; 95% CI, 1.5-5.7; P = 0.0024), and response rate of 6% to 20% (OR, 2.89; 95% CI, 1.6-5.2; P = 0.0007). Drugs tested in phase I trials with expansion cohorts had a higher rate of 5-year approval (19% vs. 5%; HR, 4.4; 95% CI, 2.2-8.8; P < 0.001).Conclusions: The use of expansion cohorts in phase I trials was associated with success of subsequent phase II trials. However, confounders may play a role in this association. Clin Cancer Res; 23(15); 4020-6. ©2017 AACR.

MET abnormalities in patients with genitourinary malignancies and outcomes with c-MET inhibitors.

BACKGROUND: The purpose of this study was to determine the prevalence of MET amplification and mutation among GU malignancies and its association with clinical factors and responses to c-MET inhibitors. PATIENTS AND METHODS: Patients with GU malignancies referred to our Phase I Clinical Trials Program were evaluated for MET mutation and amplification and outcomes using protocols with c-MET inhibitors. RESULTS: MET amplification was found in 7 of 97 (7.2%) patients (4/27 renal [all clear cell], 1/18 urothelial, and 2/12 adrenocortical carcinoma), with MET mutation/variant in 3 of 54 (5.6%) (2/20 renal cell carcinoma [RCC] [1 clear cell and 1 papillary] and 1/16 prostate cancer). No demographic characteristics were associated with specific MET abnormalities, but patients who tested positive for mutation or amplification had more metastatic sites (median, 4 vs. 3 for wild type MET). Median overall survival after phase I consultation was 6.1 and 11.5 months for patients with and without a MET alteration, respectively (hazard ratio, 2.8; 95% confidence interval, 1.1 to 6.9; P = .034). Twenty-nine (25%) patients were treated according to a c-MET inhibitor protocol. Six (21%) had a partial response (prostate and RCC) and 10 (34%) had stable disease as best response. Median time to tumor progression was 2.3 months (range, 0.4-19.7) for all treated patients with no responses in patients with a MET abnormality or single-agent c-MET inhibitor treatment. CONCLUSION: MET genetic abnormalities occur in diverse GU malignancies and are associated with a worse prognosis in a phase I setting. Efficacy of c-MET inhibitors was more pronounced in patients without MET abnormalities and when combined with other targets/drugs.

Analysis of 1,115 patients tested for MET amplification and therapy response in the MD Anderson Phase I Clinic.

PURPOSE: This study aimed to assess MET amplification among different cancers, association with clinical factors and genetic aberrations and targeted therapy response modifications. EXPERIMENTAL DESIGN: From May 2010 to November 2012, samples from patients with advanced tumors referred to the MD Anderson Phase I Clinic were analyzed for MET gene amplification by FISH. Patient demographic, histologic characteristics, molecular characteristics, and outcomes in phase I protocols were compared per MET amplification status. RESULTS: Of 1,115 patients, 29 (2.6%) had MET amplification. The highest prevalence was in adrenal (2 of 13; 15%) and renal (4 of 28; 14%) tumors, followed by gastroesophageal (6%), breast (5%), and ovarian cancers (4%). MET amplification was associated with adenocarcinomas (P = 0.007), high-grade tumors (P = 0.003), more sites of metastasis, higher BRAF mutation, and PTEN loss (all P < 0.05). Median overall survival was 7.23 and 8.62 months for patients with and without a MET amplification, respectively (HR = 1.12; 95% confidence intervals, 0.83-1.85; P = 0.29). Among the 20 patients with MET amplification treated on a phase I protocol, 4 (20%) achieved a partial response with greatest response rate on agents targeting angiogenesis (3 of 6, 50%). No patient treated with a c-MET inhibitor (0 of 7) achieved an objective response. CONCLUSION: MET amplification was detected in 2.6% of patients with solid tumors and was associated with adenocarcinomas, high-grade histology, and higher metastatic burden. Concomitant alterations in additional pathways (BRAF mutation and PTEN loss) and variable responses on targeted therapies, including c-MET inhibitors, suggest that further studies are needed to target this population.

Mutational analysis of genes coding for cell surface proteins in colorectal cancer cell lines reveal novel altered pathways, druggable mutations and mutated epitopes for targeted therapy.

We carried out a mutational analysis of 3,594 genes coding for cell surface proteins (Surfaceome) in 23 colorectal cancer cell lines, searching for new altered pathways, druggable mutations and mutated epitopes for targeted therapy in colorectal cancer. A total of 3,944 somatic non-synonymous substitutions and 595 InDels, occurring in 2,061 (57%) Surfaceome genes were catalogued. We identified 48 genes not previously described as mutated in colorectal tumors in the TCGA database, including genes that are mutated and expressed in >10% of the cell lines (SEMA4C, FGFRL1, PKD1, FAM38A, WDR81, TMEM136, SLC36A1, SLC26A6, IGFLR1). Analysis of these genes uncovered important roles for FGF and SEMA4 signaling in colorectal cancer with possible therapeutic implications. We also found that cell lines express on average 11 druggable mutations, including frequent mutations (>20%) in the receptor tyrosine kinases AXL and EPHA2, which have not been previously considered as potential targets for colorectal cancer. Finally, we identified 82 cell surface mutated epitopes, however expression of only 30% of these epitopes was detected in our cell lines. Notwithstanding, 92% of these epitopes were expressed in cell lines with the mutator phenotype, opening new venues for the use of "general" immune checkpoint drugs in this subset of patients.

Haematologic toxicities associated with the addition of bevacizumab in cancer patients.

BACKGROUND: Bevacizumab is currently approved for the treatment of several malignancies. Haematologic toxicities are not among the main concerns associated with bevacizumab, but they have been occasionally reported. We performed a meta-analysis to determine the incidence and risk of haematologic toxicities associated with bevacizumab. METHODS: Pubmed databases from 1966 to September 2010 were searched for studies reported, as well as American Society of Clinical Oncology meetings. Bevacizumab randomised clinical trials with adequate safety data profile were included. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR) and 95% confidence intervals (CI). RESULTS: 15,263 patients were included. The incidence of bevacizumab-associated all-grade and high-grade haematologic toxicities were, respectively: anaemia: 18.7% and 3.9%; neutropenia: 25.0% and 18.5%; and thrombocytopenia: 13.9% and 3.4%. Febrile neutropenia incidence was 3.8%. Compared to placebo/control arms, bevacizumab was associated with a decreased risk of all-grade (RR = 0.81; 95%CI 0.68-0.96; p = .016) and high-grade (RR = 0.73; 95%CI 0.60-0.89; p = .002) anaemia, and increased risks of all-grade (RR = 1.15; 95%CI 1.01-1.30; p = .033) and high-grade (RR = 1.08; 95%CI 1.02-1.13; p = .005) neutropenia, all-grade thrombocytopenia (RR = 1.22; 95%CI 1.00-1.48; p = .047) and febrile neutropenia (RR = 1.31; 95%CI 1.08-1.58; p = .006). CONCLUSIONS: Bevacizumab is associated with a lower risk of anaemia and increased risks of neutropenia, thrombocytopenia and febrile neutropenia.