Prevalence and Co-Occurrence of Actionable Genomic Alterations in High-Grade Bladder Cancer

We sought to define the prevalence and co-occurrence of actionable genomic alterations in patients with high-grade bladder cancer to serve as a platform for therapeutic drug discovery

Public Health and Prisons: Priorities in the Age of Mass Incarceration

Mass incarceration is a sociostructural driver of profound health inequalities in the United States. The political and economic forces underpinning mass incarceration are deeply rooted in centuries of the enslavement of people of African descent and the genocide and displacement of Indigenous people and is inextricably connected to labor exploitation, racial discrimination, the criminalization of immigration, and behavioral health problems such as mental illness and substance use disorders. This article focuses on major public health crises and advances in state and federal prisons and discusses a range of practical strategies for health scholars, practitioners, and activists to promote the health and dignity of incarcerated people. It begins by summarizing the historical and sociostructural factors that have led to mass incarceration in the United States. It then describes the ways in which prison conditions create or worsen chronic, communicable, and behavioral health conditions, while highlighting priority areas for public health research and intervention to improve the health of incarcerated people, including decarceral solutions that can profoundly minimize-and perhaps one day help abolish-the use of prisons

Evaluating the association of multiple single nucleotide polymorphisms with response to gemcitabine and platinum combination chemotherapy in urothelial carcinoma of the bladder .

OBJECTIVE: To examine germline single nucleotide polymorphisms (SNPs) as markers of response to gemcitabine platinum (GP) combination chemotherapy in urothelial carcinoma (UC). METHODS: Saliva or blood was prospectively collected from 216 patients treated with GP for UC of the bladder between 1991 and 2011. Based on reported associations with gemcitabine and cisplatin response or putative mechanisms of gemcitabine or cisplatin/carboplatin activity, we selected SNPs of interest and were able to genotype 59 SNPs (using the SequenomMass ARRAYiPLEX platform) in 261 patients randomly split 2/3 into a training set (n = 174) and 1/3 into a test set (n = 87). Logistic regression was used to test the association between response to GP and SNPs. RESULTS: The median age at diagnosis was 64 years (range: 28 - 85) for the discovery set and 67 years (range: 30 - 84) for the validation set. Males composed 76% and 69%, and white non-Hispanics composed 88% and 91% of the training and test validation sets, respectively. Three SNPs on GALNTL4 (rs7937567, rs12278731, and rs9988868) and one intergenic SNP (rs1321391) were significantly associated with response to GP in the training set and were used to build a SNP score. However, when assessed in the test set, the SNP score was not significantly associated with response. CONCLUSION: Multiple SNPs selected from previous studies failed to predict response to GP in this cohort. Larger studies capable of accounting for population-based allele frequency heterogeneity may be required for replication of genetic alterations important to pharmacogenomics

Genitourinary Cancer The Safety and Efficacy of Single-Agent Pemetrexed in Platinum-Resistant Advanced Urothelial Carcinoma: A Large Single-Institution Experience

ABSTRACT Background. Pemetrexed is a commonly used treatment for platinum-resistant advanced urothelial carcinoma (UC) based on objective response rates of 8% and 28% in two small phase II studies. To address the discrepancy in reported response rates and to assess efficacy and toxicity outside of a clinical trial setting, we performed a large retrospective analysis of pemetrexed use at Memorial Sloan Kettering Cancer Center. We also investigated candidate prognostic factors for overall survival in this setting to explore whether the neutrophil-lymphocyte ratio (NLR) had independent prognostic significance. Patients and Methods. Patients receiving pemetrexed for platinum-resistant advanced UC between 2008 and 2013 were identified. The Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) were used to determine response rate. Kaplan-Meier and Cox regression analyses were used to examine the association of various factors with efficacy and survival outcomes. Hematologic toxicity and laboratory abnormalities were recorded

Prevalence and Co-Occurrence of Actionable Genomic Alterations in High-Grade Bladder Cancer

PURPOSE: We sought to define the prevalence and co-occurrence of actionable genomic alterations in patients with high-grade bladder cancer to serve as a platform for therapeutic drug discovery. PATIENTS AND METHODS: An integrative analysis of 97 high-grade bladder tumors was conducted to identify actionable drug targets, which are defined as genomic alterations that have been clinically validated in another cancer type (eg, BRAF mutation) or alterations for which a selective inhibitor of the target or pathway is under clinical investigation. DNA copy number alterations (CNAs) were defined by using array comparative genomic hybridization. Mutation profiling was performed by using both mass spectroscopy-based genotyping and Sanger sequencing. RESULTS: Sixty-one percent of tumors harbored potentially actionable genomic alterations. A core pathway analysis of the integrated data set revealed a nonoverlapping pattern of mutations in the RTK-RAS-RAF and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathways and regulators of G(1)-S cell cycle progression. Unsupervised clustering of CNAs defined two distinct classes of bladder tumors that differed in the degree of their CNA burden. Integration of mutation and copy number analyses revealed that mutations in TP53 and RB1 were significantly more common in tumors with a high CNA burden (P < .001 and P < .003, respectively). CONCLUSION: High-grade bladder cancer possesses substantial genomic heterogeneity. The majority of tumors harbor potentially tractable genomic alterations that may predict for response to target-selective agents. Given the genomic diversity of bladder cancers, optimal development of target-specific agents will require pretreatment genomic characterization

Comprehensive molecular characterization of urothelial bladder carcinoma

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomasto provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalitiesclose27