Incidence And Distribution Of Uroseek Gene Panel In A Multi-Institutional Cohort Of Bladder Urothelial Carcinoma

Non-invasive approaches for early detection of bladder cancer are actively being investigated. We recently developed a urine based molecular assay for the detection and surveillance of bladder neoplasms (UroSEEK). UroSEEK is designed to detect alterations in 11 genes that includes most common genetic alterations in bladder cancer. In this study we analyzed 527 cases including 373 non-invasive and 154 invasive urothelial carcinomas of bladder from trans-urethral resections or cystectomies performed at 4 institutions (1991–2016). Two different mutational analysis assays of a representative tumor area were performed: first, a singleplex PCR assay for evaluation of the TERT promoter region (TERTSeqS) and second, a multiplex PCR assay using primers designed to amplify regions of interest of 10 (FGFR3, PIK3CA, TP53, HRAS, KRAS, ERBB2, CDKN2A, MET, MLL, and VHL) genes (UroSeqS). Overall 92% of all bladder tumors were positive for at least one genetic alteration in the UroSEEK panel. We found TERT promoter mutations in 77% of low-grade non-invasive papillary carcinomas with relatively lower incidence of 65% in high-grade non-invasive papillary carcinomas and carcinomas in situ; p=0.017. Seventy-two percent of pT1 and 63% of muscle-invasive bladder tumors harbored TERT promoter mutations with g.1295228C>T alteration being the most common in all groups. FGFR3 and PIK3CA mutations were more frequent in low-grade non-invasive papillary carcinomas compared to high-grade non-invasive papillary carcinomas and carcinomas in situ (p<0.0001), while the opposite was true for TP53 (p<0.0001). Significantly higher rates of TP53 and CDKN2A mutation rates (p=0.005 and 0.035, respectively) were encountered in muscle-invasive bladder tumors compared to those of pT1 stage. The overwhelming majority of all investigated tumors showed at least one mutation among UroSEEK assay genes confirming the comprehensive coverage of the panel and supporting its potential utility as a non-invasive urine based assay.PubMedWo

Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection

In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor (⍺1-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺1-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺1-AR antagonists ameliorates lower respiratory tract infection-associated hyperinflammation and death, as observed in COVID-19

Non-Invasive Detection Of Urothelial Cancer Through The Analysis Of Driver Gene Mutations And Aneuploidy

Current non-invasive approaches for detection of urothelial cancers are suboptimal. We developed a test to detect urothelial neoplasms using DNA recovered from cells shed into urine. UroSEEK incorporates massive parallel sequencing assays for mutations in 11 genes and copy number changes on 39 chromosome arms. In 570 patients at risk for bladder cancer ( BC), UroSEEK was positive in 83% of those who developed BC. Combined with cytology, UroSEEK detected 95% of patients who developed BC. Of 56 patients with upper tract urothelial cancer, 75% tested positive by UroSEEK, including 79% of those with non-invasive tumors. UroSEEK detected genetic abnormalities in 68% of urines obtained from BC patients under surveillance who demonstrated clinical evidence of recurrence. The advantages of UroSEEK over cytology were evident in low-grade BCs; UroSEEK detected 67% of cases whereas cytology detected none. These results establish the foundation for a new non-invasive approach for detection of urothelial cancer.WoSScopu