Metastatic Prostate Cancers with BRCA2 versus ATM Mutations Exhibit Divergent Molecular Features and Clinical Outcomes.

PURPOSE: In patients with metastatic prostate cancer (mPC), ATM and BRCA2 mutations dictate differences in PARPi inhibitor response and other therapies. We interrogated the molecular features of ATM- and BRCA2-mutated mPC to explain the divergent clinical outcomes and inform future treatment decisions. EXPERIMENTAL DESIGN: We examined a novel set of 1,187 mPCs after excluding microsatellite-instable (MSI) tumors. We stratified these based on ATM (n = 88) or BRCA2 (n = 98) mutations. As control groups, mPCs with mutations in 12 other homologous recombination repair (HRR) genes were considered non-BRCA2/ATM HRR-deficient (HRDother, n = 193), whereas lack of any HRR mutations were considered HRR-proficient (HRP; n = 808). Gene expression analyses were performed using Limma. Real-world overall survival was determined from insurance claims data. RESULTS: In noncastrate mPCs, only BRCA2-mutated mPCs exhibited worse clinical outcomes to AR-targeted therapies. In castrate mPCs, both ATM and BRCA2 mutations exhibited worse clinical outcomes to AR-targeted therapies. ATM-mutated mPCs had reduced TP53 mutations and harbored coamplification of 11q13 genes, including CCND1 and genes in the FGF family. BRCA2-mutated tumors showed elevated genomic loss-of-heterozygosity scores and were often tumor mutational burden high. BRCA2-mutated mPCs had upregulation of cell-cycle genes and were enriched in cell-cycle signaling programs. This was distinct from ATM-mutated tumors. CONCLUSIONS: Tumoral ATM and BRCA2 mutations are associated with differential clinical outcomes when patients are stratified by treatments, including hormonal or taxane therapies. ATM- and BRCA2-mutated tumors exhibited differences in co-occurring molecular features. These unique molecular features may inform therapeutic decisions and development of novel therapies.

Patient Outcomes and Unit Composition With Transition to a High-Intensity ICU Staffing Model: A Before-and-After Study.

Provider staffing models for ICUs are generally based on pragmatic necessities and historical norms at individual institutions. A better understanding of the role that provider staffing models play in determining patient outcomes and optimizing use of ICU resources is needed. OBJECTIVES: To explore the impact of transitioning from a low- to high-intensity intensivist staffing model on patient outcomes and unit composition. DESIGN SETTING AND PARTICIPANTS: This was a prospective observational before-and-after study of adult ICU patients admitted to a single community hospital ICU before (October 2016-May 2017) and after (June 2017-November 2017) the transition to a high-intensity ICU staffing model. MAIN OUTCOMES AND MEASURES: The primary outcome was 30-day all-cause mortality. Secondary outcomes included in-hospital mortality, ICU length of stay (LOS), and unit composition characteristics including type (e.g., medical, surgical) and purpose (ICU-specific intervention vs close monitoring only) of admission. RESULTS: For the primary outcome, 1,219 subjects were included (779 low-intensity, 440 high-intensity). In multivariable analysis, the transition to a high-intensity staffing model was not associated with a decrease in 30-day (odds ratio [OR], 0.90; 95% CI, 0.61-1.34; p = 0.62) or in-hospital (OR, 0.89; 95% CI, 0.57-1.38; p = 0.60) mortality, nor ICU LOS. However, the proportion of patients admitted to the ICU without an ICU-specific need did decrease under the high-intensity staffing model (27.2% low-intensity to 17.5% high-intensity; p < 0.001). CONCLUSIONS AND RELEVANCE: Multivariable analysis showed no association between transition to a high-intensity ICU staffing model and mortality or LOS outcomes; however, the proportion of patients admitted without an ICU-specific need decreased under the high-intensity model. Further research is needed to determine whether a high-intensity staffing model may lead to more efficient ICU bed usage.

Stereoselective Dynamic Cyclization of Allylic Azides: Synthesis of Tetralins, Chromanes, and Tetrahydroquinolines.

This report describes the stereoselective synthesis of 3-azido-tetralins, -chromanes, and -tetrahydroquinolines via a tandem allylic azide rearrangement/Friedel-Crafts alkylation. Exposure of allylic azides with a pendant trichloroacetimidate to catalytic quantities of AgSbF6 proved optimal for this transformation. This cascade successfully differentiates the equilibrating azide isomers, providing products in excellent yield and selectivity (>25 examples, up to 94% yield and >25:1 dr). In many cases, the reactive isomer is only a trace fraction of the equilibrium mixture, keenly illustrating the dynamic nature of these systems. We demonstrate the utility of this process via a synthesis of hasubanan.