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 AgSbF 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.

Tumor heterogeneity is a well‐established marker of biologically aggressive neoplastic processes and is associated with local recurrence and distant metastasis. Quantitative analysis of CT textural features is an indirect measure of tumor heterogeneity and therefore may help predict malignant disease. The purpose of this retrospective, secondary analysis study was to quantitatively evaluate CT heterogeneity in dogs with histologically confirmed liver masses to build a predictive model for malignancy. Forty dogs with liver tumors and corresponding histopathologic evaluation from a previous prospective study were included. Triphasic image acquisition was standardized across dogs and whole liver and liver mass were contoured on each precontrast and delayed postcontrast dataset. First‐order and second‐order indices were extracted from contoured regions. Univariate analysis identified potentially significant indices that were subsequently used for top‐down model construction. Multiple quadratic discriminatory models were constructed and tested, including individual models using both postcontrast and precontrast whole liver or liver mass volumes. The best performing model utilized the CT features voxel volume and uniformity from postcontrast mass contours; this model had an accuracy of 0.90, sensitivity of 0.67, specificity of 1.0, positive predictive value of 1.0, negative predictive value of 0.88, and precision of 1.0. Heterogeneity indices extracted from delayed postcontrast CT hepatic mass contours were more informative about tumor type compared to indices from whole liver contours, or from precontrast hepatic mass and whole liver contours. Results demonstrate that CT radiomic feature analysis may hold clinical utility as a noninvasive method of predicting hepatic malignancy and may influence diagnostic or therapeutic approaches.

Purpose: In metastatic prostate cancer (mPC) patients, ATM and BRCA2 mutations dictate differences in PARP 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 1187 mPCs after excluding microsatellite unstable (MSI) tumors. We stratified these based on ATM (n = 88) or BRCA2 (n = 98) mutations. As control groups, mPCs with mutations in 12 other 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 non-castrate 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 co-amplification of 11q13 genes including CCND1 and genes in the FGF family. BRCA2-mutated tumors showed elevated genomic loss-of-heterozygosity scores and were often TMB-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 taxanes 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.