Clinically Advanced Pheochromocytomas and Paragangliomas: A Comprehensive Genomic Profiling Study.

Patients with clinically advanced paragangliomas (CA-Para) and pheochromocytomas (CA-Pheo) have limited surgical or systemic treatments. We used comprehensive genomic profiling (CGP) to compare genomic alterations (GA) in CA-Para and CA-Pheo to identify potential therapeutic targets. Eighty-three CA-Para and 45 CA-Pheo underwent hybrid-capture-based CGP using a targeted panel of 324 genes. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined. The GA/tumor frequencies were low for both tumor types (1.9 GA/tumor for CA-Para, 2.3 GA/tumor for CA-Pheo). The most frequent potentially targetable GA in CA-Para were in FGFR1 (7%, primarily amplifications), NF1, PTEN, NF2, and CDK4 (all 2%) and for CA-Pheo in RET (9%, primarily fusions), NF1 (11%) and FGFR1 (7%). Germline mutations in known cancer predisposition genes were predicted in 13 (30%) of CA-Pheo and 38 (45%) of CA-Para cases, predominantly involving SDHA/B genes. Both CA-Para and CA-Para had low median TMB, low PD-L1 expression levels and none had MSI high status. While similar GA frequency is seen in both CA-Para and CA-Para, germline GA were seen more frequently in CA-Para. Low PD-L1 expression levels and no MSI high status argue against strong potential for novel immune checkpoint inhibitors. However, several important potential therapeutic targets in both CA-Para and CA-Para are identified using CGP.

Anti-CD19 CAR T Cells That Secrete a Biparatopic Anti-CLEC12A Bridging Protein Have Potent Activity Against Highly Aggressive Acute Myeloid Leukemia In Vitro and In Vivo.

Refractory acute myeloid leukemia (AML) remains an incurable malignancy despite the clinical use of novel targeted therapies, new antibody-based therapies, and cellular therapeutics. Here, we describe the preclinical development of a novel cell therapy that targets the antigen CLEC12A with a biparatopic bridging protein. Bridging proteins are designed as "CAR-T cell engagers," with a CAR-targeted protein fused to antigen binding domains derived from antibodies. Here, we created a CD19-anti-CLEC12A bridging protein that binds to CAR19 T cells and to the antigen CLEC12A. Biparatopic targeting increases the potency of bridging protein-mediated cytotoxicity by CAR19 T cells. Using CAR19 T cells that secrete the bridging protein we demonstrate potent activity against aggressive leukemic cell lines in vivo This CAR-engager platform is facile and modular, as illustrated by activity of a dual-antigen bridging protein targeting CLEC12A and CD33, designed to counter tumor heterogeneity and antigen escape, and created without the need for extensive CAR T-cell genetic engineering. CAR19 T cells provide an optimal cell therapy platform with well-understood inherent persistence and fitness characteristics.

The association of bicycle-related genital numbness and Sexual Health Inventory for Men (SHIM) score: results from a large, multinational, cross-sectional study.

OBJECTIVE: To assess the association of genital numbness and erectile dysfunction in male cyclists. SUBJECTS AND METHODS: Cyclists were recruited through Facebook advertisements and outreach to sporting clubs. This is a secondary analysis of a larger epidemiological population-based study that examined sexual and urinary wellness in athletes. We queried cycling habits and erectile function using Sexual Health Inventory for Men (SHIM). RESULTS: A total of 2 774 male cyclists were included in the analysis. Amongst cyclists, there was a statistically significant increase in the trend of genital numbness presence with more years of cycling (P = 0.002), more frequent weekly cycling (P < 0.001), and longer cycling distance at each ride (P < 0.001). Less frequent use of padded shorts (odds ratio [OR] 0.14, P < 0.001) and lower handlebar (OR 0.49, P < 0.001) were associated with numbness, but body mass index (BMI) (OR 1.1, P = 0.33) and age (OR 1.2, P = 0.15) were not. In a multivariate logistic regression model, after adjusting for age, BMI, and lifetime miles (calculated by average daily cycling mileage × cycling days/week × cycling years.), there were no statistically significant differences in mean SHIM score between cyclists with and cyclists without numbness (20.3 vs 20.2, P = 0.83). However, interestingly, the subset of cyclists who reported numbness in the buttock reported statistically significantly worse SHIM scores (20.3 vs 18.4, P < 0.001). This association was not present in cyclists who reported numbness in the scrotum, penis, or perineum and remained significant after adjusting for overall biking intensity. CONCLUSION: Cyclists report genital numbness in proportion with biking intensity but numbness is not associated with worse sexual function in this cohort.