Diversity Differences Among Cardiovascular Fellowships Across Five Geographic Regions in the United States.

Introduction Diversity and inclusion in cardiovascular fellowships are necessary for addressing the healthcare needs of diverse patient populations. However, regional disparities in the diversity of these programs persist, diminishing efforts to create a representative workforce. We observe the regional differences in the diversity of cardiovascular fellowship programs, focusing on gender, doctorate designation, and graduation within the United States (US) or other. We hypothesized that males, medical doctors (MD), and US graduates would be in majority across all regions. Methods Data for cardiovascular fellowships from the Fellowship and Residency Electronic Database Access (FREIDA) system for the matriculation year 2022-2023 was obtained to assess the representation of male vs female gender, MD vs osteopathic doctor (DO) designation, and US vs non-US graduate. We then compared these backgrounds to five defined regions (Midwest, Northeast, Southeast, Southwest, and West) in the United States to define representation for backgrounds across geographic areas. Statistical significance was determined by p<0.05 with the use of SAS Studio 3.8, version 9.4 (Cary, NC: SAS Institute, Inc.), and Wilson score for confidence intervals. Results We found significant disparities across all background factors for all regions. This includes that females, DOs, and non-US graduates were underrepresented among Midwest, Northeast, Southeast, Southwest, and West regions, and the p-value was <0.001 for all variations. Specifically for Midwest, the female frequency was 155 (23.81%; CI: 21, 27; p<0.001), DO frequency was 101 (15.51%; CI: 13, 19; p<0.001), and non-US graduate frequency was 206 (31.84%; CI: 28, 36; p<0.001). For Northeast, the female frequency was 231 (29.62; CI: 27, 33; p<0.001), DO frequency was 72 (9.22; CI: 7, 11; p<0.001), and non-US graduate frequency was 239 (30.68; CI 28, 34; p<0.001). For Southeast, the female frequency was 178 (25.99; CI: 23, 29; p<0.001), DO frequency was 67 (9.78; CI: 8, 12; p<0.001), and non-US graduate frequency 279 (41.46; CI: 38, 45; p<0.001). For Southwest, the female frequency was 74 (26.71; CI: 22, 32; p<0.001), DO frequency was 21 (7.58; CI 5, 11; p<0.001), and non-US graduate frequency was 110 (39.71; CI: 34,46; p<0.001). For West, the female frequency was 107 (31.75; CI 27, 37; p<0.001), DO frequency was 15 (4.45; CI: 3, 7; p<0.001), and non-US graduate frequency was 54 (16.07; CI: 13, 20; p<0.001). Conclusion We emphasize the regional disparities for females, DOs, and non-US graduates within cardiovascular fellowships in the past matriculation year. Understanding that we have not reached diversity goals allows for further reflection and implementation of targeted interventions and initiatives aimed at promoting equal opportunities for applicants. This is true for all regions of the United States. By addressing these disparities, fellowship programs can more effectively mirror the diverse patient populations they serve and foster a healthcare environment that is inclusive and accommodating. This, in turn, contributes to the overall enhancement of healthcare outcomes.

Genomic features of rapid versus late relapse in triple negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previously shown that rapid relapse of TNBC is associated with distinct sociodemographic features. We hypothesized that rapid versus late relapse in TNBC is also defined by distinct clinical and genomic features of primary tumors. METHODS: Using three publicly-available datasets, we identified 453 patients diagnosed with primary TNBC with adequate follow-up to be characterized as 'rapid relapse' (rrTNBC; distant relapse or death ≤2 years of diagnosis), 'late relapse' (lrTNBC; > 2 years) or 'no relapse' (nrTNBC: > 5 years no relapse/death). We explored basic clinical and primary tumor multi-omic data, including whole transcriptome (n = 453), and whole genome copy number and mutation data for 171 cancer-related genes (n = 317). Association of rapid relapse with clinical and genomic features were assessed using Pearson chi-squared tests, t-tests, ANOVA, and Fisher exact tests. We evaluated logistic regression models of clinical features with subtype versus two models that integrated significant genomic features. RESULTS: Relative to nrTNBC, both rrTNBC and lrTNBC had significantly lower immune signatures and immune signatures were highly correlated to anti-tumor CD8 T-cell, M1 macrophage, and gamma-delta T-cell CIBERSORT inferred immune subsets. Intriguingly, lrTNBCs were enriched for luminal signatures. There was no difference in tumor mutation burden or percent genome altered across groups. Logistic regression mModels that incorporate genomic features significantly outperformed standard clinical/subtype models in training (n = 63 patients), testing (n = 63) and independent validation (n = 34) cohorts, although performance of all models were overall modest. CONCLUSIONS: We identify clinical and genomic features associated with rapid relapse TNBC for further study of this aggressive TNBC subset.

Stromal Platelet-Derived Growth Factor Receptor-ß Signaling Promotes Breast Cancer Metastasis in the Brain.

Platelet-derived growth factor receptor-beta (PDGFRß) is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on paracrine ligand induction, and its preferred ligand PDGFB is released by neighboring epithelial and endothelial cells. While expression of both PDGFRß and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRß tumor-stroma signaling mediates breast cancer initiation, progression, and metastasis remains unclear. Here we demonstrate this paracrine signaling pathway that mediates both primary tumor growth and metastasis, specifically, metastasis to the brain. Elevated levels of PDGFB accelerated orthotopic tumor growth and intracranial growth of mammary tumor cells, while mesenchymal-specific expression of an activating mutant PDGFRß (PDGFRßD849V) exerted proproliferative signals on adjacent mammary tumor cells. Stromal expression of PDGFRßD849V also promoted brain metastases of mammary tumor cells expressing high PDGFB when injected intravenously. In the brain, expression of PDGFRßD849V was observed within a subset of astrocytes, and aged mice expressing PDGFRßD849V exhibited reactive gliosis. Importantly, the PDGFR-specific inhibitor crenolanib significantly reduced intracranial growth of mammary tumor cells. In a tissue microarray comprised of 363 primary human breast tumors, high PDGFB protein expression was prognostic for brain metastases, but not metastases to other sites. Our results advocate the use of mice expressing PDGFRßD849V in their stromal cells as a preclinical model of breast cancer-associated brain metastases and support continued investigation into the clinical prognostic and therapeutic use of PDGFB-to-PDGFRß signaling in women with breast cancer. SIGNIFICANCE: These studies reveal a previously unknown role for PDGFB-to-PDGFRß paracrine signaling in the promotion of breast cancer brain metastases and support the prognostic and therapeutic clinical utility of this pathway for patients.See related article by Wyss and colleagues, p. 594.