Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.

Highlights d Molecular and clinical hallmarks of tRCC are defined via analysis of 152 samples d tRCC genomic alterations are rare aside from MiT/TFE fusions and 9p21.3 deletions d tRCCs display increased NRF2 pathway activation compared with other RCC subtypes d Immunotherapy may be active in some tRCCs

BACKGROUND Preoperative brain injury is common in neonates with complex congenital heart disease. Increasing evidence suggests a complex interaction of prenatal and postnatal risk factors for development of brain white matter injury called periventricular leukomalacia (PVL) in neonates with complex congenital heart disease. To date, there remains a limited understanding of the risk factors contributing to preoperative PVL in hypoplastic left heart syndrome (HLHS). METHODS Neonates with HLHS or HLHS variants from three prospective MRI studies (2003–2010) were selected for this cohort. A preoperative brain MRI was performed the morning of the surgery. Stepwise multilogistic regression of patient characteristics, mode of delivery (cesarean section vs. vaginal), time of diagnosis (prenatal vs. postnatal), HLHS subtypes, brain total maturation score (TMS), time to surgery, individual averaged daily preoperative blood gases and CBC values was used to determine significant associations. RESULTS A total of 57 neonates with HLHS were born at 38.7 ± 2.3 weeks, 86% (49/57) had a prenatal diagnosis with 31% (18/57) delivered by cesarean section. HLHS with aortic atresia (AA) was common in this cohort, (41/57, 71%). Preoperative PVL was identified in 19% (11/57). Male patients with aortic atresia (p=0.004) were at higher risk for PVL. Lower total brain maturation score was also identified as a strong predictor for preoperative PVL (p=0.005). CONCLUSIONS In neonates with HLHS, non-modifiable patient related factors including male gender with aortic atresia (lack of antegrade blood flow) and lower total brain maturation score placed neonates at the greatest risk for preoperative white matter injury.