Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

SummarySmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant

Depuy-Synthes Award for Resident Research on Spinal Cord and Spinal Column Injury 154 Age as a Key Determinant of Inflammatory Response, Glial and Axonal Survival After Traumatic Spinal Cord Injury

Abstract INTRODUCTION: This study examines whether age is a key determinant for inflammatory response, oligodendroglial apoptosis and axonal survival after traumatic spinal cord injury (SCI). METHODS: This study includes post-mortem spinal cord tissue from 64 cases of SCI (at cervical or high-thoracic level) and 38 control cases. Each group was subdivided into younger and elderly individuals (65 years of age or older). Alternating 6-microm sections from 2 to 3 segments caudal to the SCI and age/sex/level-matched segments from controls were stained for: (i) neuroinflammation (neutrophils, macrophages, cytotoxic-T/natural-killer cells, helper/regulator-T cells, B-cell lymphocytes); (ii) apoptotic oligodendrocytes; (iii) axons; (iv) extent of degeneration. The number of cells or axons was counted in the motor and sensory areas within the spinal cord using unbiased stereological techniques. RESULTS: There were 25 women and 77 men with a mean age of 58.6 years (range from 16 to 90 years). Younger and elderly individuals had statistically similar number of neutrophils, macrophages, and lymphocytes in most of the stages after SCI. Yet, younger individuals showed significantly greater number of B-cell lymphocytes within the lateral corticospinal tracts in the subacute stage after SCI than elderly individuals. Younger and elderly individuals had a statistically similar number of oligodendrocytes in apoptosis in all stages after SCI. The number of preserved axons did not significantly differ between younger and elderly individuals with SCI and without prior central nervous system injury. Extent of degeneration within the spinal cord white matter did not significantly differ between the 2 groups. CONCLUSION: Our results indicate that age at the time of injury does not adversely affect the cellular inflammatory response, oligodendroglial apoptosis and axonal survival after traumatic SCI. Those results are consistent with prior clinical studies that have shown no significant effects of age on neurological and functional recovery following traumatic SCI when data analysis is adjusted for potential confounders