SUMMARY Glial progenitor cells (GPCs) are a potential source of malignant gliomas. We used A2B5-based sorting to extract tumorigenic GPCs from human gliomas spanning WHO grades II-IV. mRNA profiling identified a cohort of genes that distinguished tumor-initiating progenitor cells (TPCs) from A2B5+ GPCs isolated from normal white matter. A core set of genes and pathways was substantially dysregulated in A2B5+ TPCs, that included the transcription factor SIX1, and its principal co-factors, EYA1 and DACH2. shRNAi silencing of SIX1 inhibited the expansion of glioma TPCs in vitro and in vivo, suggesting a critical and unrecognized role of the SIX1-EYA1-DACH2 system in glioma genesis or progression. By comparing the expression patterns of glioma TPCs to normal GPCs, we have identified a discrete set of pathways by which glial tumorigenesis may be better understood, and more specifically targeted.

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Background Stroke mechanisms and the risk of recurrent thromboembolism are incompletely understood in patients with primary brain tumors. We sought to better delineate these important clinical features. Methods We performed a retrospective cohort study of adults with primary brain tumors diagnosed with MRI-confirmed acute ischemic stroke at Memorial Sloan Kettering Cancer Center from 2005 to 2015. Study neurologists collected data on patients’ cancer history, stroke risk factors, treatments, and outcomes. Stroke mechanisms were adjudicated by consensus. The primary outcome was recurrent thromboembolism (arterial or venous) and the secondary outcome was recurrent ischemic stroke. Kaplan-Meier statistics were used to calculate cumulative outcome rates, and Cox hazards analysis was used to evaluate the association between potential risk factors and outcomes. Results We identified 83 patients with primary brain tumors and symptomatic acute ischemic stroke. Median survival after index stroke was 2.2 years (interquartile range, 0.5–7.0). Tumors were mostly gliomas (72%) and meningiomas (13%). Most strokes were from unconventional mechanisms, particularly radiation vasculopathy (36%) and surgical manipulation (18%). Small-or large-vessel disease or cardioembolism caused 13% of strokes, while 29% were cryptogenic. Cumulative recurrent thromboembolism rates were 11% at 30 days, 17% at 180 days, and 27% at 365 days; while cumulative recurrent stroke rates were 5% at 30 days, 11% at 180 days, and 13% at 365 days. We found no significant predictors of outcomes. Conclusions Patients with primary brain tumors generally develop strokes from rare mechanisms and their risk of recurrent thromboembolism, including stroke, is high.

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