Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II-IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for Tissue Factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26–30% of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0%). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85–90% in wild-type versus 2–6% in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.

IntroductionMedical education is a rapidly evolving field that has been using new technology to improve how medical students learn. One of the recent implementations in medical education is the recording of lectures for the purpose of playback at various speeds. Though previous studies done via surveys have shown a subjective increase in the rate of knowledge acquisition when learning from sped-up lectures, no quantitative studies have measured information retention. The purpose of this study was to compare mean test scores on written assessments to objectively determine if watching a video of a recorded lecture at 1.5× speed was significantly different than 1.0× speed for the immediate retention of novel material.MethodsFifty-four University of Kentucky medical students volunteered to participate in this study. The subjects were divided into two separate groups: Group A and Group B. Each group watched two separate videos, the first at 1.5× speed and the second at 1.0× speed, then completed assessments following each. The topics of the two videos were ultrasonography artifacts and transducers. Group A watched the artifacts video first at 1.5× speed followed by the transducers video at 1.0× speed. Group B watched the transducers video first at 1.5× speed followed by the artifacts video at 1.0× speed. The percentage correct on the written assessment were calculated for each subject at each video speed. The mean and standard deviation were also calculated using a t-test to determine if there was a significant difference in assessment scores between 1.5× and 1.0× speeds.ResultsThere was a significant (p=0.0188) detriment in performance on the artifacts quiz at 1.5× speed (mean 61.4; 95% confidence interval [CI]-53.9, 68.9) compared to the control group at normal speed (mean 72.7; 95% CI−66.8, 78.6). On the transducers assessment, there was not a significant (p=0.1365) difference in performance in the 1.5× speed group (mean 66.9; CI− 59.8, 74.0) compared to the control group (mean 73.8; CI− 67.7, 79.8).ConclusionThese findings suggest that, unlike previously published studies that showed subjective improvement in performance with sped-up video-recorded lectures compared to normal speed, objective performance may be worse.

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