Faculty Bibliography

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.

BACKGROUND: Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. METHODS: In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks. RESULTS: Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60-80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. CONCLUSIONS: In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00957359.

A fundamental impediment to understanding the brain is the availability of inexpensive and robust methods for targeting and manipulating specific neuronal populations. The need to overcome this barrier is pressing because there are considerable anatomical, physiological, cognitive and behavioral differences between mice and higher mammalian species in which it is difficult to specifically target and manipulate genetically defined functional cell types. In particular, it is unclear the degree to which insights from mouse models can shed light on the neural mechanisms that mediate cognitive functions in higher species, including humans. Here we describe a novel recombinant adeno-associated virus that restricts gene expression to GABAergic interneurons within the telencephalon. We demonstrate that the viral expression is specific and robust, allowing for morphological visualization, activity monitoring and functional manipulation of interneurons in both mice and non-genetically tractable species, thus opening the possibility to study GABAergic function in virtually any vertebrate species.

High-grade glioma (HGG), a deadly primary brain malignancy, manifests radioresistance mediated by cell-intrinsic and microenvironmental mechanisms. High levels of the cytokine transforming growth factor-beta (TGF-beta) in HGG promote radioresistance by enforcing an effective DNA damage response and supporting glioma stem cell self-renewal. Our analysis of HGG TCGA data and immunohistochemical staining of phosphorylated Smad2, which is the main transducer of canonical TGF-beta signaling, indicated variable levels of TGF-beta pathway activation across HGG tumors. These data suggest that evaluating the putative benefit of inhibiting TGF-beta during radiotherapy requires personalized screening. Thus, we used explant cultures of seven HGG specimens as a rapid, patient-specific ex vivo platform to test the hypothesis that LY364947, a small molecule inhibitor of the TGF-beta type I receptor, acts as a radiosensitizer in HGG. Immunofluorescence detection and image analysis of gamma-H2AX foci, a marker of cellular recognition of radiation-induced DNA damage, and Sox2, a stem cell marker that increases post-radiation, indicated that LY364947 blocked these radiation responses in five of seven specimens. Collectively, our findings suggest that TGF-beta signaling increases radioresistance in most, but not all, HGGs. We propose that short-term culture of HGG explants provides a flexible and rapid platform for screening context-dependent efficacy of radiosensitizing agents in patient-specific fashion. This time- and cost-effective approach could be used to personalize treatment plans in HGG patients.

OBJECTIVE A randomized trial that compares clinical outcomes following microsurgery (MS) or stereotactic radiosurgery (SRS) for patients with small- and medium-sized vestibular schwannomas (VSs) is impractical, but would have important implications for clinical decision making. A matched cohort analysis was conducted to evaluate clinical outcomes in patients treated with MS or SRS. METHODS The records of 399 VS patients who were cared for by 2 neurosurgeons and 1 neurotologist between 2001 and 2014 were evaluated. From this data set, 3 retrospective matched cohorts were created to compare hearing preservation (21 matched pairs), facial nerve preservation (83 matched pairs), intervention-free survival, and complication rates (85 matched pairs) between cases managed with SRS and patients managed with MS. Cases were matched for age at surgery (+/- 10 years) and lesion size (+/- 0.1 cm). To compare hearing outcomes, cases were additionally matched for preoperative Class A hearing according to the American Academy of Otolaryngology-Head and Neck Surgery guidelines. To compare facial nerve (i.e., cranial nerve [CN] VII) outcomes, cases were additionally matched for preoperative House-Brackmann (HB) score. Investigators who were not involved with patient care reviewed the clinical and imaging records. The reported outcomes were as assessed at the time of the last follow-up, unless otherwise stated. RESULTS The preservation of preoperative Class A hearing status was achieved in 14.3% of MS cases compared with 42.9% of SRS cases (OR 4.5; p < 0.05) after an average follow-up interval of 43.7 months and 30.3 months, respectively. Serviceable hearing was preserved in 42.8% of MS cases compared with 85.7% of SRS cases (OR 8.0; p < 0.01). The rates of postoperative CN VII dysfunction were low for both groups, although significantly higher in the MS group (HB III-IV 11% vs 0% for SRS; OR 21.3; p < 0.01) at a median follow-up interval of 35.7 and 19.0 months for MS and SRS, respectively. There was no difference in the need for subsequent intervention (2 MS patients and 2 SRS patients). CONCLUSIONS At this high-volume center, VS resection or radiosurgery for tumors