Faculty Bibliography

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.

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.

Utilizing advanced 3D printing techniques, a multimaterial model was created for the surgical planning of a complex deformity of the skull base and craniovertebral junction. The model contained bone anatomy as well as vasculature and the previously placed occipital cervical instrumentation. Careful evaluation allowed for a unique preoperative perspective of the craniovertebral deformity and instrumentation options. This patient-specific model was invaluable in choosing the most effective approach and correction strategy, which was not readily apparent from standard 2D imaging. Advanced 3D multimaterial printing provides a cost-effective method of presurgical planning, which can also be used for both patient and resident education.

Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM. GPR133 is selectively expressed in CD133+ GBM stem cells (GSCs) and within the hypoxic areas of PPN in human biospecimens. GPR133 mRNA is transcriptionally upregulated by hypoxia in hypoxia-inducible factor 1alpha (Hif1alpha)-dependent manner. Genetic inhibition of GPR133 with short hairpin RNA reduces the prevalence of CD133+ GSCs, tumor cell proliferation and tumorsphere formation in vitro. Forskolin rescues the GPR133 knockdown phenotype, suggesting that GPR133 signaling is mediated by cAMP. Implantation of GBM cells with short hairpin RNA-mediated knockdown of GPR133 in the mouse brain markedly reduces tumor xenograft formation and increases host survival. Analysis of the TCGA data shows that GPR133 expression levels are inversely correlated with patient survival. These findings indicate that GPR133 is an important mediator of the hypoxic response in GBM and has significant protumorigenic functions. We propose that GPR133 represents a novel molecular target in GBM and possibly other malignancies where hypoxia is fundamental to pathogenesis.

Management of non-emergent, non-acute subdural hematomas (SDHs) ranges from observation to burr-hole evacuation or craniotomy, but recurrence rates are high. We evaluated the safety and efficacy of tranexamic acid (TXA) for the treatment of residual SDHs following bedside twist-drill evacuation. We performed a retrospective analysis of a prospectively maintained database from November 2013 to November 2014 for all patients who underwent placement of a bedside Subdural Evacuating Port System (SEPS) followed by treatment with oral TXA (650 mg daily). All demographics, evidence of VTE and volumes of pertinent CTs were obtained. Twenty subdural hematomas in 14 patients met the inclusion criteria for this study. The majority of SDHs were mixed density. Mean SDH volume on presentation was 145.96 cm3 +/- 40.22 with a mean midline shift of 9.44 mm +/- 4.84. Mean volumes decreased to 80.00 cm3 +/- 31.96, and midline shift improved to 4.44 mm +/- 3.29, after SEPS placement (p < 0.0001 and p = 0.0046). All patients were placed on TXA after their procedure. Mean follow-up with CT was 92.1 days +/- 27.5, and mean SDH volume at last follow-up was 7.41 cm3 +/- 15.54 with a mean midline shift of 0.19 mm +/- 0.69 (p < 0.0001 and p = 0.0002). Percent volume reduction was significantly higher after TXA than after SEPS (91.31% versus 40.74%, p < 0.0001). No increase or delayed recurrence of the SDH was noted during TXA treatment. All but one clinical presenting symptom improved at follow-up. No venous thromboembolisms were noted amongst the patients. In our pilot study, chronic SDH volumes were reduced by 40.74% after SEPS drainage. The residual volume was reduced by an additional 91.31% during oral TXA treatment. No patients developed delayed recurrence or expansion of their SDHs. Further prospective studies are needed to evaluate the role of TXA for adjunctive treatment of chronic SDHs.

Objective: Cerebral venous sinus thrombosis (CVST) is a rare but potentially dangerous complication following craniotomies involving the posterior fossa, the skull base, and craniotomies involving the superior sagittal sinus. Surgical manipulation of the sinuses has been shown to cause sinus thromboses of varying degrees. This phenomenon is often clinically silent, with only a small number of patients becoming symptomatic. Recent advances in neuroimaging provide higher resolution evaluation of cerebral sinuses pre and postoperatively, often revealing clinically silent filling defects. Although sinus thrombosis can be a major cause of morbidity and mortality, its incidence and factors that contribute to its formation in the postoperative population remain unclear. In addition, current guidelines advise to anticoagulate with Heparin upon diagnosis, which can be contraindicated for immediate post craniotomy patients. The goal of this study is to evaluate retrospective data of patient outcomes and factors that might contribute to sinus thrombus formation. Methods: A retrospective chart review was conducted at NYU Langone Medical Center. Ninety-seven patients were included who underwent either a retrosigmoid/translabrynthine/suboccipital resection of a posterior fossa tumor or a supratentorial craniotomy for resection of parasagittal/falcine tumor between July 1, 2014 and July 1, 2015. Pre operative Magnetic Resonance Venography (MRV) was obtained per the attending surgeon's discretion. Based on intraoperative findings, clinical symptoms, and surgeon's preference, a postoperative MRV was obtained. Decision to treat a thrombosis was made based on the results of the MRV and clinical symptoms. Treatments included observation, intravenous fluids (IVF) alone, anti-platelet therapy with Aspirin alone, or a combination of the two. Results: A total of 7 of 97 patients (7.22%) had postoperative sinus thrombosis. Of those patients, 5 had occlusion of the venous sinuses. In the occlusion group, 4 had preoperative imaging documenting patency of the sinuses. An additional 2 patients had postoperative MRVs revealing partial thrombosis of the sinus, 1 that was new and 1 that did not have a preoperative MRV for comparison. Compared with the cohort of patients without postoperative thromboses, there was no significant difference in age, BMI, length of surgery, or surgical approach. Of the 5 patients with postoperative thrombotic occlusion, 4 underwent intervention (1 with IVF alone, 2 with IVF and aspirin, and 1 with aspirin alone). Two patients with thromboses also developed CSF leaks requiring lumbar drainage and operative repair. One patient had a persistent CSF leak requiring a shunt. Of the 2 patients with partial thrombosis, 1 was placed on IVF and aspirin. At 3 months follow up, 1 out of 5 patients in the occlusion group had recanalization of the previously thrombosed sinus. Conclusions: MRV is a non-invasive method to evaluate the caliber and patency of dural venous sinuses in post craniotomy patients. Symptomatic thrombosis is rare and can be managed either conservatively or with IVF and/or anti platelet therapy, both which are safer than anticoagulation with heparin in post craniotomy patients. A larger prospective trial is necessary to further characterize the incidence of postoperative venous sinus thrombosis, identify risk factors, and to devise recommendations for therapy

Background: Salvage surgery for progressive symptoms or recurrent growth of vestibular schwannoma (VS) after stereotactic radiosurgery (SRS) is uncommon. It has been reported to be more difficult, the same or easier than expected compared with microsurgical resection (MS) of treatment-naive VS, with variable facial nerve outcomes. We conducted a matched cohort analysis to evaluate facial nerve outcomes for patients undergoing MS for progressive symptoms or recurrent growth of VS after SRS compared with MS for treatment-naive VS. Methods: We evaluated the records of 365 non-NF2 VS patients treated with MS from 2001 to 2014. All patients who had postoperative notes were considered to have "adequate follow-up" and included in the study. Nine patients underwent resection for VS after prior SRS (MS-POST SRS) with no prior intervention, 7 of which had adequate follow-up, and 331 patients that underwent MS for treatment naive VS (MS-NO SRS), 317 of which had adequate follow-up. From this dataset, we created propensity score matched cohorts to retrospectively compare facial nerve preservation and clinical outcomes. The propensity score model incorporated age at surgery, tumor size, and pre-operative HB grade, and cases were matched at a ratio of 4:1 MS-NO SRS to MS-POST SRS cases. Results: The MS-POST SRS (n = 7) and MS-NO SRS (n = 28) groups differed only in preoperative hearing status (p < 0.01). Preoperative HB grades were similar between MS-POST SRS and MS-NO SRS groups (p>0.3). The average time-to-intervention after SRS in the MS-POST SRS group was 44.4 months. The indication for MS after SRS was symptom progression with tumor growth in 4 cases, and only tumor growth in the remaining 3. Postoperatively, 3 cases in the MS-POST SRS group demonstrated improvement in HB grade and none became worse whereas 3 of 28 cases in the MS-NO SRS group demonstrated improvement and 12 cases had decrement in HB grade relative to baseline (p < 0.05). There was no significant difference in the extent of resection with both cohorts (MS-POST SRS and MS-NO SRS) attaining gross total resection in 85.7% of cases. Subsequent intervention was not required for any case in the MS-POST SRS group and 2 cases in the MS-NO SRS group, although this difference was not significant. Both cases requiring subsequent intervention in the MS-POST SRS group were gross total resections via the translabyrinthine approach, with subsequent intervention required at 62 and 48 months. There were no significant differences in the complication rate for individual complications or the overall complication rate between cohorts. Conclusions: At a center with high clinical volume, microsurgical resection of VS after prior SRS was associated with good postoperative facial nerve preservation and low morbidity, comparable to those observed in resection of treatment-naive VS. In addition there were similar outcomes in terms of extent of resection between the two groups. The good outcomes reported here may reflect a confluence of factors which include patient selection, the experience of the attending surgeons, the use of more contemporary SRS dosing protocols during initial treatment for these patients, and divergent goals of therapy between cohorts