High-Throughput Screening of Epigenetic Inhibitors in Meningiomas Identifies HDAC, G9a, and Jumonji-Domain Inhibition as Potential Therapies.

Background Epigenetics may predict treatment sensitivity and clinical course for patients with meningiomas more accurately than histopathology. Nonetheless, targeting epigenetic mechanisms is understudied for pharmacotherapeutic development for these tumors. The bio-molecular insights and potential therapeutic development of meningioma epigenetics led us to investigate epigenetic inhibition in meningiomas. Methods We screened a 43-tumor cohort using a 139-compound epigenetic inhibitor library to assess sensitivity of relevant meningioma subgroups to epigenetic inhibition. The cohort was composed of 5 cell lines and 38 tumors cultured directly from surgery; mean patient age was 56.6 years ± 13.9 standard deviation. Tumor categories: 38 primary tumors, 5 recurrent; 33 from females, 10 from males; 32 = grade 1; 10 = grade 2; 1 = grade 3. Results Consistent with our previous results, histone deacetylase inhibitors (HDACi) were the most efficacious class. Panobinostat significantly reduced cell viability in 36 of 43 tumors; 41 tumors had significant sensitivity to some HDACi. G9a inhibition and Jumonji-domain inhibition also significantly reduced cell viability across the cohort; tumors that lost sensitivity to panobinostat maintained sensitivity to either G9a or Jumonji-domain inhibition. Sensitivity to G9a and HDAC inhibition increased with tumor grade; tumor responses did not separate by gender. Few differences were found between recurrent and primary tumors, or between those with prior radiation versus those without. Conclusions Few efforts have investigated the efficacy of targeting epigenetic mechanisms to treat meningiomas, making the clinical utility of epigenetic inhibition largely unknown. Our results suggest that epigenetic inhibition is a targetable area for meningioma pharmacotherapy.

Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas With Somatic NF2 Mutations.

PURPOSE: Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS: Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS: Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION: GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Concomitant Temozolomide plus radiotherapy for high-grade and recurrent meningioma: a retrospective chart review.

BACKGROUND: High-grade and recurrent meningiomas are often treatment resistant and pose a therapeutic challenge after surgical and radiation therapy (RT) failure. Temozolomide (TMZ) is a DNA alkylating agent that appears to have a radiosensitizing effect when used in combination with RT and may be worthwhile in meningioma treatment. Thus, we investigated the potential efficacy of concomitant RT plus TMZ compared to historical controls of just RT used in the treatment of high-grade and recurrent meningiomas. METHODS: We performed a retrospective analysis of patients with meningioma treated at the University of Colorado with TMZ chemoradiation. Progression free survival (PFS) and overall survival (OS) were calculated from the start of chemoradiation to local recurrence or death, respectively. RESULTS: Eleven patients (12 tumors) were treated with chemoradiation with a median follow-up of 41.5 months. There were two WHO grade 1, eight grade 2 and two grade 3 meningiomas. Three patients died during the follow-up period-one being disease related (11.1%). Two patients had meningioma recurrence-at 2.3 months (WHO grade 3), and 5.4 years (WHO grade 2). Three-year OS and PFS for grade 2 meningiomas were each 88%. Historical controls demonstrate a 3-year median OS and PFS of 83% and 75.8%, respectively. CONCLUSIONS: Treatment options are limited for meningiomas after local failure. In this study, TMZ chemoradiation demonstrated no significant difference in PFS and OS in the treatment of grade 2 meningiomas compared to historic controls. Further study is warranted to find novel methods for the treatment of malignant and recurrent meningiomas.

Targeting DNA Methyl Transferases with Decitabine in Cultured Meningiomas.

OBJECTIVE: Meningiomas are a common primary central nervous system tumor that lack a U.S. Food and Drug Administration-approved pharmacotherapy. Approximately 20%-35% of meningiomas are classified as higher grade with poor outcome, whereas patients with lower-grade meningiomas are known to have long-term neurologic deficits and reduced overall survival. Recent efforts to understand the epigenetic landscape of meningiomas have highlighted the importance of DNA methylation for predicting tumor outcomes and prognosis; therefore, inhibition of these pathways may present a viable therapy for these tumors. METHODS: In this study, we perform dose-response curves of decitabine, a DNA methyltransferase inhibitor, on patient-cultured tumors and meningioma cell lines. RESULTS: Thirty total samples were evaluated, including 24 patient-cultured tumors and 6 established meningioma cell lines. Meningiomas were found to have a significant reduction in cell viability after decitabine treatment in a dose dependent manner. The effect was primarily driven by 11 of the 30 tumors in our cohort, or 36.7%. Decitabine significantly reduced cell viability across all grades, tumors from different sexes, recurrent and primary tumors, as well as tumors without a history of previous radiation. Surprisingly, our single radiation-induced tumor did demonstrate greater viability after decitabine treatment. CONCLUSIONS: Our work has identified a potential drug candidate in decitabine for the treatment of meningiomas regardless of clinical subgroup. These data require further evaluation in preclinical models, and the conclusions based on clinical subgroups need to be evaluated in a larger cohort to achieve appropriate statistical power.

High-Throughput Mechanistic Screening of Epigenetic Compounds for the Potential Treatment of Meningiomas.

BACKGROUND: Meningiomas are the most common primary central nervous system tumors. 20-30% of these tumors are considered high-grade and associated with poor prognosis and high recurrence rates. Despite the high occurrence of meningiomas, there are no FDA-approved compounds for the treatment of these tumors. METHODS: In this study, we screened patient-cultured meningiomas with an epigenetic compound library to identify targetable mechanisms for the potential treatment of these tumors. Meningioma cell cultures were generated directly from surgically resected patient tumors and were cultured on a neural matrix. Cells were treated with a library of compounds meant to target epigenetic functions. RESULTS: Although each tumor displayed a unique compound sensitivity profile, Panobinostat, LAQ824, and HC toxin were broadly effective across most tumors. These three compounds are broad-spectrum Histone Deacetylase (HDAC) inhibitors which target class I, IIa, and IIb HDACs. Panobinostat was identified as the most broadly effective compound, capable of significantly decreasing the average cell viability of the sample cohort, regardless of tumor grade, recurrence, radiation, and patient gender. CONCLUSIONS: These findings strongly suggest an important role of HDACs in meningioma biology and as a targetable mechanism. Additional validation studies are necessary to confirm these promising findings, as well to identify an ideal HDAC inhibitor candidate to develop for clinical use.

Effect of Vocimagene Amiretrorepvec in Combination With Flucytosine vs Standard of Care on Survival Following Tumor Resection in Patients With Recurrent High-Grade Glioma: A Randomized Clinical Trial.

Importance: New treatments are needed to improve the prognosis of patients with recurrent high-grade glioma. Objective: To compare overall survival for patients receiving tumor resection followed by vocimagene amiretrorepvec (Toca 511) with flucytosine (Toca FC) vs standard of care (SOC). Design, Setting, and Participants: A randomized, open-label phase 2/3 trial (TOCA 5) in 58 centers in the US, Canada, Israel, and South Korea, comparing posttumor resection treatment with Toca 511 followed by Toca FC vs a defined single choice of approved (SOC) therapies was conducted from November 30, 2015, to December 20, 2019. Patients received tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma. Interventions: Patients were randomized 1:1 to receive Toca 511/FC (n = 201) or SOC control (n = 202). For the Toca 511/FC group, patients received Toca 511 injected into the resection cavity wall at the time of surgery, followed by cycles of oral Toca FC 6 weeks after surgery. For the SOC control group, patients received investigators' choice of single therapy: lomustine, temozolomide, or bevacizumab. Main Outcomes and Measures: The primary outcome was overall survival (OS) in time from randomization date to death due to any cause. Secondary outcomes reported in this study included safety, durable response rate (DRR), duration of DRR, durable clinical benefit rate, OS and DRR by IDH1 variant status, and 12-month OS. Results: All 403 randomized patients (median [SD] age: 56 [11.46] years; 62.5% [252] men) were included in the efficacy analysis, and 400 patients were included in the safety analysis (3 patients on the SOC group did not receive resection). Final analysis included 271 deaths (141 deaths in the Toca 511/FC group and 130 deaths in the SOC control group). The median follow-up was 22.8 months. The median OS was 11.10 months for the Toca 511/FC group and 12.22 months for the control group (hazard ratio, 1.06; 95% CI 0.83, 1.35; P = .62). The secondary end points did not demonstrate statistically significant differences. The rates of adverse events were similar in the Toca 511/FC group and the SOC control group. Conclusions and Relevance: Among patients who underwent tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma, administration of Toca 511 and Toca FC, compared with SOC, did not improve overall survival or other efficacy end points. Trial Registration: ClinicalTrials.gov Identifier: NCT02414165.

The Neurologic Assessment in Neuro-Oncology (NANO) Scale as an Assessment Tool for Survival in Patients With Primary Glioblastoma.

BACKGROUND: The Neurologic Assessment in Neuro-Oncology (NANO) scale is a standardized objective metric designed to measure neurological function in neuro-oncology. Current neuroradiological evaluation guidelines fail to use specific clinical criteria for progression. OBJECTIVE: To determine if the NANO scale was a reliable assessment tool in glioblastoma (GBM) patients and whether it correlated to survival. METHODS: Our group performed a retrospective review of all patients with newly diagnosed GBM from January 1, 2010, through December 31, 2012, at our institution. We applied the NANO scale, Karnofsky performance score (KPS), Eastern Cooperative Oncology Group (ECOG) scale, Macdonald criteria, and the Response Assessment in Neuro-Oncology (RANO) criteria to patients at the time of diagnosis as well as at 3, 6, and 12 mo. RESULTS: Initial NANO score was correlated with overall survival at time of presentation. NANO progression was correlated with decreased survival in patients at 6 and 12 mo. A decrease in KPS was associated with survival at 3 and 6 mo, an increase in ECOG score was associated only at 3 mo, and radiological evaluation (RANO and Macdonald) was correlated at 3 and 6 mo. Only the NANO scale was associated with patient survival at 1 yr. NANO progression was the only metric that was linked to decreased overall survival when compared to RANO and Macdonald at 6 and 12 mo. CONCLUSION: The NANO scale is specific to neuro-oncology and can be used to assess patients with glioma. This retrospective analysis demonstrates the usefulness of the NANO scale in glioblastoma.

New-onset seizure during and after brain tumor excision: a risk assessment analysis.

OBJECTIVE Prophylactic use of antiepileptic drugs (AEDs) in seizure-naïve brain tumor patients remains a topic of debate. This study aimed to characterize a subset of patients at highest risk for new-onset perioperative seizures (i.e., intraoperative and postoperative seizures occurring within 30 days of surgery) who may benefit from prophylactic AEDs. METHODS The authors conducted a retrospective case-control study of all adults who had undergone tumor resection or biopsy at the authors' institution between January 1, 2004, and June 31, 2015. All patients with a history of preoperative seizures, posterior fossa tumors, pituitary tumors, and parasellar tumors were excluded. A control group was matched to the seizure patients according to age (± 0 years). Demographic data, clinical status, operative data, and postoperative course data were collected and analyzed. RESULTS Among 1693 patients who underwent tumor resection or biopsy, 549 (32.4%) had never had a preoperative seizure. Of these 549 patients, 25 (4.6%) suffered a perioperative seizure (Group 1). A total of 524 patients (95.4%) who remained seizure free were matched to Group 1 according to age (± 0 years), resulting in 132 control patients (Group 2), at an approximate ratio of 1:5. There were no differences between the patient groups in terms of age, sex, race, relationship status, and neurological deficits on presentation. Histological subtype (infiltrating glioma vs meningioma vs other, p = 0.041), intradural tumor location (p < 0.001), intraoperative cortical stimulation (p = 0.004), and extent of resection (less than gross total, p = 0.002) were associated with the occurrence of perioperative seizures. CONCLUSIONS While most seizure-naïve brain tumor patients do not benefit from perioperative seizure prophylaxis, such treatment should be considered in high-risk patients with supratentorial intradural tumors, in patients undergoing intraoperative cortical stimulation, and in patients in whom subtotal resection is likely.

A state-of-the-art review and guidelines for tumor treating fields treatment planning and patient follow-up in glioblastoma.

Tumor treating fields (TTFields) are an integral treatment modality in the management of glioblastoma and extend overall survival when combined with maintenance temozolomide in newly diagnosed patients. Complexities exist regarding correct selection of imaging sequences with which to perform TTFields treatment planning. Guidelines are warranted first, to facilitate treatment planning standardization across medical disciplines and institutions, to ensure optimal TTFields delivery to the tumor and peritumoral brain zone while maximizing patient safety, and also to mitigate the risk of premature cessation of a potentially beneficial treatment. This summary guideline outlines methods for starting patients on TTFields, for monitoring patient response to therapy and provides a framework for evaluating when therapy should be re-planned, based on the extent of sequential imaging changes.

Hypofractionated-intensity modulated radiotherapy (hypo-IMRT) and temozolomide (TMZ) with or without bevacizumab (BEV) for newly diagnosed glioblastoma multiforme (GBM): a comparison of two prospective phase II trials.

To compare progression-free (PFS) and overall survival (OS) in patients treated in two consecutive phase II trials of hypofractionated-intensity modulated radiotherapy (hypo-IMRT) and temozolomide (TMZ) with or without bevacizumab (BEV). Patients with newly diagnosed glioblastoma multiforme (GBM) after biopsy or resection were enrolled on a clinical trial with hypo-IMRT and TMZ (hypo-IMRT/TMZ alone) from 2008 to 2010, or in the second protocol with the same hypo-IMRT and TMZ plus BEV (hypo-IMRT/TMZ/BEV) from 2010 to 2013. All patients received postoperative hypo-IMRT to the surgical cavity and residual tumor plus margin to a total dose of 60 Gy and to the T2 abnormality with margin to 30 Gy, both in ten fractions. Concurrent TMZ (75 mg/m(2)/day) was given to all patients for 28 consecutive days followed by adjuvant TMZ (150-200 mg/m(2)/day). Patients enrolled on the hypo-IMRT/TMZ/BEV trial received concurrent and adjuvant BEV (10 mg/kg) on days 1 and 15 of each 28-day cycle. Hazard ratios of PFS and OS were compared between trials in a Cox proportional hazards model. Twenty-six patients were enrolled on the hypo-IMRT/TMZ alone trial and 30 patients on the hypo-IMRT/TMZ/BEV trial. Median follow-up was 13.9 and 14.7 months, respectively. Median PFS was 3.4 months longer with hypo-IMRT/TMZ/BEV but the difference was not statistically significant (12.8 vs. 9.4 months, p = 0.58). Median (OS) was 16.3 months for both trials. The addition of BEV to TMZ and hypo-IMRT did not improve OS for patients with GBM in two phase II trials with small patient numbers; PFS was longer with BEV, but the difference was not statistically significant.

Phase II trial of hypofractionated intensity-modulated radiation therapy combined with temozolomide and bevacizumab for patients with newly diagnosed glioblastoma.

Bevacizumab blocks the effects of VEGF and may allow for more aggressive radiotherapy schedules. We evaluated the efficacy and toxicity of hypofractionated intensity-modulated radiation therapy with concurrent and adjuvant temozolomide and bevacizumab in patients with newly diagnosed glioblastoma. Patients with newly diagnosed glioblastoma were treated with hypofractionated intensity modulated radiation therapy to the surgical cavity and residual tumor with a 1 cm margin (PTV1) to 60 Gy and to the T2 abnormality with a 1 cm margin (PTV2) to 30 Gy in 10 daily fractions over 2 weeks. Concurrent temozolomide (75 mg/m(2) daily) and bevacizumab (10 mg/kg) was administered followed by adjuvant temozolomide (200 mg/m(2)) on a standard 5/28 day cycle and bevacizumab (10 mg/kg) every 2 weeks for 6 months. Thirty newly diagnosed patients were treated on study. Median PTV1 volume was 131.1 cm(3) and the median PTV2 volume was 342.6 cm(3). Six-month progression-free survival (PFS) was 90 %, with median follow-up of 15.9 months. The median PFS was 14.3 months, with a median overall survival (OS) of 16.3 months. Grade 4 hematologic toxicity included neutropenia (10 %) and thrombocytopenia (17 %). Grades 3/4 non-hematologic toxicity included fatigue (13 %), wound dehiscence (7 %) and stroke, pulmonary embolism and nausea each in 1 patient. Presumed radiation necrosis with clinical decline was seen in 50 % of patients, two with autopsy documentation. The study was closed early to accrual due to this finding. This study demonstrated 90 % 6-month PFS and OS comparable to historic data in patients receiving standard treatment. Bevacizumab did not prevent radiation necrosis associated with this hypofractionated radiation regimen and large PTV volumes may have contributed to high rates of presumed radiation necrosis.

The impact of adjuvant radiation therapy for high-grade gliomas by histology in the United States population.

PURPOSE: To compare the survival impact of adjuvant external beam radiation therapy (RT) for malignant gliomas of glioblastoma (GBM), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), and mixed anaplastic oligoastrocytoma (AOA) histology. METHODS AND MATERIALS: The Surveillance, Epidemiology, and End Results (SEER) database was queried from 1998 to 2007 for patients aged ≥18 years with high-grade gliomas managed with upfront surgical resection, treated with and without adjuvant RT. RESULTS: The primary analysis totaled 14,461 patients, with 12,115 cases of GBM (83.8%), 1312 AA (9.1%), 718 AO (4.9%), and 316 AOA (2.2%). On univariate analyses, adjuvant RT was associated with significantly improved overall survival (OS) for GBMs (2-year OS, 17% vs 7%, p<.001), AAs (5-year OS, 38% vs 24%, p<.001), and AOAs (5-year OS, 55% vs 44%, p=.026). No significant differences in OS were observed for AOs (5-year OS, with RT 50% vs 56% without RT, p=.277). In multivariate Cox proportional hazards models accounting for extent of resection, age, sex, race, year, marital status, and tumor registry, RT was associated with significantly improved OS for both GBMs (HR, 0.52; 95% CI, 0.50-0.55; P<.001) and AAs (HR, 0.57; 95% CI, 0.48-0.68; P<.001) but only a trend toward improved OS for AOAs (HR, 0.70; 95% CI, 0.45-1.09; P=.110). Due to the observation of nonproportional hazards, Cox regressions were not performed for AOs. A significant interaction was observed between the survival impact of RT and histology overall (interaction P<.001) and in a model limited to the anaplastic (WHO grade 3) histologies. (interaction P=.024), characterizing histology as a significant predictive factor for the impact of RT. Subgroup analyses demonstrated greater hazard reductions with RT among patients older than median age for both GBMs and AAs (all interaction P≤.001). No significant interactions were observed between RT and extent of resection. Identical patterns of significance were observed for cause-specific survival and OS across analyses. CONCLUSIONS: In this large population-based cohort, glioma histology represented a significant predictor for the survival impact of RT. Adjuvant RT was associated with improved survival for AAs, with benefits comparable to those observed for GBMs over the same 10-year interval. No survival advantage was observed with adjuvant RT for AOs.

Prospective evaluation of health-related quality of life in patients with glioblastoma multiforme treated on a phase II trial of hypofractionated IMRT with temozolomide.

To report health-related quality of life (HRQOL) in glioblastoma (GBM) patients treated on a phase II trial of hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with temozolomide (TMZ). GBM patients received postoperative hypo-IMRT to 60 Gy in 10 fractions with TMZ. HRQOL was assessed using the EORTC quality of life questionnaire core-30 and the EORTC brain cancer module, performed at baseline, RT completion, 1 mo post-RT, and every 3 mos thereafter. Changes from baseline were calculated for each specific HRQOL scale. A ≥ 10 point change in any HRQOL scale from the mean baseline score was significant. 24 patients were treated. Compliance with HRQOL assessments at baseline, RT completion, and 1, 3, 6, 9, and 12 mos post-RT was 100, 96, 92, 79, 70, 68 and 53 %, respectively. Up to 12 mos post-RT, no significant changes were seen in global health status, physical functioning, role functioning, emotional functioning, fatigue, nausea, vision, headache or seizure. Significant improvement was seen in insomnia, future uncertainty, motor dysfunction and drowsiness. Significant worsening was observed in cognitive functioning, social functioning, appetite loss and communication deficit. 60 Gy hypo-IMRT in 6-Gy fractions with TMZ does not appear to negatively impact overall HRQOL.

Anaplastic PXA in adults: case series with clinicopathologic and molecular features.

Pleomorphic xanthoastrocytomas with anaplastic features (PXA-As) are rare tumors about which little is known regarding clinicopathologic and molecular features. Several studies have identified BRAF V600E mutations in PXA-As, but the percentage with mutation may differ between adult and pediatric examples, and limited information exists about immunohistochemistry for isocitrate dehydrogenase 1 (IDH1). Ten cases of adult PXA-As seen at our institution since 2000 were assessed for BRAF V600E mutation by polymerase chain reaction testing (PCR) and IDH1 by immunohistochemistry. Patients ranged in age from 18-68 years; four PXA-As affected temporal lobe and two were cystic. Four patients underwent gross total resection and 9 of 10 patients received cranial irradiation and/or adjuvant chemotherapy. Five survived less than 5 years, although 2 of 5 patients died from non-tumor causes. Four long-term survivors are alive at 7.5, 9.8, 11.4, and 11.9 years post-diagnosis. Two of four long term survivors had BRAF V600E mutation: patients were ages 18 and 28 years. A 48-year-old male without BRAF mutation survives at 9.8 years, even with thalamic location; conversely a 68-year-old female with temporal lobe tumor and BRAF mutation survived 1.9 years after diagnosis. All tumors were IDH1 immunonegative. This case series details clinicopathologic features of a subset of rare PXA-As in adults. BRAF V600E mutation was identified in 50 % of these cases.

Genetic characterization of gliomas arising in patients with multiple sclerosis.

The co-occurrence of gliomas and multiple sclerosis (MS) in the same patient is uncommon, but a well-reported phenomenon. Most have been high grade astrocytic tumors that developed after the diagnosis of MS, leading authors to postulate that chronic gliosis in demyelinative plaques might be the underlying substrate for secondary induction of a glial neoplasm. Until recently, however, genetic tools have not been available to test the hypothesis that high grade gliomas might arise from longstanding chronic gliosis, with transformation to low grade glioma, and eventually GBM, i.e., be secondary GBMs. We searched our surgical neuropathology and MS Brain Bank databases over the past 25 years (1987-2011) and identified eight cases of co-occurring MS and glioma. After careful review to guarantee both diagnoses, cases were studied by fluorescence in situ hybridization for genetic markers appropriate to diagnosis, as well as by direct sequencing for IDH1/2 and P53. No unusual genetic features were detected in our cohort; further, the 4 GBMs we did identify did not have clinical features of secondary glioblastomas nor did any of the four manifest IDH-1 immunohistochemical expression or IDH1/2 mutations, as might be expected in secondary GBMs. Conversely, PTEN loss and EGFR expression, features often found in primary GBMs, but seldom identified in secondary GBMs, were found in 3 of 4 GBMs. We conclude that gliomas in MS patients have genetic features paralleling counterparts in non-MS patients. There is no strong genetic evidence for GBMs to be secondary GBMs.

Phase II trial of hypofractionated IMRT with temozolomide for patients with newly diagnosed glioblastoma multiforme.

PURPOSE: To report toxicity and overall survival (OS) in patients with newly diagnosed glioblastoma multiforme (GBM) treated with hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with concurrent and adjuvant temozolomide (TMZ). METHODS AND MATERIALS: Patients with newly diagnosed GBM after biopsy or resection and with adequate performance status and organ or bone marrow function were eligible for this study. Patients received postoperative hypo-IMRT to the surgical cavity and residual tumor seen on T1-weighted brain MRI with a 5-mm margin to a total dose of 60 Gy in 10 fractions (6 Gy/fraction) and to the T2 abnormality on T2-weighted MRI with 5-mm margin to 30 Gy in 10 fractions (3 Gy/fraction). Concurrent TMZ was given at 75 mg/m(2)/day for 28 consecutive days. Adjuvant TMZ was given at 150 to 200 mg/m(2)/day for 5 days every 28 days. Toxicities were defined using Common Terminology Criteria for Adverse Events version 3.0. RESULTS: Twenty-four patients were treated, consisting of 14 men, 10 women; a median age of 60.5 years old (range, 27-77 years); and a median Karnofsky performance score of 80 (range, 60-90). All patients received hypo-IMRT and concurrent TMZ according to protocol, except for 2 patients who received only 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 6.5 (range, 0-14).With a median follow-up of 14.8 months (range, 2.7-34.2 months) for all patients and a minimum follow-up of 20.6 months for living patients, no instances of grade 3 or higher nonhematologic toxicity were observed. The median OS was 16.6 months (range, 4.1-35.9 months). Six patients underwent repeated surgery for suspected tumor recurrence; necrosis was found in 50% to 100% of the resected specimens. CONCLUSION: In selected GBM patients, 60 Gy hypo-IMRT delivered in 6-Gy fractions over 2 weeks with concurrent and adjuvant TMZ is safe. OS in this small cohort of patients was comparable to that treated with current standard of care therapy.

Window of opportunity: flexion myelopathy after drug overdose.

BACKGROUND: Cervical and thoracic flexion myelopathy are uncommon causes of spinal cord injury that can lead to irreversible paralysis, autonomic dysfunction, and death. To the authors' knowledge, this report is the first to describe the natural history of flexion myelopathy and the simultaneous occurrence of cervical and thoracic flexion myelopathy in the setting of drug overdose. OBJECTIVES: To report the association of cervical and thoracic flexion myelopathy and drug overdose; to describe the subacute natural history of flexion myelopathy in the setting of drug overdose; to emphasize the need for first responders to document positioning of unresponsive individuals; and to suggest careful neurological examination and early spinal cord imaging in appropriately identified patients at risk of flexion myelopathy. CASE REPORT: We describe the case of a 34-year-old woman who developed flexion myelopathy resulting in severe quadriparesis after overdose of quetiapine fumarate, oxycodone/acetaminophen, and chloral hydrate. CONCLUSION: Flexion myelopathy in the setting of drug overdose is a subacute injury. Early intervention may limit neurological disability. However, the clinical diagnosis of flexion myelopathy is inevitably delayed by the patient's altered level of consciousness or mental status at presentation, and concurrent multiple organ failure.

Phase I dose escalation trial of vandetanib with fractionated radiosurgery in patients with recurrent malignant gliomas.

PURPOSE: To determine the maximum tolerated dose (MTD) of vandetanib with fractionated stereotactic radiosurgery (SRS) in patients with recurrent malignant gliomas. METHODS AND MATERIALS: Patients with a recurrent malignant glioma and T1-enhancing recurrent tumor ≤ 6 cm were eligible. Vandetanib was given orally, once per day, 7 days a week, starting at least 7 days before SRS and continued until a dose-limiting toxicity (DLT) or disease progression. The planned vandetanib daily dose was 100 mg, 200 mg, and 300 mg for the cohorts 1, 2, and 3, respectively, and was escalated using a standard 3+3 design. A total SRS dose of 36 Gy, 12 Gy per fraction, was delivered over 3 consecutive days. The MTD was defined as the dose of vandetanib at which less than 33% of patients developed DLTs, defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 3 as any Grade 3 or greater nonhematologic toxicity and Grade 4 or greater hematologic toxicity. RESULTS: Ten patients were treated, 6 on cohort 1 and 4 on cohort 2. Treatment characteristics were: 7 men, 3 women; median age, 40 years (range, 22-72); 7 GBM, 3 anaplastic astrocytoma (AA); median initial radiation (RT) dose, 60 Gy (range, 59.4-70); median interval since initial RT, 14.5 months (range, 7-123); All patients received SRS per protocol. The median follow-up time was 4 months (range, 1-10 months). Median time on vandetanib was 3 months (range 1-11). One of 6 patients in the first cohort developed a DLT of Grade 3 hemothorax while on anticoagulation. The MTD was reached when 2 of the 4 patients enrolled in the second cohort developed DLTs. Six patients had radiographic response, 2 with stable disease. CONCLUSION: The MTD of vandetanib, with SRS in recurrent malignant glioma, is 100 mg daily. Further evaluation of safety and efficacy is warranted.