Antiepileptic Strategies for Patients with Primary and Metastatic Brain Tumors.

OPINION STATEMENT: Seizure activity is common in patients with primary and metastatic brain tumors, affecting more than 50% of cases over the course of their disease. Several mechanisms contribute to brain tumor-related epilepsy (BTRE), including a pro-inflammatory environment, excessive secretion of glutamate and an increase in neuronal excitatory tone, reduction of GABAergic inhibitory activity, and an increase in 2-hydroxygluturate production in isocitrate dehydrogenase mutant tumors. After a verified seizure in a brain tumor patient, the consensus is that BTRE has developed, and it is necessary to initiate an antiepileptic drug (AED). It is not recommended to initiate AED prophylaxis. Second- and third-generation AEDs are the preferred options for initiation, due to a lack of hepatic enzyme induction and reduced likelihood for drug-drug interactions, especially in regard to neoplastic treatment. The efficacy of appropriate AEDs for patients with BTRE is fairly equivalent, although some data suggests that levetiracetam may be slightly more active in suppressing seizures than other AEDs. The consensus among most Neuro-Oncology providers is to initiate levetiracetam monotherapy after a first seizure in a brain tumor patient, as long as the patient does not have any psychiatric co-morbidities. If levetiracetam is not tolerated well or is ineffective, other appropriate initial AED options for monotherapy or as an add-on anticonvulsant include lacosamide, valproic acid, briviracetam, lamotrigine, and perampanel.

Successful Intrathecal Rituximab Administration in Refractory Nonteratoma Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Case Report.

N-methyl-D-aspartate receptor (NMDA-R) antibody encephalitis is an immune-mediated disorder characterized by the presence of anti-NMDA antibody in serum and cerebrospinal fluid, with a characteristic combination of psychological and neurological signs and symptoms. The scientific knowledge pertaining to the management of anti-NMDA-R encephalitis is growing. It is important that neuroscience nurses be aware of treatments as well as the newest novel treatment options available. Early aggressive intervention is imperative to recovery. The first line of treatment often includes high-dose steroids, intravenous immunoglobulin, and therapeutic plasma exchange. Second-line therapy for refractory NMDA-R encephalitis includes intravenous rituximab and cyclophosphamide. Even with these treatments, up to 25% of patients may be left with severe deficits or have a fatal outcome. It is well known that penetration of monoclonal anti-CD20 antibody therapy (rituximab) into the cerebrospinal fluid is 0.1% of that in the serum. Therefore, efficacy of rituximab in the treatment of NMDA encephalitis may be improved by intrathecal administration in selected cases with a poor response to intravenous rituximab. We present a case of anti-NMDA-R encephalitis that was refractory to first- and second-line therapies, who responded to intrathecal rituximab, to highlight a novel treatment that may be able to prevent long-term disability and improve clinical outcomes.

Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma.

BACKGROUND: Despite aggressive standard of care (SOC) treatment, survival of malignant gliomas remains very poor. This Phase II, prospective, matched controlled, multicenter trial was conducted to assess the safety and efficacy of aglatimagene besadenovec (AdV-tk) plus valacyclovir (gene-mediated cytotoxic immunotherapy [GMCI]) in combination with SOC for newly diagnosed malignant glioma patients. METHODS: Treatment cohort patients received SOC + GMCI and were enrolled at 4 institutions from 2006 to 2010. The preplanned, matched-control cohort included all concurrent patients meeting protocol criteria and SOC at a fifth institution. AdV-tk was administered at surgery followed by SOC radiation and temozolomide. Subset analyses were preplanned, based on prognostic factors: pathological diagnosis (glioblastoma vs others) and extent of resection. RESULTS: Forty-eight patients completed SOC + GMCI, and 134 met control cohort criteria. Median overall survival (OS) was 17.1 months for GMCI + SOC versus 13.5 months for SOC alone (P = .0417). Survival at 1, 2, and 3 years was 67%, 35%, and 19% versus 57%, 22%, and 8%, respectively. The greatest benefit was observed in gross total resection patients: median OS of 25 versus 16.9 months (P = .0492); 1, 2, and 3-year survival of 90%, 53%, and 32% versus 64%, 28% and 6%, respectively. There were no dose-limiting toxicities; fever, fatigue, and headache were the most common GMCI-related symptoms. CONCLUSIONS: GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival outcomes were most notably improved in patients with minimal residual disease after gross total resection. These data should help guide future immunotherapy studies and strongly support further evaluation of GMCI for malignant gliomas. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov NCT00589875.

Central Nervous System Cancers, Version 1.2015.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System (CNS) Cancers provide interdisciplinary recommendations for managing adult CNS cancers. Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. These NCCN Guidelines Insights summarize the NCCN CNS Cancers Panel's discussion and highlight notable changes in the 2015 update. This article outlines the data and provides insight into panel decisions regarding adjuvant radiation and chemotherapy treatment options for high-risk newly diagnosed low-grade gliomas and glioblastomas. Additionally, it describes the panel's assessment of new data and the ongoing debate regarding the use of alternating electric field therapy for high-grade gliomas.

Survival outcomes and safety of carmustine wafers in the treatment of high-grade gliomas: a meta-analysis.

Carmustine wafers (CW; Gliadel(®) wafers) are approved to treat newly-diagnosed high-grade glioma (HGG) and recurrent glioblastoma. Widespread use has been limited for several reasons, including concern that their use may preclude enrollment in subsequent clinical trials due to uncertainty about confounding of results and potential toxicities. This meta-analysis estimated survival following treatment with CW for HGG. A literature search identified relevant studies. Overall survival (OS), median survival, and adverse events (AEs) were summarized. Analysis of variance evaluated effects of treatment (CW vs non-CW) and diagnosis (new vs recurrent) on median survival. The analysis included 62 publications, which reported data for 60 studies (CW: n = 3,162; non-CW: n = 1,736). For newly-diagnosed HGG, 1-year OS was 67 % with CW and 48 % without; 2-year OS was 26 and 15 %, respectively; median survival was 16.4 ± 21.6 months and 13.1 ± 29.9 months, respectively. For recurrent HGG, 1-year OS was 37 % with CW and 34 % without; 2-year OS was 15 and 12 %, respectively; median survival was 9.7 ± 20.9 months and 8.6 ± 22.6 months, respectively. Effects of treatment (longer median survival with CW than without; P = 0.043) and diagnosis (longer median survival for newly-diagnosed HGG than recurrent; P < 0.001) on median survival were significant, with no significant treatment-by-diagnosis interaction (P = 0.620). The most common AE associated with wafer removal was surgical site infection (SSI); the most common AEs for repeat surgery were mass effect, SSI, hydrocephalus, cysts in resection cavity, acute hematoma, wound healing complications, and brain necrosis. These data may be useful in the context of utilizing CW in HGG management, and in designing future clinical trials to allow CW-treated patients to participate in experimental protocols.

Efficacy and patient-reported outcomes with dose-intense temozolomide in patients with newly diagnosed pure and mixed anaplastic oligodendroglioma: a phase II multicenter study.

Standard initial therapy for patients with pure and mixed anaplastic oligodendrogliomas (AO/MAO) includes chemotherapy and radiation therapy. Anaplastic oligodendrogliomas with 1p/19q co-deletion are more responsive to chemotherapy. There is concern for potential long-term CNS toxicity of radiation. Hence an approach using chemotherapy initially and reserving radiation for progressive disease is attractive. This multicenter phase II trial included patients with newly diagnosed AO/MAO with central pathology review and 1p/19q assay. Temozolomide was given 150 mg/m(2) days 1-7 and 15-21, every 28 days for 8 cycles. The primary endpoint was progression free survival (PFS). Secondary endpoints included response rate, overall survival (OS), treatment toxicity and health-related quality of life (HRQL). Data from 62 patients enrolled between December 2001 and April 2007 at seven centers were analyzed. Among patients with measurable disease, 8 % achieved complete remission, 56 % had stable disease and 36 % had progression. The median PFS and OS were 27.2 months (95 % CI 11.9-36.3) and 105.8 months (95 % CI 51.5-N/A), respectively. Both 1p loss and 1p/19q co-deletion were positive prognostic factors for PFS (p < 0.001) and OS (p < 0.001); and there was some suggestion that 1p/19q co-deletion also predicted better response to chemotherapy (p = 0.007). Grade 3/4 toxicities were mainly hematological. Significantly improved HRQL in the future uncertainty domain of the brain cancer module was seen after cycle 4 (p < 0.001). This trial achieved outcomes similar to those reported previously. Toxicities from dose-intense temozolomide were manageable. Improvement in at least one HRQL domain increased over time. This trial supports the further study of first-line temozolomide monotherapy as an alternative to radiation therapy for patients with newly diagnosed AO/MAO with 1p 19q co-deleted tumors.

Central nervous system cancers, version 2.2014. Featured updates to the NCCN Guidelines.

The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases.

Central nervous system cancers.

Primary and metastatic tumors of the central nervous system are a heterogeneous group of neoplasms with varied outcomes and management strategies. Recently, improved survival observed in 2 randomized clinical trials established combined chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion. For metastatic disease, increasing evidence supports the efficacy of stereotactic radiosurgery in treating patients with multiple metastatic lesions but low overall tumor volume. These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus. This version includes expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, and brain metastases. The full online version, available at NCCN. org, contains recommendations on additional subtypes.

"Tumoral pseudoblush" identified within gliomas at high-spatial-resolution ultrahigh-field-strength gradient-echo MR imaging corresponds to microvascularity at stereotactic biopsy.

PURPOSE: To use directed biopsy sampling to determine whether microvascular assessment within gliomas, by means of ultrahigh-field-strength high-spatial-resolution gradient-echo (GRE) magnetic resonance (MR) imaging at 8 T, correlates with histopathologic assessment of microvascularity. MATERIALS AND METHODS: The study was institutional review board approved and HIPAA compliant. Informed consent was obtained. Thirty-five subjects with gliomas underwent 8-T and 80-cm MR imaging by using a GRE sequence (repetition time, 600-750 msec; echo time, 10 msec; in-plane resolution, 196 mm). Haphazardly arranged serpentine low-signal-intensity structures, often associated with areas of low signal intensity within the tumor bed ("tumoral pseudoblush") at MR imaging, were presumed to be related to tumoral microvascularity. Microvessel density (MVD) and microvessel size (MVS) ranked with a semiquantitative three-tier scale (high, medium, and low) relative to cortical penetrating veins were assessed from regions of interest identified at MR imaging and were compared with a similar assessment of stereotactic biopsy specimens by using Kendall τb. Tumor grade (high vs low) was compared with ultrahigh-field-strength high-resolution GRE MR analysis by using Pearson χ2. Discrepancies between 8-T and histopathologic assessment were identified and analyzed. RESULTS: Ultrahigh-field-strength high-resolution GRE MR imaging and histopathologic assessment concurred for MVS (P<.0001) and MVD (P<.0001). World Health Organization classification tumor grade was associated with number (P<.0005) and size (P<.0005) of foci of microvascularity within the tumor bed at 8-T MR imaging. Radiation-induced microvessel hyalinosis mimicked tumor microvascularity at 8-T MR imaging. Potential confounders could result from radiofrequency inhomogeneity and displaced normal microvasculature. CONCLUSION: Microvascularity identified as a tumoral pseudoblush at ultrahigh-field-strength high-resolution GRE MR imaging without contrast material shows promise as a marker for increased tumoral microvascularity.

Neurological complications of chemotherapy to the central nervous system.

One of the most common complications of chemotherapeutic drugs is toxicity to the central nervous system (CNS). This toxicity can manifest in many ways, including encephalopathy syndromes and confusional states, seizure activity, headache, cerebrovascular complications and stroke, visual loss, cerebellar dysfunction, and spinal cord damage with myelopathy. For many drugs, the toxicity is related to route of administration and cumulative dose, and can vary from brief, transient episodes to more severe, chronic sequelae. However, the neurotoxicity can be idiosyncratic and unpredictable in some cases. Among the antimetabolite drugs, methotrexate, 5-fluorouracil, and cytosine arabinoside are most likely to cause CNS toxicity. Of the alkylating agent chemotherapeutic drugs, the nitrosoureas (e.g., BCNU) and cisplatin most frequently cause toxicity to the CNS, especially when given via the intra-arterial route. Ifosfamide is also likely to cause neurotoxicity at high intravenous doses. Other alkylating agents, such as busulfan, cyclophosphamide, procarbazine, and temozolomide, are better tolerated by the CNS at moderate doses. The retinoid drugs are known to cause severe headaches at high doses. l-Asparaginase can induce an encephalopathy syndrome, as well as cerebrovascular complications such as stroke.

Bevacizumab for glioblastoma refractory to vascular endothelial growth factor receptor inhibitors.

Glioblastoma (GBM) is a highly vascular tumor dependent on angiogenesis through the vascular endothelial growth factor (VEGF) signaling cascade. Inhibition of VEGF signaling is an important therapeutic strategy. We report our experience with bevacizumab (BEV), a VEGF targeting antibody, following failure of a VEGF receptor targeting tyrosine kinase inhibitor (TKI). We retrospectively identified patients treated on clinical trials with VEGFR-TKIs for recurrent GBM followed by BEV at next recurrence. Survival was estimated by the Kaplan-Meier method. Fourteen patients were identified (six women; median age 57). All received VEGFR-TKIs (sunitinib 11, cediranib 2, sorafenib 1) then BEV at next recurrence. There were no radiographic responses to VEGFR-TKIs; best response was stable disease in 50% (7/14). Patients received BEV alone (21%, 3/14) or in combination with chemotherapy (79%, 11/14). On BEV, 29% (4/14) had a partial response, and 36% (5/14) stabilized. Of evaluable patients, 42% (5/12) had neurological improvement and 56% (5/9) reduced corticosteroid requirement. Median survival on BEV was 7.8 months (95% CI 4.0-15.8), median progression-free survival (PFS) was 4.0 months (95% CI 1.6-10.5), and the 6-month PFS rate was 29% (95% CI 9-52). Our radiographic and survival outcomes with BEV following progression after VEGFR-TKIs are similar to data from studies of BEV as initial salvage therapy, although our sample size was small. Prior exposure to VEGFR-TKIs may not preclude response to BEV, but sensitivity to BEV may be lower following more robust VEGFR inhibition.

Clinical presentation, histology, and treatment in 430 patients with primary tumors of the spinal cord, spinal meninges, or cauda equina.

OBJECT Patients having a primary tumor of the spinal cord, spinal meninges or cauda equina, are relatively rare. Neurosurgeons encounter and treat such patients, and need to be aware of their clinical presentation, tumor types, treatment options, and potential complications. The purpose of this paper is to report results from a series of 430 patients with primary intraspinal tumors, taken from a larger cohort of 9661 patients with primary tumors of the CNS. METHODS Extensive information on individuals diagnosed (in the year 2000) as having a primary CNS neoplasm was prospectively collected in a Patient Care Evaluation Study conducted by the Commission on Cancer of the American College of Surgeons. Data from US hospital cancer registries were submitted directly to the National Cancer Database. Intraspinal tumor cases were identified based on ICD-O-2 topography codes C70.1, C72.0, and C72.1. Analyses were performed using SPSS. RESULTS Patients with primary intraspinal tumors represented 4.5% of the CNS tumor group, and had a mean age of 49.3 years. Pain was the most common presenting symptom, while the most common tumor types were meningioma (24.4%), ependymoma (23.7%), and schwannoma (21.2%). Resection, surgical biopsy, or both were performed in 89.3% of cases. Complications were low, but included neurological worsening (2.2%) and infection (1.6%). Radiation therapy and chemotherapy were administered to 20.3% and 5.6% of patients, respectively. CONCLUSIONS Data from this study are suitable for benchmarking, describing prevailing patterns of care, and generating additional hypotheses for future studies.

Emergent pulmonary embolectomy and advanced glioblastoma multiforme.

Pulmonary emboli are frequent causes of morbidity and mortality in patients with brain tumors. Treatment options are limited in these complex patients. We report a case of successful acute pulmonary embolectomy in a patient with an advanced brain cancer.

Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal.

MicroRNAs (miR) show characteristic expression signatures in various cancers and can profoundly affect cancer cell behavior. We carried out miR expression profiling of human glioblastoma specimens versus adjacent brain devoid of tumor. This revealed several significant alterations, including a pronounced reduction of miR-128 in tumor samples. miR-128 expression significantly reduced glioma cell proliferation in vitro and glioma xenograft growth in vivo. miR-128 caused a striking decrease in expression of the Bmi-1 oncogene, by direct regulation of the Bmi-1 mRNA 3'-untranslated region, through a single miR-128 binding site. In a panel of patient glioblastoma specimens, Bmi-1 expression was significantly up-regulated and miR-128 was down-regulated compared with normal brain. Bmi-1 functions in epigenetic silencing of certain genes through epigenetic chromatin modification. We found that miR-128 expression caused a decrease in histone methylation (H3K27me(3)) and Akt phosphorylation, and up-regulation of p21(CIP1) levels, consistent with Bmi-1 down-regulation. Bmi-1 has also been shown to promote stem cell self-renewal; therefore, we investigated the effects of miR-128 overexpression in human glioma neurosphere cultures, possessing features of glioma "stem-like" cells. This showed that miR-128 specifically blocked glioma self-renewal consistent with Bmi-1 down-regulation. This is the first example of specific regulation by a miR of a neural stem cell self-renewal factor, implicating miRs that may normally regulate brain development as important biological and therapeutic targets against the "stem cell-like" characteristics of glioma.

CNS germinomas: what is the best treatment strategy?

CNS germ cell tumors are rare primary brain malignancies. Germinomas comprise approximately two-thirds of CNS germ cell tumors. Owing to their radiosensitivity, radiotherapy has been used to treat patients with CNS germinomas, with favorable treatment outcomes. Historically, craniospinal irradiation has been used. Given the concerns over long-term toxicities associated with craniospinal irradiation, reduced volume radiotherapy with or without chemotherapy has been employed. Data on the use of different strategies in the treatment of CNS germinomas are emerging but a standard strategy has not been established. This article reviews the different strategies used in the management of CNS germinomas.

Primary meningeal CNS lymphoma treated with intra-arterial chemotherapy and blood-brain barrier disruption.

Diffuse large B-cell lymphoma of the meninges is a particularly rare form of primary CNS lymphoma. We report a case of a 63-year-old woman found to have primary meningeal lymphoma (PML) with dural and leptomeningeal involvement whom we treated with multiple cycles of intra-arterial (IA) methotrexate, intravenous (IV) etoposide phosphate, and IV cyclophosphamide after reversible osmotic blood-brain barrier disruption (BBBD). Improvement was evident on gadolinium-enhanced brain MRI one month into therapy. At 67 months post-diagnosis there is no evidence of CNS disease. After completing her therapy regimen, she remained disease-free for 34 months, when stage IV diffuse large B-cell lymphoma was discovered in her left adrenal gland and right thigh. Following six cycles of rituximab and CHOP treatment, she is presently in complete remission. IA methotrexate and reversible osmotic BBBD without radiation therapy may be an effective therapy for treating PML.