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Recurrent GBM and AA have a dismal prognosis and a high unmet need for effective therapies. Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that encodes the transgene cytosine deaminase (CD). Toca 511 selectively infects, persists and spreads in tumor. Subsequent oral administration of 5-fluorocytosine (Toca FC) produces 5-fluorouracil (5-FU) by CD within infected cells. 5-FU kills cancer cells and myeloid derived suppressor cells, inducing robust antitumor immune responses in animal models. Clinical data from phase 1 trials are consistent with this mechanism of action, and show extended survival compared to historical controls. Toca 5 is a multicenter, randomized, open-label Phase 2/3 trial of Toca 511 and Toca FC versus standard of care administered to patients undergoing resection for first or second recurrence of GBM or AA. Phase 2 will enroll 170 patients. Primary endpoint is overall survival (OS). Key secondary endpoints are safety, objective response rate, clinical benefit rate, progression-free survival, and landmark OS. Key inclusion criteria are age 18-75 years, histologically proven GBM or AA, measurable disease preoperatively of less than 5cm, candidate for equal or greater 80% resection of enhancing tumor based on pre-operative evaluation, and KPS equal or greater to 70. Assays for immune monitoring will be performed and molecular profiling of resected tumor samples will be correlated efficacy.

Purpose: NF2-related schwannomatosis (NF2) is characterized by bilateral vestibular schwannomas (VS) often causing hearing and neurologic deficits, with currently no FDA-approved drug treatment. Pre-clinical studies highlighted the potential of mTORC1 inhibition in delaying schwannoma progression. We conducted a prospective open-label, phase II study of everolimus for progressive VS in NF2 patients and investigated imaging as a potential biomarker predicting effects on growth trajectory., Methods: The trial enrolled 12 NF2 patients with progressive VS. Participants received oral everolimus daily for 52 weeks. Brain imaging was obtained quarterly. As primary endpoint, radiographic response (RR) was defined as ≥ 20% decrease in target VS volume. Secondary endpoints included other tumors RR, hearing outcomes, drug safety and quality of life (QOL)., Results: Eight participants completed the trial and four discontinued the drug early due to significant volumetric VS progression. After 52 weeks of treatment, the median annual VS growth rate decreased from 77.2% at baseline to 29.4%. There was no VS RR and 3 of 8 (37.5%) participants had stable disease. Decreased or unchanged VS volume after 3 months of treatment was predictive of stabilization at 12 months. Seven of eight participants had stable hearing during treatment except one with a decline in word recognition score. Ten of twelve participants reported only minimal changes to their QOL scores., Conclusions: Volumetric imaging at 3 months can serve as an early biomarker to predict long-term sensitivity to everolimus treatment. Everolimus may represent a safe treatment option to decrease the growth of NF2-related VS in patients who have stable hearing and neurological condition. TRN: NCT01345136 (April 29, 2011)., (© 2024. The Author(s).)

Background: Rosette-forming glioneuronal tumors (RGNTs) are rare tumors composed of mixed glial and neurocytic components. Most lesions are confined to the posterior fossa, especially in the region of the fourth ventricle, in young adults. In few instances, diffuse involvement of the supratentorial region is identified, thereby creating significant challenges in diagnosis, surgical intervention, and prognostication., Observations: The authors present a 23-year-old female with chronic headaches, papilledema, and hydrocephalus who underwent radiographic evaluation revealing obstructive hydrocephalus and diffuse supratentorial enhancing and nonenhancing cystic and nodular lesions. The patient underwent a right frontal craniotomy and septostomy. An exophytic nonenhancing right frontal horn lesion was resected, and an enhancing third-ventricular lesion was biopsied. Final pathology of both of the lesions sampled was consistent with RGNT. Next-generation sequencing demonstrated tumor alterations in the FGFR-1 and PIK3CA genes. Targeted therapy with the FGFR inhibitor erdafitinib demonstrated a partial remission., Lessons: Diffuse supratentorial spread of RGNT is an extremely rare presentation of an already uncommon pathology. In some cases, gross-total resection may not be feasible. Goals of surgery include acquiring tissue for diagnosis, maximizing safe resection, and treating any associated hydrocephalus. FGFR inhibitors may be of benefit in cases of disease progression.

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.

Background: Fatigue is a common and disabling symptom in people with a primary brain tumour (PBT). The effectiveness of interventions for treating clinically significant levels of fatigue in this population is unclear. This is an updated version of the original Cochrane Review published in Issue 4, 2016., Objectives: To assess the effectiveness and safety of pharmacological and non-pharmacological interventions for adults with PBT and clinically significant (or high levels) of fatigue., Search Methods: For this updated review, we searched CENTRAL, MEDLINE and Embase, and checked the reference lists of included studies in April 2022. We also searched relevant conference proceedings, and ClinicalTrials.gov for ongoing trials., Selection Criteria: We included randomised controlled trials (RCTs) that investigated any pharmacological or non-pharmacological intervention in adults with PBT and fatigue, where fatigue was the primary outcome measure. We restricted inclusion specifically to studies that enrolled only participants with clinically significant levels of fatigue to improve the clinical utility of the findings., Data Collection and Analysis: Two review authors (JD, DC) independently evaluated search results for the updated search. Two review authors (JD, SYK) extracted data from selected studies, and carried out a risk of bias assessment. We extracted data on fatigue, mood, cognition, quality of life and adverse events outcomes., Main Results: The original review identified one study and this update identified a further two for inclusion. One study investigated the use of modafinil, one study the use of armodafinil and one study the use of dexamfetamine. We identified three ongoing studies. In the original review, the single eligible trial compared modafinil to placebo for 37 participants with a high- or low-grade PBT. One new study compared two doses of armodafinil (150 mg and 250 mg) to placebo for 297 people with a high-grade glioma. The second new study compared dexamfetamine sulfate to placebo for 46 participants with a low- or high-grade PBT. The evidence was uncertain for both modafinil and dexamfetamine regarding fatigue outcome measures, compared to controls, at study endpoint. Two trials did not reach the planned recruitment target and therefore may not, in practice, have been adequately powered to detect a difference. These trials were at a low risk of bias across most areas. There was an unclear risk of bias related to the use of mean imputation for one study because the investigators did not analyse the impact of imputation on the results and information regarding baseline characteristics and randomisation were not clear. The certainty of the evidence measured using GRADE was very low across all three studies. There was one identified study awaiting classification once data are available, which investigated the feasibility of 'health coaching' for people with a PBT experiencing fatigue. There were three ongoing studies that may be eligible for an update of this review, all investigating a non-pharmacological intervention for fatigue in people with PBT., Authors' Conclusions: There is currently insufficient evidence to draw reliable and generalisable conclusions regarding potential effectiveness or harm of any pharmacological or non-pharmacological treatments for fatigue in people with PBT. More research is needed on how best to treat people with brain tumours with high fatigue., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Glioblastoma (GB) is an aggressive tumor showing extensive intertumoral and intratumoral heterogeneity. Several possible reasons contribute to the historical inability to develop effective therapeutic strategies for treatment of GB. One such challenge is the inability to consistently procure high-quality biologically preserved specimens for use in molecular research and patient-derived xenograft model development. No scientifically derived standardized method exists for intraoperative tissue collection specifically designed with the fragility of RNA in mind., Methods: In this investigation, we set out to characterize matched specimens from 6 GB patients comparing the traditional handling and collection processes of intraoperative tissue used in most neurosurgical operating rooms versus an automated resection, collection, and biological preservation system (APS) which captures, preserves, and biologically maintains tissue in a prescribed and controlled microenvironment. Matched specimens were processed in parallel at various time points and temperatures, evaluating viability, RNA and protein concentrations, and isolation of GB cell lines., Results: We found that APS-derived GB slices stored in an APS modified medium remained viable and maintained high-quality RNA and protein concentration for up to 24 hours., Conclusions: Our results showed that primary GB cell cultures derived in this manner had improved growth over widely used collection and preservation methods. By implementing an automated intraoperative system, we also eliminated inconsistencies in methodology of tissue collection, handling and biological preservation, establishing a repeatable and standardized practice that does not require additional staff or a laboratory technician to manage it., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The P 53N gene maps precisely to human chromosome sub-band 22q12.1-12.3, a region where loss of heterozygosity has been reported in 30% of astrocytic tumors and associated with progression to anaplasia. Moreover, a putative tumor suppressor gene has been indicated on 22q11 region involved in pathogenesis of ependymal tumors. Our objectives to examine the expression level of novel membrane-associated protein (termed P 53N ) encoded by a novel human gene on chromosome 22q12.1-12.3 in glioblastomas and ependymomas. Serial analysis of gene expression (SAGE) and immunofluorescence analysis of the P 53N in the brain tumor tissues were performed. Our analysis revealed that there was high expression of the P 53N mRNA in brain ependymoma and brain well-differentiated astrocytoma libraries. The P 53N protein. P 53N protein contains a high mobility group (HMG) domain at amino acid positions 301 to 360 expressed highly in glioblastoma and ependymoma specimens. Anti-P 53N carboxyl-terminal peptide antibody localized the P 53N protein to the cytoplasmic membranes of protoplasmic astrocytes in the glioblastoma and ependymoma specimens. These results are in good agreement with the SAGE analysis and the predicted transmembrane topology for the P 53N protein and support a possible transmembrane model in which the P 53N contains a predicted transmembrane region with its amino terminus localized to the inside of the cytoplasmic membrane., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Introduction: Metastases to the brain (MB) occur in up to 30% of adults with cancer; of these, 15% to 35% may have seizures. We investigated clinical and pathologic associations with seizure and EEG findings in patients with MB, given the sparse literature in this area., Methods: We performed a retrospective chart review of adults with pathologically confirmed MB treated at a large tertiary care center between April 8, 2006, and December 14, 2018. Primary outcomes were odds of "chart-documented seizure" (CDS) in the full sample and EEG-captured seizure or any epileptiform discharges among those monitored on EEG., Results: We studied 187 patients with MB, of whom 55 (28.3%) were monitored on EEG. We found an overall CDS prevalence of 29.4% and an EEG-captured seizure of 18.9% among patients monitored on EEG. Of those monitored on EEG, 47.2% had epileptiform discharges. Adenocarcinoma pathology was associated with lower odds of CDS (odds ratio [OR] 0.50, 95% CI 0.26-0.96) and EEG-captured seizure (OR 0.09, 95% CI 0.01-0.87) versus other pathologies. When modeled separately, melanoma pathology was associated with CDS (OR 4.45, 95% CI 1.58-12.57) versus other pathologies. Hemorrhagic MB were associated with any epileptiform discharges (OR 5.50, 95% CI 1.65-18.37), regardless of pathology modeled. Increasing size of the largest dimension of the largest MB was associated with lower odds of CDS (OR 0.68, 95% CI 0.52-0.89 when adenocarcinoma modeled, OR 0.69, 95% CI 0.53-0.91 when melanoma modeled)., Conclusions: Seizures and epileptiform discharges are common in patients with MB. Tumor size and pathology were significantly associated with CDS. Larger studies are needed for further analysis., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2019 by the American Clinical Neurophysiology Society.)

Background: Metastatic epidural spinal cord compression (MESCC) is a debilitating sequela of cancer. Here, we evaluated various subtypes of posterior-only minimally invasive spinal (MIS) procedures utilized to address different cancers., Methods: Within this retrospective review, we analyzed the treatment of thoracolumbar MESCC treated with three MIS techniques: decompression and fusion (Subgroup A), partial corpectomy (Subgroup B), and full corpectomy (Subgroup C)., Results: There were 51 patients included in the study; they averaged 58.7 years of age, and 51% were females. Most tumors were in the thoracic spine (51%). The average preoperative Frankel grade was D (62.7%); 69% (35) improved postoperatively. The patients were divided as follows: subgroup A (15 patients = 29.4%), B (19 patients = 37.3%), and C (17 patients = 33.3%). The length of hospitalization was similar (~5.4 days) for all groups. The overall complication rate was 31%, while blood loss was lower in Subgroups A and B versus C., Conclusion: Different MIS surgical techniques were utilized in patients with thoracic and/or lumbar MESCC. Interestingly, clinical outcomes were similar between MIS subgroups, in this study, with a trend toward higher complications and greater blood loss associated with those undergoing more aggressive MIS procedures (e.g., full corpectomy and fusion)., Competing Interests: Dr. Frankel receives royalties from Orthofix and Stryker., (Copyright: © 2020 Surgical Neurology International.)

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.

Temozolomide (TMZ) therapy is the standard of care for patients with glioblastoma (GBM). Clinical studies have shown that elevated levels of DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT) or deficiency/defect of DNA mismatch repair (MMR) genes is associated with TMZ resistance in some, but not all, GBM tumors. Another reason for GBM treatment failure is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK) and c-Met (hepatocyte growth factor receptor). As such, these tyrosine kinases serve as potential targets for GBM therapy. Thus, we tested two novel drugs: INC280 (Capmatinib: a highly selective c-Met receptor tyrosine kinase-RTK inhibitor) and LDK378 (Ceritinib: a highly selective anaplastic lymphoma kinase-ALK inhibitor), aiming to overcome TMZ resistance in MGMT-unmethylated GBM cells in in vitro cell culture models. Treatments were examined using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, caspase-3 assay and western blot analysis. Results obtained from our experiments demonstrated that preconditioning with INC280 and LDK378 drugs exhibit increased MMR protein expression, specifically MMR protein MLH1 (MutL Homolog 1) and MSH6 (MutS Homolog 6) and sensitized TMZ in MGMT-unmethylated GBM cells via suppression of ALK and c-Met expression. INC280 and LDK378 plus TMZ also induced apoptosis by modulating downstream signaling of PI3K/AKT/STAT3. Taken together, this data indicates that co-inhibition of ALK and c-MET can enhance growth inhibitory effects in MGMT-unmethylated cells and enhance TMZ sensitivity in-vitro, suggesting c-Met inhibitors combined with ALK-targeting provide a therapeutic benefit in MGMT-unmethylated GBM patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Allelic losses of the q13.3 region of chromosome 19 have been documented in all major types of diffuse gliomas, strongly suggesting the presence of a 19q13.3 tumor suppressor gene responsible for these malignancies. The P 78 gene precisely maps to 19q13.3, the glioma candidate region, and encodes a recently identified novel protein (P 78 ). The purpose of this study was to determine P 78 protein expression in gliomas. Serial analysis of gene expression (SAGE) reveals P 78 mRNA expression to be significantly reduced in high-grade gliomas such as glioblastoma (GB), as compared with the low-grade tumors including astrocytomas, oligodendrogliomas, and ependymomas. We observed the distribution of staining of P 78 protein was concentrated on the cell membranes of the luminal epithelial cells, not cytoplasm. In contrast, the pre-immune serum controls demonstrated no staining. These results demonstrate that P 78 protein is highly expressed in the cytoplasmic membranes of low but not high-grade astrocytomas, and correlates with grade of malignancy. In these double immunostaining experiments, the anti-Map-2 and anti-NeuN antibodies did not stain round cells that were stained with the anti-P 78 carboxyl-terminal peptide antibodies, demonstrating that these round cells were not neurons, and likely protoplasmic astrocytes. Current results also suggest that the astrocytes stained with the anti-P 78 carboxyl-terminal peptide antibody are likely protoplasmic astrocytes. We also observed preincubation of anti-P 78 carboxyl-terminal antibodies with immunizing peptides abolished immunostaining in gliomas. These results suggest a role for the P 78 protein in the process of abnormal growth in glial tumors.

Background: Meningiomas represent ∼30% of primary central nervous system (CNS) tumors. Although advances in surgery and radiotherapy have significantly improved survival, there remains an important subset of patients whose tumors have more aggressive behavior and are refractory to conventional therapy. Recent advances in molecular genetics and epigenetics suggest that this aggressive behavior may be due to the deletion of the DNA repair and tumor suppressor gene, CHEK2, neurofibromatosis Type 2 (NF2) mutation on chromosome 22q12, and genetic abnormalities in multiple RTKs including FGFRs. Management of higher-grade meningiomas, such as anaplastic meningiomas (AM: WHO grade III), is truly challenging and there isn't an established chemotherapy option. We investigate the effect of active multi tyrosine receptor kinase inhibitor Dovitinib at stopping AM cell growth in in vitro with either frequent codeletion or mutated CHEK2 and NF2 gene. Methods: Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot analysis, caspases assay, and DNA fragmentation assay. Results: Treatment of CH157MN and IOMM-Lee cells with Dovitinib suppressed multiple angiokinases-mainly FGFRs, leading to suppression of downstream signaling by RAS-RAF-MAPK molecules and PI3K-AKT molecules which are involved in cell proliferation, cell survival, and tumor invasion. Furthermore, Dovitinib induced apoptosis via downregulation of survival proteins (Bcl-XL), and over-expression of apoptotic factors (Bax and caspase-3) regardless of CHEK2 and NF2 mutation status. Conclusions : This study establishes the groundwork for the development of Dovitinib as a therapeutic agent for high-grade AM with either frequent codeletion or mutated CHEK2 and NF2 , an avenue with high translational potential.

Background: Current treatments for glioblastoma (GB), the most common and malignant primary brain tumor are inadequate and as such, the median survival for most patients with GB is on the order of months, even after cytoreductive surgery, radiation and chemotherapy., Case Description: Current study reports two cases of glioblastoma (GB) with subventricular zone (SVZ) involvement. SVZ biopsies demonstrated the presence of hypercellularity, nestin immunoreactivity, and a Ki-67 labeling index (LI) of 1-2%. Interestingly, tumor morphology and proliferative indices are different in the SVZ specimens than the hemispheric recurrences, which displayed similar nestin immunoreactivity, but a greater LI of 10%. Biopsy specimens demonstrated both intense nestin immunoreactivity and GFAP immunoreactivity in and around the GB recurrence. Nestin positive cells were more abundant closer to the SVZ nearest to the dorsolateral horn of the left lateral ventricle, while GFAP immunoreactivity was more intense closer to the center of the tumor recurrence. Additionally, co-labeling of cells with Ki67 and several different progenitor markers (CD133, CD140, TUJ-1, and nestin) demonstrated that these cells found in and around the GB recurrence were actively dividing. Having failed standard therapy with evidence of bi-hemispheric spread and progression to GB, we report a novel approach of using intraventricular liposomal encapsulated cytarabine (DepoCyt) for the treatment for GB by suppressing glial progenitor cells that surround the ventricular system in patients with GB., Conclusions: MRI and immunohistochemistry demonstrated that the SVZ is the incubator for future recurrences of GB and propose targeting SVZ progenitor cells with intraventricular liposomal encapsulated Ara-C. Two patients treated using this novel regimen have demonstrated partial radiographic responses warranting further studies looking at targeting the subventricular zone., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest.

Purpose: To evaluate the clinical implications of status epilepticus in patients with metastases to the brain as well as associated demographic, clinical, EEG and radiographic features., Methods: Retrospective chart review of 19 patients with metastases to the brain who subsequently developed status epilepticus., Results: Of the patients who developed status epilepticus only 36.8% had a prior history of seizures since diagnosis of brain metastases. Status epilepticus most commonly occurred in the setting of a new structural injury to the brain such as new metastases, increase in size of metastases or hemorrhage. 57.9% of patients had either refractory or super-refractory status epilepticus. Focal non-convulsive status epilepticus was the most common subtype occurring in 42.1% of patients. 31.6% of patients died within 30 days of the onset of status epilepticus., Conclusion: Status epilepticus eventually resolved with treatment in all patients with brain metastases; however, it is associated with poor outcomes as nearly one-third was deceased within 30-days of onset. Nevertheless, no patients died during status epilepticus. Thus, status epilepticus may be indicative of an overall poor clinical status among patients with brain metastases., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Primary central nervous system (CNS) lymphoma (PCNSL) is a rare, aggressive, yet highly chemosensitive form of non-Hodgkin lymphoma which is associated with significant morbidity. Very little is known about the long-term risk for and features of seizures associated with this condition., Methods: We performed a retrospective and longitudinal analysis of 36 patients with pathologically and radiographically confirmed primary CNS lymphoma to evaluate the incidence, prevalence and features associated with seizures. Demographic, radiographic, histological and electroencephalographic (EEG) data were included as part of the study., Results: One-third of patients with primary CNS lymphoma had clinical seizures of which two-thirds occurred at time of initial presentation, while the remainder developed during a mean follow-up time of 1.49 years. The incidence rate of first seizure in PCNSL was 224.4 per 1000 persons, per year. There was a trend towards association with seizures in patients with cortical lesions relative to patients with subcortical lesions. EEG revealed epileptiform discharges in 44.4% of patients with both PCNSL and clinical seizures which suggests that it is a useful diagnostically in a substantial proportion of patients., Conclusions: A significant percentage of patients with primary CNS lymphoma develop comorbid seizures during their disease course. Increased awareness and collaboration between neuro-oncologists and epileptologists may enhance and improve care for these patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: It is estimated only 8-11% of patients with glioblastoma (GBM) enrol in clinical trials, limiting treatment development. We analysed the clinical and demographic features of patients with GBM enroled in clinical trials at the University of Texas MD Anderson Cancer Center (MDACC)., Methods: We reviewed the records of adult patients treated for primary GBM between 2007 and 2012 at the MDACC. A total of 755 patients were identified: 133 were deemed non-eligible, 111 were deemed trial eligible but received standard care and 511 participated in a clinical trial (311 for newly diagnosed glioblastoma [nGBM] and 200 for recurrent glioblastoma [rGBM]). Population characteristics were analysed using descriptive statistics, and survival end-points were evaluated with the Kaplan-Meier method., Results: The median age of clinical trial participants and trial eligible patients was 53.2 years (standard deviation 12.1). Most patients (49.4%) were enroled in a clinical trial protocol for nGBM. The majority of nGBM trial participants were male patients (65.1%), white (86.3%), married (84.4%) and in state (59.9%). Employment status, education, symptoms, tumour location, performance status, extent of resection and treatment facility differed between nGBM trial participants and non-participants. Patients who were eligible but did not enrol tended to be older, have worse performance status and live farther away from the MDACC., Conclusion: Numerous disease and demographic barriers exist in trial enrolment in patients with GBM. This study highlights some of these obstacles, which require attention to improve patient enrolment to clinical trials. Patient and physician engagement in novel therapeutic strategies is essential to improving outcomes in this disease., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors.

Purpose/introduction: Glioblastoma (GB) remains incurable despite aggressive chemotherapy, radiotherapy, and surgical interventions; immunotherapies remain experimental in clinical practice. Relevant preclinical models that can accurately predict tumor response to therapy are equally challenging. This study aimed to validate the effect of the naturally occurring agent diallyl trisulfide (DATS) in human GB in relevant pre-clinical models., Methods: Ex vivo slice culture, in vivo cell line derived orthotopic xenograft and patient-derived orthotopic xenograft (PDX) animal models of GB were utilized to assess efficacy of treatment with DATS., Results: Our results showed 72-h treatments of 25 µM DATS induced cell death in ex vivo human GB slice culture. We treated U87MG orthotopic xenograft models (U87MGOX) and patient-derived orthotopic xenograft models (PDX) with daily intraperitoneal injections of DATS for 14 days. Magnetic resonance (MR) imaging of mice treated with DATS (10 mg/kg) demonstrated reduced tumor size at 5 weeks when compared with saline-treated U87MGOX and PDX controls. Hematoxylin (H&E) staining demonstrated dose-dependent reduction in gross tumor volume with decreased proliferation and decreased angiogenesis. Western blotting showed that DATS was associated with increases in histone acetylation (Ac-Histone H3/H4) and activated caspase-3 in this novel preclinical model. Histological assessment and enzyme assays showed that even the highest dose of DATS did not negatively impact hepatic function., Conclusions: DATS may be an effective and well-tolerated therapeutic agent in preventing tumor progression and inducing apoptosis in human GB.

Ependymomas are rare primary central nervous system (CNS) tumors in adults. They occur most commonly in the spinal cord, and have classically been graded histologically into World Health Organization (WHO) grades I, II, or III based on the level of anaplasia. Recent data are showing that genetic heterogeneity occurs within the same histological subgroup and that ependymomas arising from different CNS locations have different molecular signatures. This has renewed interest in developing targeting therapies based on molecular profiles especially given the variable outcomes with radiation and the poor results with cytotoxic agents. In this paper, we present the case of a 46-year-old woman with a classic presentation of spinal cord ependymoma and discuss the current histopathological and molecular classification for ependymomas as well as current guidelines for patient management.

Background: Glioblastoma is the most common primary malignant brain tumor in adults, but effective therapies are lacking. With the scarcity of positive phase III trials, which are increasing in cost, we examined the ability of positive phase II trials to predict statistically significant improvement in clinical outcomes of phase III trials., Methods: A PubMed search was conducted to identify phase III clinical trials performed in the past 25 years for patients with newly diagnosed or recurrent glioblastoma. Trials were excluded if they did not examine an investigational chemotherapy or agent, if they were stopped early owing to toxicity, if they lacked prior phase II studies, or if a prior phase II study was negative., Results: Seven phase III clinical trials in newly diagnosed glioblastoma and 4 phase III clinical trials in recurrent glioblastoma met the inclusion criteria. Only 1 (9%) phase III study documented an improvement in overall survival and changed the standard of care., Conclusion: The high failure rate of phase III trials demonstrates the urgent need to increase the reliability of phase II trials of treatments for glioblastoma. Strategies such as the use of adaptive trial designs, Bayesian statistics, biomarkers, volumetric imaging, and mathematical modeling warrant testing. Additionally, it is critical to increase our expectations of phase II trials so that positive findings increase the probability that a phase III trial will be successful., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Extracranial and extraspinal ependymomas are extremely rare tumors mostly published in the literature as case reports., Methods: MD Anderson Cancer Center institutional database was screened for patients with extra CNS ependymomas over a 25 year period., Results: Eight patients with extra CNS ependymoma were identified. Five cases originated in the sacrum or subcutaneous sacral area, and the other 3 cases originating in the breast, lung and adnexa of the uterus. By histology, most cases were myxopapillary ependymomas (5 cases), 2 cases were grade II ependymoma and 1 case was an anaplastic ependymoma. Metastases occurred in 6 cases and 3 patients died due to progressive disease. Most cases required surgery, radiation and chemotherapy., Conclusion: Extra CNS ependymomas are very rare tumors that tend to metastasize, even though most cases are histologically classified as low grade ependymomas., (Copyright © 2017. Published by Elsevier Ltd.)

Treatment response and survival after bevacizumab failure remains poor in patients with glioblastoma. Several recent publications examining glioblastoma patients treated with bevacizumab have described specific radiographic patterns of disease progression as correlating with outcome. This study aims to scrutinize these previously reported radiographic prognostic models in an independent data set to inspect their reproducibility and potential for clinical utility. Sixty four patients treated at MD Anderson matched predetermined inclusion criteria. Patients were categorized based on previously published data by: (1) Nowosielski et al. into: T2-diffuse, cT1 Flare-up, non-responders and T2 circumscribed groups (2) Modified Pope et al. criteria into: local, diffuse and distant groups and (3) Bahr et al. into groups with or without new diffusion-restricted and/or pre-contrast T1-hyperintense lesions. When classified according to Nowosielski et al. criteria, the cT1 Flare-up group had the longest overall survival (OS) from bevacizumab initiation, with non-responders having the worst outcomes. The T2 diffuse group had the longest progression free survival (PFS) from start of bevacizumab. When classified by modified Pope at al. criteria, most patients did not experience a shift in tumor pattern from the pattern at baseline, while the PFS and OS in patients with local-to-local and local-to-diffuse/distant patterns of progression were similar. Patients developing restricted diffusion on bevacizumab had worse OS. Diffuse patterns of progression in patients treated with bevacizumab are rare and not associated with worse outcomes compared to other radiographic subgroups. Emergence of restricted diffusion during bevacizumab treatment was a radiographic marker of worse OS.

Intrathecal chemotherapy with methotrexate, a folate antagonist, is widely used to treat central nervous system malignancies. The mechanisms underlying methotrexate-induced neurotoxicity are unclear but may be related to increased homocysteine levels. Intrathecal methotrexate-induced myelopathy mimicking subacute combined degeneration, with normal B12 levels, has been documented. We examined treatment and magnetic resonance imaging (MRI) characteristics of 13 patients with leukemia who received intrathecal methotrexate and developed urinary and bowel incontinence, ascending motor weakness, and sensory loss with dorsal column hyperintensity on MRI between 2000 and 2016. Cerebrospinal fluid evaluation was negative for leukemia in all patients and positive for elevated protein in 12 patients. Seven of eight patients with available data had reduced serum folate, increased serum homocysteine, or both, implicating methotrexate as the cause of neurotoxicity. Autopsy of one patient revealed loss of myelinated axons in the posterior columns. These findings suggest that methotrexate neurotoxicity may be mediated by folate antagonism. Awareness and a high index of suspicion of these characteristic clinical and radiographic features in patients who develop myelopathy after intrathecal methotrexate may help to avoid additional neurotoxic therapy in such patients., (© 2016 Wiley Periodicals, Inc.)

IDH1 mutated glioblastoma (GB) has a better prognosis than IDH1 wildtype GB. However, it remains unknown whether patients (pts) with IDH1 mutated GB have a higher 6-month progression free survival (PFS6) or radiographic response (RR) rate on clinical trials for recurrence. Retrospective review of GB pts at MDACC between 2006 and 2012 identified 330 patients in recurrent GB trials. 93 patients (28 %) had either PFS6 or a complete/partial RR per RANO criteria. 49/93 (53 %) patients with PFS6 or a complete/partial RR had tumor tissue for IDH1 testing. A matched cohort of 49 patients on recurrent GB clinical trials that failed to achieve PFS6 or RR (also with tissue for IDH1 testing) was identified for comparison. IDH1 status was obtained in 92/98 (94 %) patients of which 17 (18 %) had an IDH1 mutation. PFS6 was seen in 26/49 (53 %) patients. IDH status was unknown in two of these patients. 5/24 (21 %) were IDH1 mutated compared to 5/24 (21 %) of their matched cohort without PFS6. RR was found in 47/49 (94 %) patients. IDH status was unknown in four of these patients. IDH1 mutation was present in 7/43 (16 %) patients with RR compared to 10/43 (23 %) in the matched cohort without RR (p = 0.48). Median OS for trials at first recurrence was 9.8 months for IDH1 wildtype GB vs. 19.32 months for IDH1 mutated GB (p = 0.14). IDH1 mutation status was not predictive of PFS6 or RR in recurrent GB trials for this data set. However, further examination in larger randomized prospective studies is needed., Competing Interests: Conflict of Interest:No conflict of interests to report

Background: Pituitary carcinomas (PC) are uncommon neuroendocrine tumors, accounting for 0.1 % of all pituitary tumors. The diagnosis of PC is based on the presence of metastases from a pituitary adenoma, and not by local invasion or pathological features alone. PC is typically resistant to therapy, with a median overall survival of only 31 months. There is no standard treatment for PC, but maximal safe resection and radiation are performed when possible. Encouraging preliminary data on the use of temozolomide (TMZ)-based therapy has been previously reported., Methods: We report the response to therapy and safety of radiation with concurrent temozolomide (RT/TMZ) in 2 adult patients with heavily pretreated PC and extraneural metastases., Results: Both patients had prior history of pituitary macroadenoma. At the time of diagnosis of PC, Ki-67 % was 24.2 and 10 %, with positive p53 staining in one case. Metastatic sites included lymph nodes, liver and bone. Case-1 received RT/TMZ to the tumor bed in the skull base and to the metastases in the cervical lymph nodes. Case-2 received RT/TMZ to recurrent tumor involving portacaval lymph nodes. Both patients achieved excellent long-term control of the sites of treated extraneural metastases, with no significant acute or delayed toxicity., Conclusions: RT/TMZ was safely delivered and might provide sustained control of extraneural metastases in PC. Although this retrospective report has limitations, RT/TMZ can be considered as a therapeutic option for the management of extraneural metastases in PC., Competing Interests: The authors report no conflicts of interest.

Radiation-induced necrosis (RN) is a relatively common side effect of radiation therapy for glioblastoma. However, the molecular mechanisms involved and the ways RN mechanisms differ from regulated cell death (apoptosis) are not well understood. Here, we compare the molecular mechanism of cell death (apoptosis or necrosis) of C6 glioma cells in both in vitro and in vivo (C6 othotopically allograft) models in response to low and high doses of X-ray radiation. Lower radiation doses were used to induce apoptosis, while high-dose levels were chosen to induce radiation necrosis. Our results demonstrate that active caspase-8 in this complex I induces apoptosis in response to low-dose radiation and inhibits necrosis by cleaving RIP1 and RI. When activation of caspase-8 was reduced at high doses of X-ray radiation, the RIP1/RIP3 necrosome complex II is formed. These complexes induce necrosis through the caspase-3-independent pathway mediated by calpain, cathepsin B/D, and apoptosis-inducing factor (AIF). AIF has a dual role in apoptosis and necrosis. At high doses, AIF promotes chromatinolysis and necrosis by interacting with histone H2AX. In addition, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. Analysis of inflammatory markers in matched plasma and cerebrospinal fluid (CSF) isolated from in vivo specimens demonstrated the upregulation of chemokines and cytokines during the necrosis phase. Using RIP1/RIP3 kinase specific inhibitors (Nec-1, GSK'872), we also establish that the RIP1-RIP3 complex regulates programmed necrosis after either high-dose radiation or TNF-α-induced necrosis requires RIP1 and RIP3 kinases. Overall, our data shed new light on the relationship between RIP1/RIP3-mediated programmed necrosis and AIF-mediated caspase-independent programmed necrosis in glioblastoma.

Background: Fatigue is a common and disabling symptom in people with a primary brain tumour (PBT). The effectiveness of interventions for treating clinically significant levels of fatigue in this population is unclear., Objectives: To assess the effectiveness and safety of pharmacological and non-pharmacological interventions for adults with PBT and high levels of fatigue., Search Methods: In March 2016, we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO and CINAHL and checked the reference lists of included studies. We also searched relevant conference proceedings, searched for ongoing trials via ClinicalTrials.gov and contacted major co-operative groups with trials in this area., Selection Criteria: We included randomised controlled trials (RCTs) that investigated any pharmacological or non-pharmacological intervention in adults with PBT and fatigue, where fatigue was the primary outcome measure. We restricted inclusion specifically to studies that enrolled only participants with clinically significant levels of fatigue., Data Collection and Analysis: Three review authors (JD, SYK, DC) independently evaluated search results, extracted data from selected studies and carried out a bias risk assessment. We extracted data on fatigue, cognition, mood, quality of life and adverse events outcomes., Main Results: We identified nine studies. We excluded eight of these as they did not restrict participation to people with high fatigue. The single eligible trial investigated the use of modafinil compared to placebo. Although this study found a significant improvement over time in the primary outcome of fatigue, the improvement occurred after both modafinil and placebo with no significant difference in response between the two groups. The included trial did not reach its planned recruitment target and therefore may not, in practice, have been adequately powered to detect a difference. The trial was at a low risk of bias across most areas. There was an unclear risk of bias related to the use of mean imputation because the investigators did not analyse the impact of imputation on the results., Authors' Conclusions: There was insufficient evidence to draw reliable and generalisable conclusions regarding potential effectiveness or harm of any pharmacological or non-pharmacological treatments for fatigue in people with PBT. More research is needed on how best to treat people with brain tumours with high fatigue.

Background and Importance: Spinal cord oligodendrogliomas are rare tumors, with a reported incidence varying between 0.8% and 4.7% of all spinal cord tumors and just over 50 cases reported in the literature. Of these, only 9 cases are histologically defined as anaplastic oligodendrogliomas, with few having complete molecular characterization. The diffuse tumor spread that can occur along the subarachnoid space with secondary invasion of the leptomeninges is called oligodendrogliomatosis and is associated with poor outcome., Clinical Presentation: A 68-year-old man with a history of lumbar stenosis status after lumbar decompression presented with new-onset right lower-extremity weakness. Magnetic resonance imaging demonstrated an intramedullary lesion from T9 to T12. During an attempted diagnostic biopsy, numerous intradural intramedullary lesions not present on magnetic resonance imaging were observed. Tissue biopsy demonstrated a 1p/19q-codeleted anaplastic oligodendroglioma with diffuse oligodendrogliomatosis. Postoperative treatment included 39.2-Gy radiation over 22 fractions from T1 to the bottom of the thecal sac with a boost to the T9-T12 area, the primary site of disease, to a total dose of 43.2 Gy in 24 fractions, followed by adjuvant temozolomide at a dose of 200 mg/m on days 1 to 5 in a 28-day cycle. At the 1-year follow-up, the patient demonstrated moderate neurological improvement., Conclusion: Management, prognosis, and use of molecular data in the decision-making algorithm for these patients are discussed, together with a review of all cases of primary intradural intramedullary spinal anaplastic oligodendrogliomas reported to date. Our study indicates that the combination of sequential treatment with radiation and temozolomide might provide a favorable outcome in the case of 1p/19q-codeleted spinal anaplastic oligodendrogliomas and that molecular analysis can be beneficial in guiding treatment strategies, although the impact of IDH mutations on these tumors is still unclear.

Glioblastoma (GB) is the most common malignant brain tumor. Drug resistance frequently develops in these tumors during chemotherapy. Therefore, predicting drug response in these patients remains a major challenge in the clinic. Thus, to improve the clinical outcome, more effective and tolerable combination treatment strategies are needed. Robust experimental evidence has shown that the main reason for failure of treatments is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK), c-Met (hepatocyte growth factor receptor), and oncogenic c-ros oncogene1 (ROS1: RTK class orphan) fusion kinase FIG (fused in GB)-ROS1. As such, these could be attractive targets for GB therapy. The study subjects consisted of 19 patients who underwent neurosurgical resection of GB tissues. Our in vitro and ex vivo models promisingly demonstrated that treatments with crizotinib (PF-02341066: dual ALK/c-Met inhibitor) and temozolomide in combination induced synergistic antitumor activity on FIG-ROS1-positive GB cells. Our results also showed that ex vivo FIG-ROS1+ slices (obtained from GB patients) when cultured were able to preserve tissue architecture, cell viability, and global gene-expression profiles for up to 14 days. Both in vitro and ex vivo studies indicated that combination blockade of FIG, p-ROS1, p-ALK, and p-Met augmented apoptosis, which mechanistically involves activation of Bim and inhibition of survivin, p-Akt, and Mcl-1 expression. However, it is important to note that we did not see any significant synergistic effect of crizotinib and temozolomide on FIG-ROS1-negative GB cells. Thus, these ex vivo culture results will have a significant impact on patient selection for clinical trials and in predicting response to crizotinib and temozolomide therapy. Further studies in different animal models of FIG-ROS1-positive GB cells are warranted to determine useful therapies for the management of human GBs.