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High-dose methotrexate (MTX) results in high rates of acute kidney injury (AKI), neutropenia, and hepatotoxicity. Glucarpidase is a recombinant enzyme that cleaves MTX, but clinical data supporting its use are scarce. We examined the association between glucarpidase administration and outcomes in adults with MTX-AKI from 28 cancer centers across the U.S using a sequential target trial emulation framework. The primary end point was kidney recovery at hospital discharge, defined as survival to discharge with serum creatinine <1.5-fold baseline and without dialysis-dependence. Key secondary end points were time-to-kidney recovery, neutropenia and transaminitis on day 7, and time-to-death. Using multivariable logistic and Cox regression models, we compared outcomes in patients who received glucarpidase within 4 days following MTX initiation with those in patients who did not. Among 708 patients with MTX-AKI, 209 (29.5%) received glucarpidase. Overall, 183 (25.8%) had a primary end point event. Glucarpidase receipt was associated with a 2.70-fold higher adjusted odds of kidney recovery (95% CI, 1.69-4.31) compared to no glucarpidase receipt. Patients treated with glucarpidase also had faster time-to-kidney recovery (adjusted hazard ratio [aHR], 1.88, 95% CI, 1.18-3.33) and lower risks of grade ≥2 neutropenia (adjusted odds ratio [aOR], 0.50, 95% CI, 0.28-0.91) and grade ≥2 transaminitis (aOR, 0.50, 95% CI, 0.28-0.91) on day 7. There was no difference in time-to-death (aHR, 0.76; 95 CI, 0.49-1.18). These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI., (Copyright © 2025 American Society of Hematology.)

Background: This study is a phase II clinical trial to evaluate the efficacy, safety, and tolerability of the blood-brain barrier (BBB) permeable peptide-paclitaxel conjugate ANG1005 in patients with recurrent high-grade glioma (HGG) (NCT01967810)., Methods: Seventy-three patients were enrolled in 3 separate arms-recurrent glioblastoma (GBM) (Arm 1), bevacizumab refractory GBM (Arm 2), and grade 3 anaplastic gliomas (AGs) (Arm 3). The study was started in October 2013, and the data were locked on September 29, 2017. Safety was evaluated for all three arms ( n  = 73), and the primary endpoint for Arms 1 and 3 was objective response rate (ORR), and Arm 2 primary endpoint was progression-free survival rate at 3 months (PFS3)., Results: Overall, the safety of ANG1005 was found to be consistent with a taxane toxicity profile. Otherwise, the primary efficacy endpoints of ORR and PFS were not met. The most common adverse events (AEs) were hematologic (32.9%), alopecia (31.5%), and fatigue (30.1%). The median PFS was 1.4 months (95% CI: 1.4, 2.1) and similar across all the treatment arms. The median overall survival was 13.4 months (95% CI: 3.4, 14.6) in Arm 1, 5.8 months (95% CI: 1.9, 9.7) in Arm 2, and 18.2 months (95% CI: 10.7, 35.3) in Arm 3., Conclusion: A dose of 600 mg/m 2 was determined to be safe in this study. However, the primary efficacy endpoint was not met in the NCT01967810-ANG1005 trial, and no further studies are planned in the glioma setting with this compound., Competing Interests: P.K. holds ownership interest (including patents) in Angiochem and is an advisory board member/unpaid consultant for Elevate Bio. A.M.S. is a consultant for Carthera and Angiochem. A.M.S. has received in-kind and funding support from Carthera, Agenus, and BMS. J.D. receives research support from Novartis, Servier, Novocure, hemerion is a consultant with Servier, Elsevier, and has stocks with Gilead, Pfizer, GSK, Wolters Kluwer. M.A. is a consultant for Bayer, Novocure, Kiyatec, Insightec, GSK, Xoft, Nuvation, Cellularity, SDP Oncology, Apollomics, Prelude, Janssen, Tocagen, Voyager Therapeutics, Viewray, Caris Lifesciences, Pyramid Biosciences, Varian Medical Systems, Cairn Therapeutics, Anheart Therapeutics, Theraguix, Menarini Ricerche, Sumitomo Pharma Oncology, Autem therapeutics, GT Medical Technologies, Allovir. He is on the scientific advisory board of Cairn Therapeutics, Modifi biosciences. Bugworks and holds stock options with Mimivax, Cytodyn, MedInnovate Advisors LLC, Trisalus Lifesciences. All the other authors declare that they have no competing interests., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Importance: The prognosis for patients with glioblastoma is poor following standard therapy with surgical resection, radiation, temozolomide, and tumor-treating fields., Objectives: To evaluate the combination of veliparib and temozolomide in glioblastoma based on preclinical data demonstrating significant chemosensitizing effects of the polyadenosine diphosphate-ribose polymerase 1/2 inhibitor veliparib when combined with temozolomide., Design, Setting, and Participants: Patients with newly diagnosed glioblastoma with MGMT promoter hypermethylation who had completed concomitant radiation and temozolomide were enrolled between December 15, 2014, and December 15, 2018, in this Alliance for Clinical Trials in Oncology trial. The data for this analysis were locked on April 21, 2023., Interventions: Patients were randomized and treated with standard adjuvant temozolomide (150-200 mg/m2 orally, days 1-5) combined with either placebo or veliparib (40 mg orally, twice daily, days 1-7) for 6 cycles., Main Outcomes and Measures: The primary end point for the phase 3 portion of the trial was overall survival (OS)., Results: There were 322 patients randomized during the phase 2 accrual period and an additional 125 patients randomized to complete the phase 3 accrual, for a total of 447 patients in the final phase 3 analysis. The median (range) age for patients was 60 (20-85) years and 190 patients (42.5%) were female. The median OS was 24.8 months (90% CI, 22.6-27.7) for the placebo arm and 28.1 months (90% CI, 24.3-33.3) for the veliparib arm (P = .17). The difference in survival did not meet the prespecified efficacy end point. However, there was a separation of the survival curves that favored the veliparib arm over 24 to 48 months of follow-up. The experimental combination was well tolerated with an acceptable elevation in grade 3 or 4 hematologic toxic effects., Conclusions and Relevance: This trial found that adding veliparib to adjuvant temozolomide did not significantly extend OS in patients with newly diagnosed, MGMT-hypermethylated glioblastoma., Trial Registration: ClinicalTrials.gov Identifier: NCT02152982.

Background: Glioblastoma (GBM) is an aggressive cancer with limited treatment options. Immunotherapy targeting CD69, an early activation marker on T cells, has shown promise in preclinical models of non-CNS malignancies. This study investigates anti-CD69 therapy alone or in combination with anti-PD-1 in a preclinical GBM model., Research Design and Methods: CD69 expression in GBM patient tissues was analyzed using the TCGA database. Therapeutic efficacy of anti-CD69 was tested in a murine GBM model with different regimens. Immune cell populations in the tumor microenvironment (TME) were assessed by flow cytometry., Results: Increased CD69 expression was observed in GBM patients compared to normal brain tissue and was associated with worse prognosis. Anti-CD69 treatment reduced percentages of CD69 + immune cells but did not improve survival in GBM-bearing mice. Increased PD-1 expression on NK cells was observed following anti-CD69 treatment. Anti-CD69 treatment was not improved by the addition of anti-PD-1 in vivo., Conclusions: This is the first study evaluating anti-CD69 therapy in a preclinical GBM model. Despite promising preclinical data in other cancers, anti-CD69 monotherapy or combination therapy with anti-PD-1 did not improve survival in this GBM model.

Purpose: Patients with glioblastoma (GBM) have a dismal prognosis. Although the DNA alkylating agent temozolomide (TMZ) is the mainstay of chemotherapy, therapeutic resistance rapidly develops in patients. Base excision repair inhibitor TRC102 (methoxyamine) reverses TMZ resistance in preclinical glioma models. We aimed to investigate the efficacy and safety of oral TRC102+TMZ in recurrent GBM (rGBM)., Patients and Methods: A preregistered (NCT02395692), nonrandomized, multicenter, phase 2 clinical trial (BERT) was planned and conducted through the Adult Brain Tumor Consortium (ABTC-1402). Arm 1 included patients with bevacizumab-naïve GBM at the first recurrence, with the primary endpoint of response rates. If sufficient activity was identified, a second arm was planned for the bevacizumab-refractory patients. The secondary endpoints were overall survival (OS), progression-free survival (PFS), PFS at 6 months (PFS6), and toxicity., Results: Arm 1 enrolled 19 patients with a median of two treatment cycles. Objective responses were not observed; hence, arm 2 did not open. The median OS was 11.1 months [95% confidence interval (CI), 8.2-17.9]. The median PFS was 1.9 months (95% CI, 1.8-3.7). The PFS6 was 10.5% (95% CI, 1.3%-33.1%). Most toxicities were grades 1 and 2, with two grade 3 lymphopenias and one grade 4 thrombocytopenia. Two patients with PFS ≥ 17 months and OS > 32 months were deemed "extended survivors." RNA sequencing of tumor tissue, obtained at diagnosis, demonstrated significantly enriched signatures of DNA damage response (DDR), chromosomal instability (CIN70, CIN25), and cellular proliferation (PCNA25) in "extended survivors.", Conclusions: These findings confirm the safety and feasibility of TRC102+TMZ in patients with rGBM. They also warrant further evaluation of combination therapy in biomarker-enriched trials enrolling GBM patients with baseline hyperactivated DDR pathways., (©2024 American Association for Cancer Research.)

Purpose: Multidisciplinary tumor boards (MTBs) integrate clinical, molecular, and radiological information and facilitate coordination of neuro-oncology care. During the COVID-19 pandemic, our MTB transitioned to a virtual and multi-institutional format. We hypothesized that this expansion would allow expert review of challenging neuro-oncology cases and contribute to the care of patients with limited access to specialized centers., Methods: We retrospectively reviewed records from virtual MTBs held between 04/2020-03/2021. Data collected included measures of potential clinical impact, including referrals to observational or therapeutic studies, referrals for specialized neuropathology analysis, and whether molecular findings led to a change in diagnosis and/or guided management suggestions., Results: During 25 meetings, 32 presenters discussed 44 cases. Approximately half (n = 20; 48%) involved a rare central nervous system (CNS) tumor. In 21% (n = 9) the diagnosis was changed or refined based on molecular profiling obtained at the NIH and in 36% (n = 15) molecular findings guided management. Clinical trial suggestions were offered to 31% (n = 13), enrollment in the observational NCI Natural History Study to 21% (n = 9), neuropathology review and molecular testing at the NIH to 17% (n = 7), and all received management suggestions., Conclusion: Virtual multi-institutional MTBs enable remote expert review of CNS tumors. We propose them as a strategy to facilitate expert opinions from specialized centers, especially for rare CNS tumors, helping mitigate geographic barriers to patient care and serving as a pre-screening tool for studies. Advanced molecular testing is key to obtaining a precise diagnosis, discovering potentially actionable targets, and guiding management., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design., Patients and Methods: Patients with newly diagnosed O 6 -methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780)., Results: Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit ( P > .05)., Conclusion: The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.

Abstract: BACKGROUND: Negative physical health results from the emotional stress of providing care to a family member with a primary malignant brain tumor; however, the downstream effects on caregivers' healthcare utilization (HCU) are unknown. This analysis examined associations between caregivers' emotional health and markers of HCU during the 6 months after patients' diagnoses. METHODS: Caregivers' self-report HCU data from a longitudinal study with 116 neuro-oncology caregivers were analyzed. Healthcare utilization was operationalized as number of prescription medications, reporting visits to primary care providers (PCPs), nature of PCP visit, number of comorbid conditions, and change in comorbid conditions. Potential predictors were caregivers' depressive symptoms (Center for Epidemiologic Studies-Depression Scale), hours providing care per day, mastery (Pearlin and Schooler), and burden (Caregiver Reaction Assessment). Logistic mixed effects modeling were used. RESULTS : Caregivers with higher levels of depressive symptoms ( P < .01), anxiety ( P = .02), burden related to schedule ( P = .02), and abandonment ( P < .01) were more likely to report worsening comorbid conditions. Those with higher mastery ( P = .02) were less likely to report worsening comorbid conditions. Caregivers who had a PCP visit and reported higher burden related to feelings of self-esteem ( P = .03) were more likely to report an illness-related visit. CONCLUSION : Findings suggest a relationship between neuro-oncology caregivers' emotional health and their HCU. Data highlight the importance of caregivers' PCPs identifying caregivers at risk for deteriorating health and increased HCU and intervene to ensure caregivers' self-care., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 American Association of Neuroscience Nurses.)

Purpose: Recurrent glioblastoma is universally fatal with limited effective treatment options. The aim of this phase 2 study of Border Zone SRS plus bevacizumab was to evaluate OS in patients with recurrent GBM., Methods: Patients with histologically confirmed GBM with recurrent disease who had received prior first-line treatment with fractionated radiotherapy and chemotherapy and eligible for SRS were enrolled. Bevacizumab 10 mg/kg was given day -1, day 14, and then every 14 days until disease progression. 1-14 days before BZ-SRS procedure, patients underwent brain MRI /MRS. MRS with measurement of choline-to-N-acetyl aspartate index (CNI) area ≥ 3 was targeted for SRS., Results: From 2015-2017, sixteen of planned 40 patients were enrolled. The median age was 62 (range, 48-74Y). 3/16 (0.188) participants experienced grade 2 toxicity. No AREs were reported. The mOS was 11.73 months compared to 8.74 months (P = 0.324) from date of SRS for the BZ-SRS and institutional historical controls, respectively. PFS-6 and OS-6 were 31.2% (p = 0.00294) and 81.2%(p = 0.058), respectively. Of 13 evaluable for best response: 1 CR (p = 0.077), 4 PR (p = 0.308), 7 SD (p = 0.538), and 1 PD (p = 0.077). 11/16 participants had MRS scans with an estimated probability that MRS changes a treatment plan of 0 (0, 0.285)., Conclusion: BZ-SRS with bevacizumab was feasible and well tolerated. There is no significant survival benefit using BZ-SRS with bevacizumab compared to institutional historical controls. Secondary analysis revealed a trend toward improved PFS-6, but not OS-6 after BZ-SRS. MRS scans did not result in changes to SRS treatment plans., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Immunotherapy may be promising for the treatment of some patients with GBM; however, there is a need for noninvasive neuroimaging techniques to predict immunotherapeutic responses. The effectiveness of most immunotherapeutic strategies requires T-cell activation. Therefore, we aimed to evaluate an early marker of T-cell activation, CD69, for its use as an imaging biomarker of response to immunotherapy for GBM. Herein, we performed CD69 immunostaining on human and mouse T cells following in vitro activation and post immune checkpoint inhibitors (ICI) in an orthotopic syngeneic mouse glioma model. CD69 expression on tumor-infiltrating leukocytes was assessed using single-cell RNA sequencing (scRNA-seq) data from patients with recurrent GBM receiving ICI. Radiolabeled CD69 Ab PET/CT imaging (CD69 immuno-PET) was performed on GBM-bearing mice longitudinally to quantify CD69 and its association with survival following immunotherapy. We show CD69 expression is upregulated upon T-cell activation and on tumor-infiltrating lymphocytes (TIL) in response to immunotherapy. Similarly, scRNA-seq data demonstrated elevated CD69 on TILs from patients with ICI-treated recurrent GBM as compared with TILs from control cohorts. CD69 immuno-PET studies showed a significantly higher tracer uptake in the tumors of ICI-treated mice compared with controls. Importantly, we observed a positive correlation between survival and CD69 immuno-PET signals in immunotherapy-treated animals and established a trajectory of T-cell activation by virtue of CD69-immuno-PET measurements. Our study supports the potential use of CD69 immuno-PET as an immunotherapy response assessment imaging tool for patients with GBM., Significance: Immunotherapy may hold promise for the treatment of some patients with GBM. There is a need to assess therapy responsiveness to allow the continuation of effective treatment in responders and to avoid ineffective treatment with potential adverse effects in the nonresponders. We demonstrate that noninvasive PET/CT imaging of CD69 may allow early detection of immunotherapy responsiveness in patients with GBM., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Introduction: Meningiomas represent the most common primary neoplasms of the central nervous system (CNS). 20% present with atypical (WHO grade II) or malignant (grade III) meningiomas, which show aggressive biologic behavior and high recurrence. Although surgical resection and radiation therapy are the primary treatment options for these tumors, there is a subgroup of patients who do not respond well to or are poor candidates for these approaches, leading to the exploration of systemic therapies as an alternative., Areas Covered: The literature on different therapeutic groups of systemic drugs for recurrent meningiomas is reviewed, with a focus on the different molecular targets. Past and current ongoing clinical trials are also discussed., Expert Opinion: To date, there is no recognized treatment that has demonstrated a substantial increase in progression-free or overall survival rates. Nonetheless, therapies targeting anti-VEGF have exhibited more encouraging results in general. The examination of genomic and epigenomic traits of meningiomas, along with the integration of molecular markers into the latest WHO tumor grading system, has provided valuable insights. This has opened avenues for exploring numerous intracellular and extracellular pathways, as well as mutations, that have been targeted in ongoing clinical trials.

Advances clarifying the genetics and function of the immune system within the central nervous system (CNS) and brain tumor microenvironment have led to increasing momentum and number of clinical trials using immunotherapy for primary brain tumors. While neurological complications of immunotherapy in extra-cranial malignancies is well described, the CNS toxicities of immunotherapy in patients with primary brain tumors with their own unique physiology and challenges are burgeoning. This review highlights the emerging and unique CNS complications associated with immunotherapy including checkpoint inhibitors, oncolytic viruses, adoptive cell transfer/chimeric antigen receptor (CAR) T cell and vaccines for primary brain tumors, as well as reviews modalities that have been currently employed or are undergoing investigation for treatment of such toxicities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mantica and Drappatz.)

Purpose: Isocitrate dehydrogenase ( IDH ) 1 and IDH2 mutations ( IDH1/2 mt) are frequent in glioma. Preclinical studies suggest IDH1/2 mts confer "BRCAness" phenotype, a vulnerability that can be targeted through PARP inhibition. To test this hypothesis, we conducted a multicenter study of olaparib monotherapy in patients with IDH1/2 mt gliomas., Methods: Patients with recurrent, contrast-enhancing IDH1/2 mt gliomas were enrolled in a two-step phase II trial; the primary endpoint was overall response rate per Response Assessment in Neuro-Oncology (RANO) criteria. Olaparib 300 mg orally twice daily was given., Results: A total of 15 evaluable patients were enrolled. Histology was astrocytoma ( N = 12) and oligodendroglioma ( N = 3). Most toxicities were grade 1 or 2. Best response was stable disease (SD) in 9 (60%) patients. Median progression-free survival (PFS) was 3.63 months and median overall survival was 20.7 months. For patients with SD, median PFS was 5.53 months; 4 patients had SD for >6 months. Among patients with best response progressive disease ( N = 6), 5 had grade 4 tumor and 4 had known CDKN2A alteration. PFS was 5.23 months for grades 2 or 3 tumors ( N = 10) versus 1.8 months for grade 4 ( N = 5; P = 0.0013)., Conclusion: The study did not meet the prespecified response-based activity threshold for moving to step 2. However, prolonged SD was observed in patients with grades 2 and 3 histologies, suggesting olaparib monotherapy could be of clinical benefit in select populations. Grade 4 tumors per 2021 World Health Organization classification defined by histology or CDKN2A alteration derived no benefit from this drug, highlighting the usefulness of this classification for future patient stratification and trial design., Significance: A single-arm phase II trial of olaparib in IDH -mutant glioma demonstrated clinically significant prolonged SD for select patients with grade 2/3 disease, suggesting potential benefit of olaparib in IDH -mutant gliomas., Competing Interests: Y. Shyr reports grants from NIH/NCI during the conduct of the study; grants from NIH outside the submitted work. S. Boerner reports grants from NCI-CTEP and Rising Tide Foundation during the conduct of the study. D. Durecki reports grants from NIH/NCI UM1CA186689 during the conduct of the study. J. Drappatz reports other from Pfizer, GSK, Gilead, and Vertex outside the submitted work. V. Puduvalli reports personal fees and other from Servier and Novocure, other from Karyopharm, and personal fees from Orbus therapeutics during the conduct of the study; other from Amarin and Gilead outside the submitted work. F.S. Lieberman reports grants from ABTC during the conduct of the study; grants from Novocure, Chimerix, Blue Diamond Therapeutics, and Abbvie outside the submitted work. J. Gonzalez reports other from AstraZeneca outside the submitted work. P. Giglio reports grants from NCI during the conduct of the study; other from Vanguard Funds; grants from BioMimetix, Denovo Biopharma, Institut de Recherches Internationales Servier, Novocure, and Prelude Therapeutics outside the submitted work. R.S. Bindra reports a patent to 62/344,678 pending. A. Omuro reports grants from Arcus Biosciences; personal fees from Pyramid, Merck, Kiyatec, and Ono outside the submitted work. P. LoRusso reports other from AbbVie, Agios, Five Prime, GenMab, Halozyme, Roche-Genetech, Genentech, CytomX, Takeda, Sotio, Cybrexa, Agenus, Tyme, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, Glaxo-Smith Kline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin Pharmaceutical, Kineta, Zentalis, Molecular Templates, ABL Bio, SK Life Science, STCube Pharmaceuticals, Bayer, I-Mab, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana Therapeutics, BAKX Therapeutics, Scenic Biotech, Qualigen, Roivant, and NeuroTrials outside the submitted work. No disclosures were reported by the other authors., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Background: Glioblastoma multiforme (GBM) is an aggressive brain tumor. Patients commonly rely on family caregivers for physical and emotional support. We previously demonstrated that caregiver mastery measured shortly after diagnosis was predictive of GBM patient survival, corrected for known predictors of survival (n = 88)., Objective: The aims of this study were to verify the contribution of caregiver mastery and investigate the added value of mastery over other predictors to predict 15-month survival., Methods: Data collected for a longitudinal study (NCT02058745) were used. Multivariable Cox regression analyses were performed for models with known clinical predictors (patient age, Karnofsky Performance Status, type of surgery, O6-methylguanine-DNA-methyltransferase promotor methylation status), with and without adding caregiver mastery to predict mortality. The added value of each model in discriminating between patients with the lowest and highest chances of survival at 15 months was investigated through Harrell's concordance index., Results: In total, 41 caregiver-patient dyads were included. When evaluating solely clinical predictors, Karnofsky Performance Status and patient age were significant predictors of mortality (hazard ratio [HR], 0.974; 95% confidence interval [CI], 0.949-1.000; and HR, 1.045; 95% CI, 1.002-1.091, respectively). Adding caregiver mastery, these clinical predictors remained statistically significant, and mastery showed an HR of 0.843 (95% CI, 0.755-0.940). The discriminative value improved from C = 0.641 (model with known clinical predictors) to C = 0.778 (model with mastery), indicating the latter is superior., Conclusions: We confirm that caregiver mastery is associated with GBM patient survival., Implications for Practice: Incorporating support and guidance for caregivers into standard care could lead to benefits for caregiver well-being and patient outcomes., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Meningiomas that progress despite surgery and radiotherapy represent an unmet medical need. Expression of PD-1 and PDL-1 has been demonstrated in meningiomas and is proportional to tumor grade, suggesting a potential role for anti-PD-1/anti-PDL-1 inhibitor therapy. We explored the potential role of immunotherapy for recurrent meningiomas by describing progression-free survival (PFS) and overall survival (OS) in a single-center patient sample., Methods: This is a retrospective chart review of patients with meningioma who were treated with PD-1 inhibitors at UPMC Hillman Cancer Center. Any patient over age 18 who received immunotherapy was included in this study. Patients received treatment until development of disease progression, intolerable toxicities or adverse events, death, or oncologist decision. Serial radiographic assessments were made every 3-6 months., Results: Between January 2015 and November 2021, eight patients received anti-PD-1 therapy. All patients underwent tumor resection and radiosurgery, and four patients received prior systemic therapy. Six out of eight patients experienced symptomatic perilesional edema and three patients experienced exacerbation of seizures. Median PFS was 7 months (95% CI 1-24) and median OS was 1.75 years (95% CI 1.5-4.0). In patients with positive PD-1/PD-L1 expression, median PFS was 2 years and median OS was 3 years., Conclusion: Anti-PD-1 therapy was associated with a manageable safety profile in patients with recurrent meningiomas. Patients with WHO Grade III tumors and positive PD-1/PD-L1 expression were noted to have increased PFS and OS, suggesting a potential role for immunotherapy in these patients, but further studies are needed to investigate this in a larger patient population., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Patients with primary malignant brain tumors have high symptom burden and commonly rely on family caregivers for practical and emotional support. This can lead to negative mental and physical consequences for caregivers. We investigated effectiveness of an 8-week nurse-led online needs-based support program (SmartCare © ) with and without online self-guided cognitive behavioral therapy (CBT) for depression compared to enhanced care as usual (ECAU) on depressive symptoms, caregiving-specific distress, anxiety, mastery, and burden., Methods: Family caregivers scoring ≥ 6 on a depressive symptoms inventory were randomized to three groups: ECAU plus self-guided CBT and SmartCare © ; ECAU plus SmartCare © ; ECAU only. Primary outcomes (depressive symptoms; caregiving-specific distress) and secondary outcomes (anxiety, caregiver mastery, and caregiver burden) were assessed online. Intention to treat (ITT) and per protocol (PP) analyses of covariance corrected for baseline scores were performed for outcomes at 4 months., Results: In total, 120 family caregivers participated. Accrual and CBT engagement were lower than expected, therefore intervention groups were combined (n = 80) and compared to ECAU (n = 40). For depressive symptoms, no statistically significant group differences were found. Caregiving-specific distress decreased in the intervention group compared with ECAU (ITT: p = 0.01, partial ɳ 2  = 0.08; PP: p = 0.02, partial ɳ 2  = 0.08). A trend towards improvement in mastery for the intervention group compared with ECAU was identified (ITT: p = 0.08, partial ɳ 2  = 0.04; PP: p = 0.07, partial ɳ 2  = 0.05)., Conclusions: SmartCare © , with or without self-guided CBT, reduced caregiving-specific distress with a trend towards improving mastery. SmartCare © has the potential to improve the lives of families coping with a brain tumor diagnosis., Trial Registration Number: NCT02058745; 10 February 2014., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Glioblastoma (GBM) has a 5-year survival rate of 3%-5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome C oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of MGMT promoter methylation status., Methods: This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival (OS) time, and the secondary end point was progression-free survival (PFS) time. Tumor CcO activity and MGMT promoter methylation status were assayed in a centralized laboratory., Results: OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival., Conclusions: Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may reveal a subgroup of GBM patients with improved long-term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: The COVID-19 pandemic has placed excessive strain on health care systems and is especially evident in treatment decision-making for cancer patients. Glioblastoma (GBM) patients are among the most vulnerable due to increased incidence in the elderly and the short survival time. A virtual meeting was convened on May 9, 2020 with a panel of neuro-oncology experts with experience using Tumor Treating Fields (TTFields). The objective was to assess the risk-to-benefit ratio and provide guidance for using TTFields in GBM during the COVID-19 pandemic., Panel Discussion: Topics discussed included support and delivery of TTFields during the COVID-19 pandemic, concomitant use of TTFields with chemotherapy, and any potential impact of TTFields on the immune system in an intrinsically immunosuppressed GBM population. Special consideration was given to TTFields' use in elderly patients and in combination with radiotherapy regimens. Finally, the panel discussed the need to better capture data on COVID-19positive brain tumor patients to analyze longitudinal outcomes and changes in treatment decision-making during the pandemic., Expert Opinion: TTFields is a portable home-use device which can be managed via telemedicine and safely used in GBM patients during the COVID-19 pandemic. TTFields has no known immunosuppressive effects which is important during a crisis where other treatment methods might be limited, especially for elderly patients with multiple co-morbidities. It is too early to estimate the full impact of COVID-19 on the global healthcare system and on patient outcomes and the panel strongly recommended collaboration with existing cancer COVID-19 registries to follow CNS tumor patients., Competing Interests: PH was employed by Novocure Inc. NG, JB-S, JD, RH, AH, PH, VP, DT, EW, and MG served on the May 2020 Advisory Board for Novocure, and declare that they received funding from Novocure for their attendance. CK received funding in support of its overall program in 2020 from Novocure. MG has received an honorarium from Novocure, is on a Novocure advisory board, and received funding from Novocure for a phase I/II trial. AH has received travel support for medical meeting to present trial results (paid to his institution). The authors declare that this study received funding from Novocure Inc. The funder had the following involvement with the study: Novocure provided editorial support only for the development of this manuscript: which is a summary of the authors opinions, discussions, and recommendations that were garnered from the Advisory Board., (Copyright 2021 Gatson, Barnholtz-Sloan, Drappatz, Henriksson, Hottinger, Hinoul, Kruchko, Puduvalli, Tran, Wong and Glas.)

Patients with brain tumors are at high risk for thromboembolic complications and frequently require anticoagulation. Direct oral anticoagulants (DOACs) are a less burdensome treatment for cancer-associated thrombosis with safety and efficacy comparable to those of low molecular weight heparin (LMWH); however, there are few data to support the use of DOACs in patients with brain tumors. The purpose of this study was to better understand the safety profile of anticoagulants in patients with primary and metastatic brain tumors, with particular interest in the safety and efficacy of DOACs. Our hypothesis was that DOACs are as safe and effective as LWMH in this population. This study was conducted through a single-center retrospective chart review of 125 patients with primary and metastatic brain tumors on anticoagulation. Our primary outcomes were major bleeding and intracranial hemorrhage (ICH), with secondary outcomes of minor bleeding and recurrent thrombosis. The rate of major bleeding was 26% in the LMWH group versus 9.6% in the DOAC group (p = .03). The rate of ICH was 15% in the LMWH group versus 5.8% in the DOAC group (p = .09). The severity of ICH in both groups was low with median Common Terminology Criteria for Adverse Events version 5 scores of 2 in the LMWH group and 3 in the DOAC group. The rates of minor bleeding and recurrent thrombosis were low in both groups. Our conclusion is that DOAC use in patients with brain tumors is not associated with increased rates of major bleeding compared with LMWH and is a safe and effective option. IMPLICATIONS FOR PRACTICE: Patients with brain tumors are at high risk for venous thromboembolism and frequently require anticoagulation. Direct oral anticoagulants (DOACs) are less burdensome than low molecular weight heparin (LMWH) for treatment of thromboembolism, but there is concern in the community over increased risk of bleeding. This study provides much-needed objective evidence that there are fewer major bleeding events in patients with brain tumors on DOACs compared to LMWH with similar efficacy. As the paradigm of anticoagulation in patients with cancer shifts from LWMH toward DOACs, this work is particularly meaningful as it suggests DOACs are safe and effective for patients with brain tumors., (© 2021 AlphaMed Press.)

Background: Receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) and their downstream signaling pathways such as the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway play important roles in glioblastoma (GBM). This study investigated the safety, pharmacokinetics, and efficacy of sorafenib (Ras/Raf/MAPK inhibitor) in combination with erlotinib (EGFR inhibitor) for treatment of recurrent GBMs., Methods: Patients with recurrent GBM were eligible. A novel sequential accrual trial design was used, where patients were sequentially accrued into separate treatment arms in phase I and phase II investigations to optimize recruitment efficiency. In phase I, a standard 3 + 3 format was used to identify dose-limiting toxicities (DLTs), determine maximum tolerated dose (MTD), and investigate pharmacokinetics. Phase II followed a 2-stage design with the primary endpoint being 6-month progression-free survival (PFS6)., Results: Sixteen patients were recruited for phase I, and the MTD was determined to be sorafenib 200 mg twice daily and erlotinib 100 mg once daily. DLTs include Grade 3 hypertension, Grade 3 elevated liver transaminases, and Grade 4 elevated lipase. While erlotinib did not affect sorafenib levels, sorafenib reduced erlotinib levels. In phase II, 3 of 19 stage 1 participants were progression free at 6 months. This did not meet the predetermined efficacy endpoint, and the trial was terminated., Conclusion: This study identified the MTD and DLTs for sorafenib and erlotinib combination therapy for recurrent GBMs; however, efficacy data did not meet the primary endpoint. This study also demonstrates the feasibility of a novel sequential accrual clinical trial design that optimizes patient recruitment for multiarm studies, which is particularly effective for multicenter clinical trials., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology 2020.)

Lessons Learned: The findings from this study using monotherapy with pemetrexed in a pretreated patient population are, overall, encouraging. Unlike high-dose methotrexate, which requires several days of inpatient hospitalization, pemetrexed is relatively easy to administer in the outpatient setting and remains a viable treatment option in this patient population. The maximum tolerated dose of pemetrexed administered (900 mg/m 2 every 2 weeks) was generally well tolerated and showed activity in patients with relapsed or refractory CNSL., Background: There is currently no standard salvage treatment for patients with relapsed/refractory central nervous system (CNS) lymphoma (CNSL). We report the results of a phase I study of pemetrexed, an antifolate drug with broader activity than methotrexate (MTX). We provide the safety, tolerability, and maximum tolerated dose (MTD) of pemetrexed in patients with recurrent CNSL., Methods: Through October 2015, 17 patients with relapsed/refractory CNSL received pemetrexed every 2 weeks with the first cohort receiving 600 mg/m 2 and dose escalation in increments of 300 mg/m 2 to a maximum of 1,200 mg/m 2 . Three patients were to enroll at each dose level with expansion to six patients in the event of dose-limiting toxicity. Patients with both primary CNS lymphoma (PCNSL) and secondary CNS lymphoma (SCNSL) could be enrolled., Results: Seventeen patients were evaluable with a median age of 63.7 years. Main adverse events included fatigue (82.4%), anemia (82.4%), and neutropenia (70.6%). The MTD was established at 900 mg/m 2 . Dose-limiting toxicities were recorded in one patient in the 600 mg/m 2 cohort and in two patients in the 1,200 mg/m 2 cohort. Fourteen patients were evaluable for response assessment; 21.4% achieved a complete response, 35.7% had a partial response, 14.3% had stable disease, and 28.6% had progressive disease. The median progression-free survival was 4.2 months. The median overall survival was 44.5 months. In the original study protocol, the plan was to add an expansion cohort of six patients at MTD level. However, the first phase of the study was characterized by slow recruitment. Therefore, after achieving the primary objective of the study and establishing the MTD, the investigators decided to amend the protocol and to close the study., Conclusion: Pemetrexed administered at 900 mg/m 2 every 2 weeks exhibits single-agent activity in patients with recurrent CNSL; it is well tolerated, and side effects are manageable., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Background and Purpose: The informal care demands of primary malignant brain tumor (PMBT) patients include unique issues associated with neurological and cognitive symptoms. Existing caregiver needs questionnaires do not include these disease-specific symptoms, which are particularly distressing. Therefore, we have developed the neuro-oncology Caregiver Needs Screen (CNS) and evaluated its psychometric properties., Methods: The 32-item instrument was developed based on PMBT caregiver interviews ( N = 109) and expert review. The CNS was tested along measures of depression, anxiety, burden, and mastery in 122 PMBT caregivers. Principal components analysis was used to examine item properties and internal structure. Internal consistency reliability and construct validity were assessed., Results: Six subscales were identified with internal consistency ranging between alpha = .653 and .857. Convergent validity was verified by moderate/high correlations between measures of caregiver well-being and CNS scale scores., Conclusions: Findings provide preliminary evidence of reliability and validity for the CNS. This instrument can be useful when assessing caregivers' needs for supportive care., (© Copyright 2019 Springer Publishing Company, LLC.)