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Questions and recommendations from the prior version of these guidelines without changeTarget populationAdult patients (older than 18 years of age) with newly diagnosed World Health Organization (WHO) Grade II gliomas (Oligodendroglioma, astrocytoma, mixed oligoastrocytoma).QuestionIs there a role for chemotherapy as adjuvant therapy of choice in treatment of patients with newly diagnosed low-grade gliomas?RecommendationLevel III: Chemotherapy is recommended as a treatment option to postpone the use of radiotherapy, to slow tumor growth and to improve progression free survival (PFS), overall survival (OS) and clinical symptoms in adult patients with newly diagnosed LGG.QuestionWho are the patients with newly diagnosed LGG that would benefit the most from chemotherapy?RecommendationLevel III: Chemotherapy is recommended as an optional component alone or in combination with radiation as the initial adjuvant therapy for all patients who cannot undergo gross total resection (GTR) of a newly diagnosed LGG. Patients with residual tumor >1 cm on post-operative MRI, presenting diameter of 4 cm or older than 40 years of age should be considered for adjuvant therapy as well.QuestionAre there tumor markers that can predict which patients can benefit the most from initial treatment with chemotherapy?RecommendationLevel III: The addition of chemotherapy to standard RT is recommended in LGG patients that carry IDH mutation. In addition, temozolomide (TMZ) is recommended as a treatment option to slow tumor growth in patients who harbor the 1p/19q co-deletion.QuestionHow soon should the chemotherapy be started once the diagnosis of LGG is confirmed?RecommendationThere is insufficient evidence to make a definitive recommendation on the timing of starting chemotherapy after surgical/pathological diagnosis of LGG has been made. However, using the 12 weeks mark as the latest timeframe to start adjuvant chemotherapy is suggested. It is recommended that patients be enrolled in properly designed clinical trials to assess the timing of chemotherapy initiation once diagnosis is confirmed for this target population.QuestionWhat chemotherapeutic agents should be used for treatment of newly diagnosed LGG?RecommendationThere is insufficient evidence to make a recommendation of one particular regimen. Enrollment of subjects in properly designed trials comparing the efficacy of these or other agents is recommended so as to determine which of these regimens is superior.QuestionWhat is the optimal duration and dosing of chemotherapy as initial treatment for LGG?RecommendationInsufficient evidence exists regarding the duration of any specific cytotoxic drug regimen for treatment of newly diagnosed LGG. Enrollment of subjects in properly designed clinical investigations assessing the optimal duration of this therapy is recommended.QuestionShould chemotherapy be given alone or in conjunction with RT as initial therapy for LGG?RecommendationInsufficient evidence exists to make recommendations in this regard. Hence, enrollment of patients in properly designed clinical trials assessing the difference between chemotherapy alone, RT alone or a combination of them is recommended.QuestionShould chemotherapy be given in addition to other type of adjuvant therapy to patients with newly diagnosed LGG?RecommendationLevel II: It is recommended that chemotherapy be added to the RT in patients with unfavorable LGG to improve their progression free survival.Updated Question and Recommendations from the Prior Version of These GuidelinesQuestionIn adult patients with pathologically confirmed WHO Grade II diffuse glioma does chemotherapy alone, combined with radiation therapy or after radiation therapy compared to radiotherapy alone result in better overall survival, progression free survival, local control, fewer complications, neurocognitive preservation, and quality of life?RecommendationLevel I: It is recommended that chemotherapy (PCV) be added to radiation therapy (RT) in all patients with newly diagnosed high-risk WHO Grade II diffuse glioma (Patients younger than 40 unable to get gross total resection and older than 40 regardless of the degree of resection) to improve their overall survival., Level Ii: It is recommended that chemotherapy be added to radiation therapy in all patients with newly diagnosed high-risk WHO Grade II diffuse glioma to improve overall survival without a decline in neurocognitive function., Level Iii: It is suggested that chemotherapy (temozolomide) be added to RT in all patients with newly diagnosed high-risk WHO Grade II diffuse glioma to improve progression free survival and overall survival., Level Iii: It is suggested that chemotherapy alone should be considered in patients with newly diagnosed WHO Grade II diffuse glioma in cases with 1p/19q co-deletion.New questions and recommendationsTarget populationThese recommendations apply to adult patients diagnosed with WHO Grade II diffuse glioma.QuestionIn adult patients with newly diagnosed WHO grade II diffuse glioma does administration of chemotherapy prior to surgical resection improve extent of resection, provide longer progression free survival and overall survival when compared to chemotherapy alone?RecommendationLevel III: Neo-adjuvant temozolomide may be used in patients with WHO Grade II diffuse gliomas deemed unsafe for resection due to infiltration of eloquent areas or with large contralateral extension as an initial step to improve the extent of resection.There is insufficient evidence to support a recommendation regarding the ability of chemotherapy provided prior to surgical resection to improve progression free survival (PFS) and overall survival (OS).QuestionIn adult patients with newly diagnosed WHO grade II diffuse glioma does the administration of temozolomide increase the rate of malignant transformation when compared to no chemotherapy or other chemotherapy regimens?RecommendationThere is insufficient evidence to support a recommendation against the use of temozolomide for WHO Grade II diffuse gliomas due to concern over increasing the rate of malignant transformation.QuestionIn adult patients with newly diagnosed WHO grade II diffuse glioma does administration of multi-agent chemotherapy improve progression free survival and overall survival when compared to administration of single-agent chemotherapy?RecommendationThere is insufficient evidence to support a recommendation for or against the use of multi-agent chemotherapy to improve progression free survival and overall survival when compared to administration of single-agent chemotherapy in patients with newly diagnosed WHO Grade II diffuse glioma., Competing Interests: Declarations. Conflict of interest: All Guideline Task Force members were required to disclose all potential COIs prior to beginning work on the guideline, using the COI disclosure form of the AANS/CNS Joint Guidelines Review Committee. The CNS Guidelines Committee and Guideline Task Force Chair reviewed the disclosures and either approved or disapproved the nomination and participation on the task force. The CNS Guidelines Committee and Guideline Task Force Chair may approve nominations of task force members with possible conflicts and restrict the writing, reviewing, and/or voting privileges of that person to topics that are unrelated to the possible COIs. The task force has not made any disclosures., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

Introduction: Central Neurocytoma (CN) is a rare, WHO grade 2 brain tumor that predominantly affects young adults. Gross total resection (GTR) is often curative for CNs, but the optimal treatment paradigm including incorporation of RT, following subtotal resection (STR) and for scarcer pediatric cases has yet to be established., Methods: Patients between 2001 and 2021 with a pathologic diagnosis of CN were reviewed. Demographic, treatment, and tumor characteristics were recorded. Recurrence free survival (RFS) and overall survival (OS) were calculated according to the Kaplan Meier-method. Post-RT tumor volumetric regression analysis was performed., Results: Seventeen adults (≥ 18 years old) and 5 children (< 18 years old) met the criteria for data analysis (n = 22). With a median follow-up of 6.9 years, there was no tumor-related mortality. Patients who received STR and/or had atypical tumors (using a cut-off of Ki-67 > 4%) experienced decreased RFS compared to those who received GTR and/or were without atypical tumors. RFS at 5 years for typical CNs was 67% compared to 22% for atypical CNs. Every pediatric tumor was atypical and 3/5 recurred within 5 years. Salvage RT following tumor recurrence led to no further recurrences within the timeframe of continued follow-up; volumetric analysis for 3 recurrent tumors revealed an approximately 80% reduction in tumor size., Conclusion: We provide encouraging evidence that CNs treated with GTR or with RT after tumor recurrence demonstrate good long-term tumor control., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Tumor Treating Fields (TTFields) Therapy is an FDA-approved therapy in the first line and recurrent setting for glioblastoma. Despite Phase 3 evidence showing improved survival with TTFields, it is not uniformly utilized. We aimed to examine patient and clinician views of TTFields and factors shaping utilization of TTFields through a unique research partnership with medical neuro oncology and medical social sciences., Methods: Adult glioblastoma patients who were offered TTFields at a tertiary care academic hospital were invited to participate in a semi-structured interview about their decision to use or not use TTFields. Clinicians who prescribe TTFields were invited to participate in a semi-structured interview about TTFields., Results: Interviews were completed with 40 patients with a mean age of 53 years; 92.5% were white and 60% were male. Participants who decided against TTFields stated that head shaving, appearing sick, and inconvenience of wearing/carrying the device most influenced their decision. The most influential factors for use of TTFields were the efficacy of the device and their clinician's opinion. Clinicians (N = 9) stated that TTFields was a good option for glioblastoma patients, but some noted that their patients should consider the burdens and benefits of TTFields as it may not be the desired choice for all patients., Conclusions: This is the first study to examine patient decision making for TTFields. Findings suggest that clinician support and efficacy data are among the key decision-making factors. Properly understanding the path to patients' decision making is crucial in optimizing the use of TTFields and other therapeutic decisions for glioblastoma patients., (© 2024. The Author(s).)

Objective: Central nervous system (CNS) metastases include brain parenchymal, spinal cord, and leptomeningeal metastases. This article discusses the diagnostic and therapeutic advances of the last decade that have improved outcomes for patients with these CNS metastases., Latest Developments: The diagnostic tools for CNS metastases, particularly leptomeningeal disease, have evolved over the past decade with respect to advancements in CSF analysis. Multiple medical therapies are now available for brain metastasis treatment that have shown CNS efficacy, including targeted therapies and antibody-drug conjugates. Molecular testing for CNS metastases has become more common and the repertoire of molecularly targeted therapies continues to expand. Advancements in radiation therapy, including improvements in stereotactic radiation techniques, whole-brain radiation with hippocampal avoidance, and proton beam radiation, have changed the radiation management of patients with CNS metastases. New intrathecal agents are currently being tested for the management of leptomeningeal metastases., Essential Points: CNS metastases are far more common than primary brain tumors and are increasing in prevalence in the setting of improved treatments and prolonged survival in patients with systemic cancers. There have been many changes in the diagnostics and treatment of CNS metastases, yielding subsequent improvements in patient outcomes with further advancements on the horizon., (Copyright © 2023 American Academy of Neurology.)

MGMT promoter methylation testing is required for prognosis and predicting temozolomide response in gliomas. Accurate results depend on sufficient tumor cellularity, but histologic estimates of cellularity are subjective. We sought to determine whether driver mutation variant allelic frequency (VAF) could serve as a more objective metric for cellularity and identify possible false-negative MGMT samples. Among 691 adult-type diffuse gliomas, MGMT promoter methylation was assessed by pyrosequencing (N = 445) or DNA methylation array (N = 246); VAFs of TERT and IDH driver mutations were assessed by next generation sequencing. MGMT results were analyzed in relation to VAF. By pyrosequencing, 56% of all gliomas with driver mutation VAF ≥ 0.325 had MGMT promoter methylation, versus only 37% with VAF < 0.325 (p < 0.0001). The mean MGMT promoter pyrosequencing score was 19.3% for samples with VAF VAF ≥ 0.325, versus 12.7% for samples with VAF < 0.325 (p < 0.0001). Optimal VAF cutoffs differed among glioma subtypes (IDH wildtype glioblastoma: 0.12-0.18, IDH mutant astrocytoma: ~0.33, IDH mutant and 1p/19q co-deleted oligodendroglioma: 0.3-0.4). Methylation array was more sensitive for MGMT promoter methylation at lower VAFs than pyrosequencing. Microscopic examination tended to overestimate tumor cellularity when VAF was low. Re-testing low-VAF cases with methylation array and droplet digital PCR (ddPCR) confirmed that a subset of them had originally been false-negative. We conclude that driver mutation VAF is a useful quality assurance metric when evaluating MGMT promoter methylation tests, as it can help identify possible false-negative cases., (© 2023. The Author(s).)

Sex differences play a large role in oncology. It has long been discussed that the incidence of different types of tumors varies by sex, and this holds in neuro-oncology. There are also profound survival sex differences, biologic factors, and treatment effects. This review aims to summarize some of the main sex differences observed in primary brain tumors and goes on to focus specifically on gliomas and meningiomas, as these are two commonly encountered primary brain tumors in clinical practice. Additionally, considerations unique to female individuals, including pregnancy and breastfeeding, are explored. This review sheds light on many of the unique attributes that must be considered when diagnosing and treating female patients with primary brain tumors in clinical practice., Competing Interests: Conflicts of interest L. Singer has no conflicts of interest. D. Primdahl has no conflicts of interest. P. Kumthekar has had advisory roles at Biocept, Enclear, Affinia Therapeutics. P. Kumthekar served on advisory boards/advised Orbus Therapeutics, Berg, Bioclinia Sintetica, Novocure, Janssen, Angiochem, Celularity, Mirati and SDP Oncology and received research funding from Novocure, Switzerland, Genetech. P. Kumthekar holds European Patent 3,307,327, August 12, 2020 and US Patent Pending 15/737,188., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Palbociclib is highly efficacious and well tolerated in hormone-receptor positive (HR+) metastatic breast cancer (BC) but its activity for HER2+ BC with brain metastases (BM) is unknown., Methods: In a single-arm phase II study we evaluated palbociclib with trastuzumab for patients with HER2+ MBC and BM. The primary endpoint was BM response rate. Circulating tumor DNA (ctDNA) was evaluated at baseline, and in a subset of patients at cycle 3 and progression. We also retrospectively identified additional patients with metastatic BC, active BM, and a ctDNA assessment prior to therapy for BM., Results: Twelve patients with HER2+ MBC were enrolled, 4 with HR+ and 8 with HR- disease. No responses were seen. Best response was stable disease for 6 patients and progressive disease for 6 patients. The median PFS was 2.2 months, interquartile range (IQR) was 1.56 to 3.63 months. The median OS was 13.1 months and IQR was 9.4 to 23.8 months The CNS was the primary site of progression for all patients. The median variant allele fraction (VAF) of the dominant variant in each patient was 0.18% (interquartile range [IQR] 0.12%-0.47%) with a median number of somatic alterations of 1. We additionally evaluated ctDNA results from 26 patients with BC and active BM, among whom the median VAF was 11.8% (IQR 3.9%-27.3%) with a median number of alterations was 6 (IQR 4-9). Notably, progressive systemic disease was significantly less frequent in the trial cohort compared with additional retrospectively identified patients (8% vs. 81%)., Conclusion: Palbociclib did not demonstrate activity in HER2+ MBC with BM. Patients with progressive BM but stable, responding, or absent systemic disease have low VAF and number of alterations detected by ctDNA analysis from blood., (Copyright © 2022. Published by Elsevier Inc.)

Background: Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis., Methods: Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The Kappa coefficient was used to evaluate the interobserver pairwise agreement., Results: Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons, and 2 medical oncologists. Among single leptomeningeal metastases-related imaging findings at baseline, the best median concordance was noted for hydrocephalus (Kappa = 0.63), and the worst median concordance for spinal linear enhancing disease (Kappa = 0.46). The median concordance of raters for the overall response assessment was moderate (Kappa = 0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was fair (Kappa = 0.29) and virtually absent for their response to treatment. 394 of 700 ratings (20 patients x 35 raters, 56%) were fully completed. In 308 of 394 fully completed ratings (78%), the overall response assessment perfectly matched the summary interpretation of the single ratings as proposed in the scorecard instructions., Conclusion: This study confirms the principle utility of the new scorecard, but also indicates the need for training of MRI assessment with a dedicated reviewer panel in clinical trials. Electronic case report forms with "blocking options" may be required to enforce completeness and quality of scoring., (© The Author(s) 2022. 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.)

Brain metastases occur commonly in patients with advanced solid malignancies. Yet, less is known about brain metastases than cancer-related entities of similar incidence. Advances in oncologic care have heightened the importance of intracranial management. Here, in this consensus review supported by the Society for Neuro-Oncology (SNO), we review the landscape of brain metastases with particular attention to management approaches and ongoing efforts with potential to shape future paradigms of care. Each coauthor carried an area of expertise within the field of brain metastases and initially composed, edited, or reviewed their specific subsection of interest. After each subsection was accordingly written, multiple drafts of the manuscript were circulated to the entire list of authors for group discussion and feedback. The hope is that the these consensus guidelines will accelerate progress in the understanding and management of patients with brain metastases, and highlight key areas in need of further exploration that will lead to dedicated trials and other research investigations designed to advance the field., (© The Author(s) 2022. 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.)

Despite advances in the treatment of metastatic, HER2+ breast cancer, the development of central nervous system metastases remains a therapeutic challenge. The challenge is amplified by the exclusion of patients with active brain metastases from many clinical trials. Initial HER2-targeted therapies, such as trastuzumab and pertuzumab, have shown limited efficacy for patients with brain metastases. In addition, the landscape of systemic therapy for HER2+ metastatic breast cancer is changing rapidly. In recent years, the development of small-molecule inhibitors in combination with chemotherapy has shown promise, though the efficacy is often balanced by key toxicities. Other HER2-targeted therapies, including antibody-drug conjugates, have presented new therapeutic options for this patient population; however, additional data for both small-molecule inhibitors and antibody-drug conjugates with respect to patients with central nervous system metastases is needed. Here, we specifically review the data for the management of HER2+ parenchymal brain metastases. A limited discussion of leptomeningeal disease is included; a more detailed review of this specific subgroup is outside the scope of this article. Key clinical trial data supporting the use of HER2-targeted and non-targeted therapies, including monoclonal antibodies and antibody-drug conjugates, are reviewed, with a specific focus on the use of HER2-targeted small-molecule inhibitors. We also review future directions and provide an overview of ongoing clinical trials which include patients with HER2+ brain metastases. With future focus on inclusive clinical trial design, particularly inclusion of patients with brain metastases, optimal strategies for management will be better elucidated., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Survival is dismal for bevacizumab refractory high-grade glioma patients. We prospectively investigated the efficacy of re-irradiation, bevacizumab, and temozolomide in bevacizumab-naïve and bevacizumab-exposed recurrent high-grade glioma, without volume limitations, in a single arm trial., Methods: Recurrent high-grade glioma patients were stratified based on WHO grade (4 vs. < 4) and prior exposure to bevacizumab (yes vs. no). Eligible patients received radiation using a simultaneous integrated boost technique (55 Gy to enhancing disease, 45 Gy to non-enhancing disease in 25 fractions) with bevacizumab 10 mg/kg every 2 weeks IV and temozolomide 75 mg/m 2 daily followed by maintenance bevacizumab 10 mg/kg every 2 weeks and temozolomide 50 mg/m 2 daily for 6 weeks then a 2 week holiday until progression. Primary endpoint was overall survival. Quality of life was studied using FACT-Br and FACT-fatigue scales., Results: Fifty-four patients were enrolled. The majority (n = 36, 67%) were bevacizumab pre-exposed GBM. Median OS for all patients was 8.5 months and 7.9 months for the bevacizumab pre-exposed GBM group. Patients ≥ 36 months from initial radiation had a median OS of 13.3 months compared to 7.5 months for those irradiated < 36 months earlier (p < 0.01). FACT-Br and FACT-Fatigue scores initially declined during radiation but returned to pretreatment baseline. Treatment was well tolerated with 5 patients experiencing > grade 3 lymphopenia and 2 with > grade 3 thrombocytopenia. No radiographic or clinical radiation necrosis occurred., Conclusions: Re-irradiation with bevacizumab and temozolomide is a safe and feasible salvage treatment for patients with large volume bevacizumab-refractory high-grade glioma. Patients further from their initial radiotherapy may derive greater benefit with this regimen., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Effective therapies are needed for the treatment of patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) with brain metastases. A trastuzumab radioisotope has been shown to localize in brain metastases of patients with HER2-positive MBC, and intracranial xenograft models have demonstrated a dose-dependent response to trastuzumab., Methods: In the phase II PATRICIA study (ClinicalTrials.gov identifier: NCT02536339), patients with HER2-positive MBC with CNS metastases and CNS progression despite prior radiotherapy received pertuzumab plus high-dose trastuzumab (6 mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. The primary end point was confirmed objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases criteria. Secondary end points included duration of response, clinical benefit rate (complete response plus partial response plus stable disease ≥ 4 or ≥ 6 months) in the CNS, and safety., Results: Thirty-nine patients were treated for a median (range) of 4.5 (0.3-37.3) months at clinical cutoff. Thirty-seven patients discontinued treatment, most commonly because of CNS progression (n = 27); two remained on treatment. CNS ORR was 11% (95% CI, 3 to 25), with four partial responses (median duration of response, 4.6 months). Clinical benefit rate at 4 months and 6 months was 68% and 51%, respectively. Two patients permanently discontinued study treatment because of adverse events (left ventricular dysfunction [treatment-related] and seizure, both grade 3). No grade 5 adverse events were reported. No new safety signals emerged with either agent., Conclusion: Although the CNS ORR was modest, 68% of patients experienced clinical benefit, and two patients had ongoing stable intracranial and extracranial disease for > 2 years. High-dose trastuzumab for HER2-positive CNS metastases may warrant further study., Competing Interests: Nancy U. LinConsulting or Advisory Role: Seattle Genetics, Puma Biotechnology, Daiichi Sankyo, California Institute for Regenerative Medicine (CIRM), Denali TherapeuticsResearch Funding: Genentech, Pfizer, Seattle Genetics, Merck, NovartisPatents, Royalties, Other Intellectual Property: Royalties for chapter in Up-to-Date regarding management of breast cancer brain metastases, Royalties, Jones & Bartlett Mark PegramConsulting or Advisory Role: Genentech/Roche, Pfizer, Seattle Genetics, Puma, Novartis Solmaz SahebjamConsulting or Advisory Role: Merck, Boehringer IngelheimResearch Funding: Bristol Myers Squibb, Brooklyn ImmunoTherapeutics, MerckTravel, Accommodations, Expenses: Lilly Nuhad IbrahimConsulting or Advisory Role: Ipsen, ImmunomedicsResearch Funding: Nektar Therapeutics Anita FungEmployment: Genentech/RocheStock and Other Ownership Interests: Genentech/Roche Anna ChengEmployment: GenentechStock and Other Ownership Interests: Roche Alan NicholasEmployment: GenentechStock and Other Ownership Interests: Genentech Whitney KirschbrownEmployment: Genentech/RocheStock and Other Ownership Interests: Genentech/Roche Priya KumthekarConsulting or Advisory Role: Orbus Therapeutics, Janssen, ElevateBioResearch Funding: AngiochemNo other potential conflicts of interest were reported.

Background: Malignant glioma is the most common and lethal primary brain tumour, with dismal survival rates and no effective treatment. We examined the safety and activity of NSC-CRAd-S-pk7, an engineered oncolytic adenovirus delivered by neural stem cells (NSCs), in patients with newly diagnosed high-grade glioma., Methods: This was a first-in-human, open-label, phase 1, dose-escalation trial done to determine the maximal tolerated dose of NSC-CRAd-S-pk7, following a 3 + 3 design. Patients with newly diagnosed, histologically confirmed, high-grade gliomas (WHO grade III or IV) were recruited. After neurosurgical resection, NSC-CRAd-S-pk7 was injected into the walls of the resection cavity. The first patient cohort received a dose starting at 6·25 × 10 10 viral particles administered by 5·00 × 10 7 NSCs, the second cohort a dose of 1·25 × 10 11 viral particles administered by 1·00 × 10 8 NSCs, and the third cohort a dose of 1·875 × 10 11 viral particles administered by 1·50 × 10 8 NSCs. No further dose escalation was planned. Within 10-14 days, treatment with temozolomide and radiotherapy was initiated. Primary endpoints were safety and toxicity profile and the maximum tolerated dose for a future phase 2 trial. All analyses were done in all patients who were included in the trial and received the study treatment and were not excluded from the study. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT03072134., Findings: Between April 24, 2017, and Nov 13, 2019, 12 patients with newly diagnosed, malignant gliomas were recruited and included in the safety analysis. Histopathological evaluation identified 11 (92%) of 12 patients with glioblastoma and one (8%) of 12 patients with anaplastic astrocytoma. The median follow-up was 18 months (IQR 14-22). One patient receiving 1·50 × 10 8 NSCs loading 1·875 × 10 11 viral particles developed viral meningitis (grade 3) due to the inadvertent injection of NSC-CRAd-S-pk7 into the lateral ventricle. Otherwise, treatment was safe as no formal dose-limiting toxicity was reached, so 1·50 × 10 8 NSCs loading 1·875 × 10 11 viral particles was recommended as a phase 2 trial dose. There were no treatment-related deaths. The median progression-free survival was 9·1 months (95% CI 8·5-not reached) and median overall survival was 18·4 months (15·7-not reached)., Interpretation: NSC-CRAd-S-pk7 treatment was feasible and safe. Our immunological and histopathological findings support continued investigation of NSC-CRAd-S-pk7 in a phase 2/3 clinical trial., Funding: US National Institutes of Health., Competing Interests: Declaration of interests JP reports grants from The Ivy Foundation, during the conduct of this study. CDH reports salary payments from Southern Research, outside the submitted work. RVL reports honoraria from Novocure for advisory roles, EBSCO Publishing and Medlink Neurology for medical editing, ECRI for reviewing medical content, and the American Physician Institute for creating and presenting board review continuing medical education material, outside the submitted work. RS reports non-financial support from CarThera, and personal fees from Celularity, CranioVation, TriAct, Hemispherian, Northwest Biotherapeutics, GT Medical Technologies, Insightec, and ZaiLab, outside the submitted work. DTC, KSA, and MSL have an issued patent that is related to the study (US10238699 and US10709745). KSA was the CSO and Director of TheraBiologics (company in process of being dissolved) during the conduct of this study; she neither has assets nor receives financial benefit from the company. MSL reports grants from the National Institutes of Health, during the conduct of this study. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Glioblastoma is a primary brain cancer with a near 100% recurrence rate. Upon recurrence, the tumour is resistant to all conventional therapies, and because of this, 5-year survival is dismal. One of the major drivers of this high recurrence rate is the ability of glioblastoma cells to adapt to complex changes within the tumour microenvironment. To elucidate this adaptation's molecular mechanisms, specifically during temozolomide chemotherapy, we used chromatin immunoprecipitation followed by sequencing and gene expression analysis. We identified a molecular circuit in which the expression of ciliary protein ADP-ribosylation factor-like protein 13B (ARL13B) is epigenetically regulated to promote adaptation to chemotherapy. Immuno-precipitation combined with liquid chromatography-mass spectrometry binding partner analysis revealed that that ARL13B interacts with the purine biosynthetic enzyme inosine-5'-monophosphate dehydrogenase 2 (IMPDH2). Further, radioisotope tracing revealed that this interaction functions as a negative regulator for purine salvaging. Inhibition of the ARL13B-IMPDH2 interaction enhances temozolomide-induced DNA damage by forcing glioblastoma cells to rely on the purine salvage pathway. Targeting the ARLI3B-IMPDH2 circuit can be achieved using the Food and Drug Administration-approved drug, mycophenolate mofetil, which can block IMPDH2 activity and enhance the therapeutic efficacy of temozolomide. Our results suggest and support clinical evaluation of MMF in combination with temozolomide treatment in glioma patients., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Glioblastoma (GBM) is one of the most difficult cancers to effectively treat, in part because of the lack of precision therapies and limited therapeutic access to intracranial tumor sites due to the presence of the blood-brain and blood-tumor barriers. We have developed a precision medicine approach for GBM treatment that involves the use of brain-penetrant RNA interference-based spherical nucleic acids (SNAs), which consist of gold nanoparticle cores covalently conjugated with radially oriented and densely packed small interfering RNA (siRNA) oligonucleotides. On the basis of previous preclinical evaluation, we conducted toxicology and toxicokinetic studies in nonhuman primates and a single-arm, open-label phase 0 first-in-human trial (NCT03020017) to determine safety, pharmacokinetics, intratumoral accumulation and gene-suppressive activity of systemically administered SNAs carrying siRNA specific for the GBM oncogene Bcl2Like12 (Bcl2L12). Patients with recurrent GBM were treated with intravenous administration of siBcl2L12-SNAs (drug moniker: NU-0129), at a dose corresponding to 1/50th of the no-observed-adverse-event level, followed by tumor resection. Safety assessment revealed no grade 4 or 5 treatment-related toxicities. Inductively coupled plasma mass spectrometry, x-ray fluorescence microscopy, and silver staining of resected GBM tissue demonstrated that intravenously administered SNAs reached patient tumors, with gold enrichment observed in the tumor-associated endothelium, macrophages, and tumor cells. NU-0129 uptake into glioma cells correlated with a reduction in tumor-associated Bcl2L12 protein expression, as indicated by comparison of matched primary tumor and NU-0129-treated recurrent tumor. Our results establish SNA nanoconjugates as a potential brain-penetrant precision medicine approach for the systemic treatment of GBM., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.

Opinion Statement: Corticosteroids have been essential in the management of brain tumor patients for decades, primarily for the treatment of peritumoral cerebral edema and its associated neurologic deficits. Dexamethasone is the drug of choice with standard practice being administration up to four times per day, however, because of its long biologic half-life and high potency, once or twice a day dosing is likely adequate in patients without elevated intracranial pressure. The length of corticosteroid treatment should be limited to the shortest period of time to minimize the risk of potential toxicities that can significantly affect quality of life, as well as to avoid a possible detrimental impact on survival in high-grade glioma patients and abrogation of the effect of immunotherapy. Agents such as bevacizumab should be considered in patients who are unable to wean completely off of steroids as well as those who have symptomatic edema and are on immunotherapy. Several other agents have been studied without much success. An increased understanding of the complex pathophysiology of peritumoral vasogenic edema is critically needed to discover new agents that are safer and more effective.

Purpose: ANG1005, a novel taxane derivative, consists of three paclitaxel molecules covalently linked to Angiopep-2, designed to cross the blood-brain and blood-cerebrospinal barriers and to penetrate malignant cells via LRP1 transport system. Preclinical and clinical evidence of efficacy with ANG1005 has been previously shown., Patients and Methods: A multicenter, open-label phase II study in adult patients with measurable recurrent brain metastases from breast cancer (BCBM), with or without leptomeningeal carcinomatosis was conducted ( n = 72 BCBM; n = 28 leptomeningeal carcinomatosis subset). ANG1005 was administered intravenously at 600 mg/m 2 every 3 weeks. Tumor assessment was based on central nervous system (CNS) RECIST 1.1 for intracranial, and RECIST 1.1 for extracranial response. The primary endpoint was determination of intracranial objective response rate (iORR)., Results: Median age was 47.5 years. Safety profile was similar to that of paclitaxel with myelosuppression as the predominating toxicity. Average number of prior CNS-directed therapies was 2.8 and 94% of the patients had prior taxane treatment. Patient benefit (stable disease or better) was seen in 77% (intracranial) and 86% (extracranial) of the evaluable patients, with iORR of 15% (investigator) or 8% (independent radiology facility [IRF] review). In the leptomeningeal carcinomatosis subset, 79% of the patients had intracranial disease control and estimated median overall survival of 8.0 months (95% CI, 5.4-9.4)., Conclusions: Even though the study preset rule for iORR per IRF was not met in this heavily pretreated population, a notable CNS and systemic treatment effect was seen in all patients including symptom improvement and prolonged overall survival compared to historical control for the subset of patients with leptomeningeal carcinomatosis ( n = 28)., (©2020 American Association for Cancer Research.)

Background: Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences., Methods: Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females)., Results: Among males, tumor (T1Gd) radius was a predictor of overall survival (HR = 1.027, p = 0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR = 1.011, p < 0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p = 0.010 t-test), but tumor size was not correlated with female overall survival (p = 0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p = 0.004, F p = 0.001, t-test)., Conclusion: Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

Background: Progress in extending the survival of glioblastoma (GBM) patients has been slow. A better understanding of why patient survival remains poor is critical to developing new strategies. Postmortem studies on GBM can shed light on why patients are dying., Methods: The brains of 33 GBM patients were autopsied and examined for gross and microscopic abnormalities. Clinical-pathologic correlations were accomplished through detailed chart reviews. Data were compared with older published autopsy GBM studies that predated newer treatment strategies, such as more extensive surgical resection and adjuvant temozolomide., Results: In older GBM autopsy series, mass effect was observed in 72% of brains, with herniation in 50% of all cases. Infiltration of tumor into the brainstem was noted in only 21% of those older cases. In the current series, only 10 of 33 (30%) GBMs showed mass effect (P = 0.0003), and only 1 (3%) showed herniation (P < 0.0001). However, extensive GBM infiltration of the brainstem was present in 22 cases (67%, P < 0.0001), with accompanying destruction of the pons and white matter tracts. There was a direct correlation between longer median patient survival and the presence of brainstem infiltration (16.1 mo in brainstem-invaded cases vs 9.0 mo in cases lacking extensive brainstem involvement; P = 0.0003)., Conclusions: With improving care, severe mass effect appears to be less common in GBM patients today, whereas dissemination, including life-threatening brainstem invasion, is now more pronounced. This has major implications regarding preclinical GBM models, as well as the design of clinical trials aimed at further improving patient survival., (© The Author(s) 2019. 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.)

Bevacizumab is FDA-approved in the treatment of primary brain tumors, but its efficacy in patients with brain metastases could be better-studied. This study examines a population of non-small cell lung cancer (NSCLC) patients with synchronous brain metastases to identify predictors of the decision to use bevacizumab and survival following bevacizumab treatment. Primary cancer registry data were used to determine which NSCLC patients diagnosed in the years 2010 through 2012 had synchronous brain metastases at the time of diagnosis, and Medicare claims used to identify a population of patients treated with bevacizumab. Record of bevacizumab treatment was found for 81 and 666 patients with and without brain metastases, respectively. After adjusting for clinical and demographic characteristics, bevacizumab was associated with 0.88 times the hazard of mortality in the elderly NSCLC population (95% CI: 0.81-0.96, p: 0.003) and a corresponding hazard ratio of 0.75 in the population of elderly NSCLC patients with synchronous brain metastases (95% CI: 0.59-0.96, p: 0.020). Bevacizumab may benefit NSCLC patients with synchronous brain metastases more than it does patients without intracranial disease, possibly as a result of its multiple potential mechanisms of action simultaneously inhibiting angiogenesis and minimizing vasogenic edema.

Pleomorphic xanthoastrocytoma (PXA) is a rare primary CNS tumor. Recent advances in the molecular characterization are helping to define subtypes of tumor. The discovery of BRAF mutations within a substantial percentage of PXA fosters a clearer understanding of the pathophysiology of these tumors with clear prognostic and therapeutic implications. These findings are expected to provide insight into the spectrum of clinical behavior observed in PXA, ranging from cure with surgery to diffuse dissemination throughout the neuraxis. This review details the clinical presentation including radiographic appearance of PXA. Pathology, including molecular pathology is discussed. Therapeutic management including surgical resection, radiotherapy and systemic therapies are reviewed.

Although glioblastoma (GBM) is a fatal primary brain cancer with short median survival of 15 months, a small number of patients survive >5 years after diagnosis; they are known as extreme survivors (ES). Because of their rarity, very little is known about what differentiates these outliers from other patients with GBM. For the purpose of identifying unknown drivers of extreme survivorship in GBM, the ENDURES consortium (ENvironmental Dynamics Underlying Responsive Extreme Survivors of GBM) was developed. This consortium is a multicenter collaborative network of investigators focused on the integration of multiple types of clinical data and the creation of patient-specific models of tumor growth informed by radiographic and histologic parameters. Leveraging our combined resources, the goals of the ENDURES consortium are 2-fold: (1) to build a curated, searchable, multilayered repository housing clinical and outcome data on a large cohort of ES patients with GBM; and (2) to leverage the ENDURES repository for new insights into tumor behavior and novel targets for prolonging survival for all patients with GBM. In this article, the authors review the available literature and discuss what is already known about ES. The authors then describe the creation of their consortium and some preliminary results.

Survival outcomes for patients with glioblastoma (GBM) are universally poor with only a small percentage of patients surviving five years beyond initial diagnosis. Activation of the immune system against tumor cells is the basis of immunotherapy and aims to facilitate long-term immune surveillance and tumor suppression. Cytomegalovirus (CMV) has emerged as an immunologic target in GBM given that tumor cells have been shown to express the CMV-associated proteins IE1 and pp65. Moreover, vaccine therapy targeting CMV antigens has promoted improved survival outcomes with long-term survivors. In this report, we present the case of a 69 year-old woman with GBM who survived seven years post-diagnosis. Following tumor resection, the patient underwent concomitant radiation and temozolomide therapy that was complicated by CMV colitis and abdominal abscesses. Despite not receiving adjuvant temozolomide, the patient demonstrated a five year progression-free survival before requiring re-resection for radiation necrosis. Following re-resection, the patient survived for two additional years. As the patient's tumor stained positive for CMV antigens IE1 and pp65, it is hypothesized that she developed an immune response against CMV during recovery that contributed to anti-tumor surveillance and prolonged survival. Overall, this case supports further investigation into the role of CMV and immunotherapy in GBM., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The Surveillance, Epidemiology, and End Results (SEER) Program recently released data on brain metastases (BM) diagnosed during primary cancer staging workup ("synchronous" BM, or SBM); this study examines the incidence of SBM compared with that of lifetime BM (LBM) identified using Medicare claims for patients diagnosed with lung cancer, breast cancer, or melanoma., Methods: Incidence proportions (IP) and age-adjusted rates for each of SEER SBM and Medicare LBM are presented along with measures of concordance between the two sources of data, where Medicare LBM were defined by several combinations of diagnosis and putative diagnostic imaging procedure codes., Results: The SBM IP in lung, breast, and melanoma cancers were 9.6%, 0.3%, and 1.1%, respectively; the corresponding LBM IP were 13.5%, 1.8%, and 3.6%. The greatest SBM IP among patients with lung cancer was 13.4% for non-small cell lung cancer, and among patients with breast cancer was 0.7% for triple-negative breast cancer. The greatest LBM IP among lung cancers was 23.1% in small-cell lung cancer, and among breast cancers was 4.2% for cases of the triple negative subtype., Conclusions: Using a large dataset that is representative of the elderly population in the United States, these analyses estimate synchronous and lifetime incidence of BM in lung cancers, breast cancers, and melanomas., Impact: These and other population-based estimates may be used to guide development of BM screening policy and evaluation of real-world data sources., (©2019 American Association for Cancer Research.)

Background: Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM., Methods: M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5-1.5 mg/kg) on days 1 and 15, and TMZ (150-200 mg/m2) on days 1-5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve., Results: There were 60 patients, median age 56 years (range, 20-79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%., Conclusions: Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).

Central nervous system metastasis in non-small cell lung cancer remains a therapeutic challenge and confers a poor prognosis. Here we describe a patient with lung adenocarcinoma, parenchymal brain metastases, and leptomeningeal carcinomatosis who demonstrated a sustained response to programmed death 1 inhibition combined with stereotactic radiosurgery., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Background: We recently reported an acceptable safety and pharmacokinetic profile of depatuxizumab mafodotin (depatux-m), formerly called ABT-414, plus radiation and temozolomide in newly diagnosed glioblastoma (arm A). The purpose of this study was to evaluate the safety and pharmacokinetics of depatux-m, either in combination with temozolomide in newly diagnosed or recurrent glioblastoma (arm B) or as monotherapy in recurrent glioblastoma (arm C)., Methods: In this multicenter phase I dose escalation study, patients received depatux-m (0.5-1.5 mg/kg in arm B, 1.25 mg/kg in arm C) every 2 weeks by intravenous infusion. Maximum tolerated dose (MTD), recommended phase II dose (RP2D), and preliminary efficacy were also determined., Results: Thirty-eight patients were enrolled as of March 1, 2016. The most frequent toxicities were ocular, occurring in 35/38 (92%) patients. Keratitis was the most common grade 3 adverse event observed in 6/38 (16%) patients; thrombocytopenia was the most common grade 4 event seen in 5/38 (13%) patients. The MTD was set at 1.5 mg/kg in arm B and was not reached in arm C. RP2D was declared as 1.25 mg/kg for both arms. Depatux-m demonstrated a linear pharmacokinetic profile. In recurrent glioblastoma patients, the progression-free survival (PFS) rate at 6 months was 30.8% and the median overall survival was 10.7 months. Best Response Assessment in Neuro-Oncology responses were 1 complete and 2 partial responses., Conclusion: Depatux-m alone or in combination with temozolomide demonstrated an acceptable safety and pharmacokinetic profile in glioblastoma. Further studies are currently under way to evaluate its efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).

Breast cancer is the most common malignancy among women and accounts for the second highest number of cancer-related deaths. With patients surviving longer due to advances in systemic control, the incidence of CNS involvement is increasing; however, the management of CNS metastases has not undergone parallel advancements. The blood-brain barrier limits the efficacy of most systemic chemotherapies, and the utilization of surgery and radiation beyond first-line therapy is limited. We will explore the recent developments in the medical management of breast cancer brain metastasis. Beyond traditional chemotherapy, we will also discuss targeted therapies and immunotherapies which may provide a survival benefit to this population and thus, offer further treatment options and a path for future research and treatment advances.

Background: The purpose of this study was to determine the maximum tolerated dose (MTD), recommended phase II dose (RPTD), safety, and pharmacokinetics of ABT-414 plus radiation and temozolomide in newly diagnosed glioblastoma. ABT-414 is a first-in-class, tumor-specific antibody-drug conjugate that preferentially targets tumors expressing overactive epidermal growth factor receptor (EGFR)., Methods: In this multicenter phase I study, patients received 0.5-3.2 mg/kg ABT-414 every 2 weeks by intravenous infusion. EGFR alterations, O6-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, and isocitrate dehydrogenase (IDH1) gene mutations were assessed in patient tumors. Distinct prognostic classes were assigned to patients based on a Molecular Classification Predictor model., Results: As of January 7, 2016, forty-five patients were enrolled to receive ABT-414 plus radiation and temozolomide. The most common treatment emergent adverse events were ocular: blurred vision, dry eye, keratitis, photophobia, and eye pain. Ocular toxicity at any grade occurred in 40 patients and at grades 3/4 in 12 patients. RPTD and MTD were set at 2 mg/kg and 2.4 mg/kg, respectively. Among 38 patients with pretreatment tumor tested centrally, 39% harbored EGFR amplification, of which 73% had EGFRvIII mutation. Among patients with available tumor tissue (n = 30), 30% showed MGMT promoter methylation and none had IDH1 mutations. ABT-414 demonstrated an approximately dose proportional pharmacokinetic profile. The median duration of progression-free survival was 6.1 months; median overall survival has not been reached., Conclusion: ABT-414 plus chemoradiation demonstrated an acceptable safety and pharmacokinetic profile in newly diagnosed glioblastoma. Randomized studies are ongoing to determine efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406)., (© The Author(s) 2016. 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)

Standard treatment for GBM is radiation (RT) and temozolomide (TMZ). Arsenic trioxide (ATO) is synergistic with RT based on several mechanisms of action previously identified, however not tested herein. The MTD of ATO, RT and TMZ was determined in a Phase I trial. We now present the combined Phase I/II data. Patients with newly diagnosed malignant gliomas were eligible for treatment. Patients were treated with RT (60 GY), TMZ (75 mg/m 2 daily × 42 days) and ATO 0.20 mg/kg daily in week 1 then twice a week ×5 weeks, after completing RT they were treated with TMZ 5/28 for up to 12 months. MRIs were performed every 8 weeks. A total of 42 patients were enrolled in both the Phase I and II trials for this study treatment. Of the 42 enrolled patients (24 M and 18 W) the median age was 54 (24-80) and median KPS 90 (60-100). 28 patients had a GBM and 14 had anaplastic glioma (AG). All patients completed RT/TMZ/ATO and went on to maintenance TMZ. Median number of post RT cycles of TMZ was 4 (0-12). Median PFS was 7 m for GBM and 75 m for AG and median OS was 17 m for GBM and NR for AG. Best response was CR in 2, SD in 28, PR in 5 and PD in 7. There were no unexpected adverse events. Grade 3 toxicities likely attributable to ATO included prolonged Qtc (n = 1), elevated liver enzymes (n = 2 for ALT/n = 1 for AST) and elevated bilirubin (n = 1). Adding ATO to RT and TMZ is feasible with no increased side effects. The addition of arsenic did not improve overall survival in the GBM patients as compared to historic data. MGMT status was analyzed in 20 of the 42 patients where tissue was available for retrieval and MGMT testing.

Objective: Because the d-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1 mut ) is released by tumor cells into the microenvironment and is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1 mut increases the risk of seizures in patients with glioma, and whether D2HG increases the electrical activity of neurons., Methods: Three WHO grade II-IV glioma cohorts from separate institutions (total N = 712) were retrospectively assessed for the presence of preoperative seizures and tumor location, WHO grade, 1p/19q codeletion, and IDH1 mut status. Rat cortical neurons were grown on microelectrode arrays, and their electrical activity was measured before and after treatment with exogenous D2HG, in the presence or absence of the selective NMDA antagonist, AP5., Results: Preoperative seizures were observed in 18%-34% of IDH1 wild-type (IDH1 wt ) patients and in 59%-74% of IDH1 mut patients ( p < 0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe location, showed that IDH1 mut was an independent correlate with seizures (odds ratio 2.5, 95% confidence interval 1.6-3.9, p < 0.001). Exogenous D2HG increased the firing rate of cultured rat cortical neurons 4- to 6-fold, but was completely blocked by AP5., Conclusions: The D2HG product of IDH1 mut may increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1 mut gliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1 mut inhibitors may improve antiepileptic therapy in patients with IDH1 mut gliomas., (© 2017 American Academy of Neurology.)

Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II-IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for tissue factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26-30 % of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0 %). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85-90 % in wild-type versus 2-6 % in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.

Non-small-cell lung cancer (NSCLC) brain metastases are common. Even though there are various subsets of NSCLC with molecular alterations, there is a common theme of brain metastases. Current treatment modalities are suboptimal. Systemic therapies for the treatment of NSCLC brain metastases have been explored and recent advances may pave the way for their successful employment in this patient population. While no specific agents have been associated with a marked benefit, stability of disease as well as radiographic responses have been noted in some patients. Biological activity of systemic therapies in some patients with NSCLC brain metastases raises hope for future advances and supports further investigation for this patient population with limited treatment options.

Low-grade gliomas are slower growing than their high-grade counterparts. They account for 10-20 % of all primary brain tumors. Median survival is between 4.7 and 9.8 years. The goal of treatment is to prolong overall survival while maintaining good quality of life (QOL). Recent data favors early surgical resection. EOR is associated with delayed tumor recurrence and improved survival. Additional therapy with chemotherapy or radiation is indicated in patients with high-risk features. Lower doses (between 45 and 50.4 Gy) have been shown to be as effective without adverse effects compared to higher doses. Recent trials have shown benefit in combining chemotherapy with radiation compared to radiation alone. The optimal chemotherapeutic regimen (PCV or temozolomide (TMZ)) remains unknown, although TMZ is easier to administer and better tolerated by patients. Novel molecular markers including 1p/19q chromosomal codeletion and isocitrate dehydrogenase 1 (IDH1) mutation have been correlated with treatment response and survival.

Primary central nervous system lymphoma (PCNSL) comprises approximately 5 % of all primary brain tumors. During the past two decades the incidence of PCNSL has increased, and as a result clinical research to determine the optimal treatment for PCNSL patients also has increased. Diagnosis is based on histopathologic findings traditionally established by biopsy only. More recent data raise controversy and challenges this biopsy-only paradigm, showing a potential advantage for surgical resection with progression-free survival (PFS) and overall survival (OS). Using high-dose intravenous (IV) methotrexate-based chemotherapy alone or as part of a regimen can lead to disease cure. The role of whole brain radiotherapy (WBRT) remains controversial and more frequently is omitted to avoid potential delayed neurocognitive effects, especially in patients older than age 60 years. Newer data from Memorial Sloan Kettering Cancer Center (MSKCC) using five cycles of Rituximab, Methotrexate, Vincristine, and Procarbazine (R-MVP) followed by low-dose WBRT (2,340 cgy), and then two cycles of Ara-C had excellent disease control with low neuro-toxicity and is now the basis of an ongoing RTOG (Radiation Treatment Oncology Group) trial comparing early versus delayed WBRT. Other chemotherapeutics and novel treatments, such as autologous stem cell transplantation, are being studied for potential use in PCNSL. Unlike many other primary brain tumors seen in adults, PCNSL is potentially curable; therefore, balancing treatment decisions with long-term neurocognitive effects and toxicities is crucial.

Brain metastases (BM) and leptomeningeal metastases (LM) are devastating neurologic complications. Pemetrexed is a multi-targeted anti-folate agent approved for treatment of nonsquamous non-small cell lung cancer but has anti-tumor activity in other solid tumors. We performed two trials using pemetrexed in patients with BM and LM to assess CSF penetration and anti-tumor activity. Patients were treated with intravenous pemetrexed at doses of 500 (n = 3), 750 (n = 3), 900 (n = 12) or 1,050 mg/m(2) (n = 3) every 3 weeks. Neuro-imaging was done every 6 weeks. Matched CSF and plasma samples were obtained serially from three patients with Ommaya reservoirs; the remaining patients had a single paired collection. Twenty-one patients (15 women and six men) with median age of 50 years and median KPS of 90 were treated. Primary tumors included breast (13), lung (4), colorectal (1), endometrial (1), esophageal (1) and pinealoblastoma (1). Nine patients had prior whole brain RT and median number of prior chemotherapies was two including prior methotrexate in four patients. Median pemetrexed doses administered was three (range 1-14). Responses included one partial response, ten stable disease and ten progressive disease. Median time to progression and survival was 2.7 and 7.3 months; PFS six was 22 %. No major toxicities were seen. Pemetrexed distributed from the plasma to the CSF within 1-4 h with the resulting CSF concentrations < 5 % of plasma. Pemetrexed was tolerated in solid tumor patients with CNS metastases. Limited anti-tumor activity was seen, which might have been due to low CSF concentrations, although some patients displayed prolonged benefit.