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The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2–3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2–4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non–AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding molecular profiling of gliomas.

Chimeric antigen receptor (CAR) T-cells are now a well-established treatment for hematologic malignancies. Their use in clinical practice has expanded quite rapidly and hospitals have developed CAR T-cell protocols to evaluate patients for associated toxicities, and particularly for neurotoxicity. There are many variables that influence the risk for developing this complication, many of which are not fully understood. The severity can be related to a particular product. Clinical vigilance is critical to facilitate early recognition of neurotoxicity, hence the importance of pre-CAR T-cell neurological evaluation of each patient. While details of such an evaluation may slightly differ between institutions, generally a comprehensive neurological evaluation including assessment of cognitive abilities along with magnetic resonance imaging (MRI) of the brain is a gold standard. Management of neurotoxicity requires a well-orchestrated team approach with specialists from oncology, neurology, oftentimes neurosurgery and neuro-intensive care. Diagnostic work-up frequently includes detailed neurologic evaluation with comparison to the baseline assessment, imaging of the brain, electroencephalogram, and lumbar puncture. While steroids are uniformly used for treatment, many patients also receive tocilizumab for an underlying and frequently concomitant cytokine release syndrome (CRS) in addition to symptom-driven supportive care. Novel CAR T-cell constructs and other agents allowing for potentially lower risk of toxicity are being explored. While neurotoxicity is predominantly an early, and reversible, event, a growing body of literature suggests that late neurotoxicity with variable clinical presentation can also occur.

Neuro-oncology encompasses a broad field focusing on an array of neoplasms, many of which can mimic several diseases. Neurologists will often be involved in the initial diagnostic evaluation and management of these patients. Their insight is central to optimizing the diagnostic yield and providing high-level clinical care. Several neuro-oncologic cases are reviewed with a goal of increasing the understanding of these diseases in a clinically relevant manner and providing updates on the contemporary thinking in the subspecialty.

Figure A3 from Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial

Web Extra Material - 2 tables and 3 figures

Purpose:Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma.Patients and Methods:In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2.Results:Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32–0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5–22.2) vs. 5.6 (95% CI, 3.7–7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07–0.45; P < 0.0001).Conclusions:Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM.See related commentary by Wick and Wagener, p. 1535

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Glioblastoma multiforme is the most aggressive type of primary brain tumor. Glioblastoma growth dynamics vary widely across patients, making it difficult to accurately gauge their response to treatment. We developed a model-based metric of therapy response called Days Gained that accounts for this heterogeneity. Here, we show in 63 newly diagnosed patients with glioblastoma that Days Gained scores from a simple glioblastoma growth model computed at the time of the first postradiotherapy MRI scan are prognostic for time to tumor recurrence and overall patient survival. After radiation treatment, Days Gained also distinguished patients with pseudoprogression from those with true progression. Because Days Gained scores can be easily computed with routinely available clinical imaging devices, this model offers immediate potential to be used in ongoing prospective studies. Cancer Res; 73(10); 2976–86. ©2013 AACR.

While the COVID-19 pandemic has catalyzed the expansion of telemedicine into nearly every specialty of medicine, few articles have summarized current practices and recommendations for integrating virtual care in the practice of neuro-oncology. This article identifies current telemedicine practice, provides practical guidance for conducting telemedicine visits, and generates recommendations for integrating virtual care into neuro-oncology practice. Practical aspects of telemedicine are summarized including when to use and not use telemedicine, how to conduct a virtual visit, who to include in the virtual encounter, unique aspects of telehealth in neuro-oncology, and emerging innovations.

Brain cancers pose a novel set of difficulties due to the limited accessibility of human brain tumor tissue. For this reason, clinical decision-making relies heavily on MR imaging interpretation, yet the mapping between MRI features and underlying biology remains ambiguous. Standard tissue sampling fails to capture the full heterogeneity of the disease. Biopsies are required to obtain a pathological diagnosis and are predominantly taken from the tumor core, which often has different traits to the surrounding invasive tumor that typically leads to recurrent disease. One approach to solving this issue is to characterize the spatial heterogeneity of molecular, genetic, and cellular features of glioma through the intraoperative collection of multiple image-localized biopsy samples paired with multi-parametric MRIs. We have adopted this approach and are currently actively enrolling patients for our ‘Image-Based Mapping of Brain Tumors’ study. Patients are eligible for this research study (IRB #16-002424) if they are 18 years or older and undergoing surgical intervention for a brain lesion. Once identified, candidate patients receive dynamic susceptibility contrast (DSC) perfusion MRI and diffusion tensor imaging (DTI), in addition to standard sequences (T1, T1Gd, T2, T2-FLAIR) at their presurgical scan. During surgery, sample locations are tracked using neuronavigation and genetic aberrations are later quantified through whole-exome and RNA sequencing. The collected specimens from this NCI-funded research study will be primarily used to generate regional maps of the spatial distribution of tumor cell density and/or treatment-related key genetic marker status across tumors, within clinically feasible time frames, to identify biopsy and/or treatment targets based on insight from the entire tumor makeup regional histologic and genetic makeup. This type of methodology, when delivered within clinically feasible time frames, has the potential to further inform medical decision-making by improving surgical intervention, radiation, and targeted drug therapy for patients with glioma. From October 1, 2017 to October 31, 2022, this study has enrolled 186 patients with 197 surgeries, of which 163 resulted in the successful collection of image-guided biopsy samples. A total of 995 biopsies have been collected of which 962 are image localized, with a mean of 5.90 image-localized samples per surgery.

Combined PD-1/PD-L1 and CTLA-4 immune checkpoint inhibition for the has been shown to produce superior results in the treatment of malignant melanoma when compared to monotherapy. However, patients with intracranial disease were excluded from these studies given their poor prognosis.The objective of this study was to critically assess current evidence supporting the co-administration of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of melanoma brain metastases.The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of neuro-oncology.A recent, open-label, non-comparative randomized phase II trial was selected for critical appraisal. This trial evaluated the efficacy and safety of nivolumab alone or in combination with ipilimumab in 79 adult patients with untreated, asymptomatic melanoma brain metastases. The rates of the primary outcome (intracranial response at ≥12 wk) in the primary endpoint cohort were 46% for cohort A (combination therapy) and 20% for cohort B (nivolumab monotherapy). No treatment related deaths were observed in the study. Grade 4 adverse events occurred in 9% of patients in cohort A and none in cohort B.Co-administration of ipilimumab and nivolumab as first-line therapy is effective in the treatment of asymptomatic melanoma brain metastases, with an acceptable safety profile.

Patients with glioblastoma (GBM) face poor outcomes; the 5-year survival rate is 7% with standard of care treatments, which are frequently associated with systemic toxicity. Tumor Treating Fields (TTFields) are electric fields that disrupt critical cancer cell processes. The TTFields therapy device consists of a portable electric field generator and arrays placed on the patient’s scalp, thus delivery is locoregional and noninvasive. Currently, TTFields therapy is approved for recurrent and newly diagnosed GBM, based on the phase 3 EF-11 (TTFields 200 kHz) and EF-14 studies (TTFields therapy 200 kHz + temozolomide), respectively. These studies confirmed that TTFields therapy had a tolerable safety profile with mild-to-moderate localized skin adverse events (AEs) being the most common related AEs. Here, we present an updated analysis of the largest global real-world evidence dataset of patients with brain tumors receiving TTFields therapy over an 11-year time period. Unsolicited safety data were obtained from routine post-marketing activities, including published literature and interactions with patients, caregivers, and healthcare professionals. Safety data were grouped according to age, diagnosis, and sex. AEs were categorized using MedDRA version 25. Data from 25,898 patients were included in this analysis; median age was 59 years (range: 3-103) for patients with known age. Diagnoses were ndGBM (67.7%), rGBM (26.1%), anaplastic astrocytoma/oligodendroglioma (4.2%) and other (2.1%). Most (n=17,817, 68.8%) patients were 18-65 years of age; n=93 (0.4%) were pediatric/adolescent patients (65 years). For 130 patients (0.5%) age was not known. Two-thirds of patients were male, which reflects the preponderance of CNS tumors in males. Most patients were based in North America (72.1%), followed by Europe, the Middle East and Africa (23.3%), and Japan (4.6%). Overall, 72.4% of patients experienced at least one AE, with 55.9% being related to TTFields therapy. The most common AEs (overall and related to TTFields therapy) were skin reactions (42.0%), electric (tingling) sensations (13.5%), and heat (warmth) sensations (11.8%). The percentage of patients experiencing ≥1 AE in the pediatric/adolescent, 18-65, and elderly groups was 63.4%, 74.6%, and 68.4%, respectively. The percentage of females and males experiencing ≥1 AE was 75.2% and 70.9%, respectively. These long-term, real-world data from the largest global dataset of patients with brain tumors using TTFields therapy to date demonstrate a tolerable safety profile consistent with pivotal clinical studies. There were no new safety signals, and most AEs were manageable localized mild-moderate skin events that can be resolved. The distribution of AEs between age and sex was similar, with broad applicability among different patient groups. Citation Format: Maciej M. Mrugala, Wenyin Shi, Fabio Iwamoto, Rimas V. Lukas, Joshua D. Palmer, John H. Suh, Martin Glas. Patients with glioblastoma (GBM) treated with tumor treating fields (TTFields) therapy: post-marketing safety data over the last decade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3221.

Background Molecular testing (MT) is utilized in neuro-oncology with increasing frequency. The aim of this study was to determine clinical practice patterns to acquire this information, interpret and utilize MT for patient care, and identify unmet needs in the practical clinical application of MT. Methods We conducted a voluntary online survey of providers within the Society for Neuro-Oncology (SNO) membership database between March and April 2019. Results We received 152 responses out of 2022 SNO members (7.5% of membership). 88.8% of respondents routinely order MT for newly diagnosed gliomas. Of those who do not, testing is preferentially performed in younger patients or those with midline tumors. 82.8% use MT in recurrent gliomas. Other common indications included: metastatic tumors, meningioma, and medulloblastoma. Many providers utilize more than one resource (36.0%), most frequently using in-house (41.8%) over commercially available panels. 78.1% used the results for clinical decision-making, with BRAF, EGFR, ALK, and H3K27 mutations most commonly directing treatment decisions. Approximately, half (48.5%) of respondents have molecular tumor boards at their institutions. Respondents would like to see SNO-endorsed guidelines on MT, organized lists of targeted agents available for specific mutations, a database of targetable mutations and clinical trials, and more educational programs on MT. Conclusion This survey was marked by several limitations including response rate and interpretation of MT. Among respondents, there is routine use of MT in Neuro-Oncology, however, there remains a need for increased guidance for providers to effectively incorporate the expanding genomic data resulting from MT into daily Neuro-Oncology practice.

Advanced molecular and pathophysiologic characterization of primary central nervous system lymphoma (PCNSL) has revealed insights into promising targeted therapeutic approaches. Medical imaging plays a fundamental role in PCNSL diagnosis, staging, and response assessment. Institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability and reproducibility of clinical response assessment. In this context, we aimed to: (1) critically review the use of advanced positron emission tomography (PET) and magnetic resonance imaging (MRI) in the setting of PCNSL; (2) provide results from an international survey of clinical sites describing the current practices for routine and advanced imaging, and (3) provide biologically based recommendations from the International PCNSL Collaborative Group (IPCG) on adaptation of standardized imaging practices. The IPCG provides PET and MRI consensus recommendations built upon previous recommendations for standardized brain tumor imaging protocols (BTIP) in primary and metastatic disease. A biologically integrated approach is provided to addresses the unique challenges associated with the imaging assessment of PCNSL. Detailed imaging parameters facilitate the adoption of these recommendations by researchers and clinicians. To enhance clinical feasibility, we have developed both “ideal” and “minimum standard” protocols at 3T and 1.5T MR systems that will facilitate widespread adoption.

The influence of biological sex differences on human health and disease, while being increasingly recognized, has long been underappreciated and underexplored. While humans of all sexes are more alike than different, there is evidence for sex differences in the most basic aspects of human biology and these differences have consequences for the etiology and pathophysiology of many diseases. In a disease like cancer, these consequences manifest in the sex biases in incidence and outcome of many cancer types. The ability to deliver precise, targeted therapies to complex cancer cases is limited by our current understanding of the underlying sex differences. Gaining a better understanding of the implications and interplay of sex differences in diseases like cancer will thus be informative for clinical practice and biological research. Here we review the evidence for a broad array of biological sex differences in humans and discuss how these differences may relate to observed sex differences in various diseases, including many cancers and specifically glioblastoma. We focus on areas of human biology that play vital roles in healthy and disease states, including metabolism, development, hormones, and the immune system, and emphasize that the intersection of sex differences in these areas should not go overlooked. We further propose that mathematical approaches can be useful for exploring the extent to which sex differences affect disease outcomes and accounting for those in the development of therapeutic strategies.

Discordant prognostic awareness (PA) can cause distress, impact goals of care and future planning, especially in patients with high grade glioma (pwHGG) who have limited survival. We aimed to evaluate the feasibility of assessing PA of pwHGG, caregivers and clinicians using a single question and to evaluate these responses for discord, alignment and fluctuation over time. This is a sub-study of an IRB-approved pilot study evaluating early palliative care and longitudinal symptom monitoring via a smart-device tool in 16 pwHGG and their caregivers receiving treatment at the Mayo Clinic Arizona (United States). Eligible patients were ≥ 18 years, English-speaking, newly-diagnosed, and had a willing caregiver. Participants answered a multiple-choice question asking for an estimate of their own or their loved one’s survival on a monthly basis. All except one patient/caregiver dyad answered the question each time it was asked. The question did not appear to cause discomfort or increase conversations with clinicians around prognosis. PA of patients and caregivers fluctuated monthly, ranging from dismal to overtly optimistic, with a discordance frequency of 68%. Patients tended to be more optimistic than caregivers, and a higher QOL correlated to a more optimistic response. Clinicians’ were more hopeful; their prediction tended to fluctuate less than those of patients and caregivers. PA may be assessed in pwHGG and caregivers with a single, frank question. There is clear discordance between PA of patients, their caregivers and clinicians. Understanding fluctuates longitudinally through disease and treatment course. Additional studies on timing and ways of discussing prognosis in this population are needed. NCT04630379.

Primary central nervous system lymphomas (PCNSLs) are rare cancers of the central nervous system (CNS) and are predominantly diffuse large B-cell lymphomas of the activated B-cell (ABC) subtype. They typically present in the sixth and seventh decade of life, with the highest incidence among patients aged >75 years. Although many different regimens have demonstrated efficacy in newly diagnosed and relapsed or refractory PCNSL, there have been few randomized prospective trials, and most recommendations and treatment decisions are based on single-arm phase II trials or even retrospective studies. High-dose methotrexate (HD-MTX; 3–8 g/m2) is the backbone of preferred standard induction regimens. Various effective regimens with different toxicity profiles can be considered that combine other chemotherapies and/or rituximab with HD-MTX, but there is currently no consensus for a single preferred regimen. There is controversy about the role of various consolidation therapies for patients who respond to HD-MTX–based induction therapy. For patients with relapsed or refractory PCNSL who previously experienced response to HD-MTX, repeat treatment with HD-MTX–based therapy can be considered depending on the timing of recurrence. Other more novel and less toxic regimens have been developed that show efficacy in recurrent disease, including ibrutinib, or lenalidomide ± rituximab. There is uniform agreement to delay or avoid whole-brain radiation therapy due to concerns for significant neurotoxicity if a reasonable systemic treatment option exists. This article aims to provide a clinically practical approach to PCNSL, including special considerations for older patients and those with impaired renal function. The benefits and risks of HD-MTX or high-dose chemotherapy with autologous stem cell transplantation versus other, better tolerated strategies are also discussed. In all settings, the preferred treatment is always enrollment in a clinical trial if one is available.

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.

Primary central nervous system lymphoma is an aggressive form of non-Hodgkin lymphoma arising in the eyes, meninges, spinal cord, or brain. Treatment of primary CNS lymphoma with a combination of high-dose chemotherapy and autologous stem cell transplantation has been shown to have high rates of remission which is frequently sustained for multiple years. Recurrence of primary CNS lymphoma generally presents with one or multiple contrast enhancing lesions on MRI. In rare cases, lymphoma cells may proliferate diffusely within the brain parenchyma without mass formation, a pattern termed lymphomatosis cerebri. Lymphomatosis cerebri presents a significant diagnostic challenge, and has not been reported to present with parkinsonism. Here, we present a case of initially mass forming, contrast-enhancing primary CNS lymphoma which remitted following chemotherapy and autologous stem cell transplantation, and recurred 7 years post-transplant with symptoms of parkinsonism and a lack of typical lesions on imaging, with lymphomatosis cerebri confirmed at autopsy.

Purpose: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma. Patients and Methods: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2. Results: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32–0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5–22.2) vs. 5.6 (95% CI, 3.7–7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07–0.45; P < 0.0001). Conclusions: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM. See related commentary by Wick and Wagener, p. 1535

BACKGROUND AND PURPOSE: Perfusion MR imaging measures of relative CBV can distinguish recurrent tumor from posttreatment radiation effects in high-grade gliomas. Currently, relative CBV measurement requires normalization based on user-defined reference tissues. A recently proposed method of relative CBV standardization eliminates the need for user input. This study compares the predictive performance of relative CBV standardization against relative CBV normalization for quantifying recurrent tumor burden in high-grade gliomas relative to posttreatment radiation effects. MATERIALS AND METHODS: We recruited 38 previously treated patients with high-grade gliomas (World Health Organization grades III or IV) undergoing surgical re-resection for new contrast-enhancing lesions concerning for recurrent tumor versus posttreatment radiation effects. We recovered 112 image-localized biopsies and quantified the percentage of histologic tumor content versus posttreatment radiation effects for each sample. We measured spatially matched normalized and standardized relative CBV metrics (mean, median) and fractional tumor burden for each biopsy. We compared relative CBV performance to predict tumor content, including the Pearson correlation (r), against histologic tumor content (0%–100%) and the receiver operating characteristic area under the curve for predicting high-versus-low tumor content using binary histologic cutoffs (≥50%; ≥80% tumor). RESULTS: Across relative CBV metrics, fractional tumor burden showed the highest correlations with tumor content (0%–100%) for normalized (r = 0.63, P

Lacunarity, a quantitative morphological measure of how shapes fill space, and fractal dimension, a morphological measure of the complexity of pixel arrangement, have shown relationships with outcome across a variety of cancers. However, the application of these metrics to glioblastoma (GBM), a very aggressive primary brain tumor, has not been fully explored. In this project, we computed lacunarity and fractal dimension values for GBM-induced abnormalities on clinically standard magnetic resonance imaging (MRI). In our patient cohort (n = 402), we connect these morphological metrics calculated on pretreatment MRI with the survival of patients with GBM. We calculated lacunarity and fractal dimension on necrotic regions (n = 390), all abnormalities present on T1Gd MRI (n = 402), and abnormalities present on T2/FLAIR MRI (n = 257). We also explored the relationship between these metrics and age at diagnosis, as well as abnormality volume. We found statistically significant relationships to outcome for all three imaging regions that we tested, with the shape of T2/FLAIR abnormalities that are typically associated with edema showing the strongest relationship with overall survival. This link between morphological and survival metrics could be driven by underlying biological phenomena, tumor location or microenvironmental factors that should be further explored.

Primary central nervous system lymphomas (PCNSLs) are very rare neoplasms and continue to be challenging to treat. While high-dose methotrexate (HD-MTX)-based regimens are the currently accepted standard first-line therapy for newly diagnosed patients, the optimal induction therapies are still unknown. The role of consolidation therapies continues to evolve with a variety of chemotherapy regimens, including high-dose chemotherapy with stem cell rescue and reduced or deferred whole brain radiotherapy being used. Importantly, several recent advances have been made in the treatment of PCNSL. The incorporation of targeted therapy and immune therapy remain promising strategies. Several agents, successfully used in treatment of systemic lymphomas, have shown activity in PCNSL, frequently leading to durable responses in the relapsed/refractory patients. Many ongoing studies will likely lead to a better understanding of the roles of these treatments, especially as the first line and potentially also as maintenance. In addition, the use of molecular profiling to predict disease response to targeted agents and understand relapse patterns will become increasingly important. Clinical trials in PCNSL are critical yet frequently challenging to conduct given the rarity of the condition and lack of suitable subjects. Therefore, multi-institutional and international collaboration is of utmost importance to accelerate progress in understanding the biology and design better treatments for this disease. It is critical to consider patients of all demographics in the design and study of future treatment algorithms to have the largest impact on patient care and outcomes.

Background High-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) is a promising alternative to whole brain radiation therapy (WBRT) in the treatment of primary central nervous system lymphoma (PCNSL). The objective of this study was to critically assess current evidence supporting the use of HD-ASCT as first-line consolidative therapy in PCNSL. Methods The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of neuro-oncology. Results A recent, open-label, noncomparative randomized phase II trial was selected for critical appraisal. This trial evaluated the efficacy and toxicity of consolidative therapy with HD-ASCT and WBRT in PCNSL in 2 separate treatment arms. A total of 140 patients with newly diagnosed PCNSL between the ages of 18 and 60 years were included. The primary endpoint of 2-year progression-free survival was met in 63% of patients in the WBRT arm and 87% in the HD-ASCT arm. Notably, an overall improvement in neurocognitive scores was observed following HD-ASCT, while WBRT was associated with worsened cognitive outcomes. Conclusions In young patients with newly diagnosed PCNSL, consolidative therapy with HD-ASCT appears to be associated with less neurocognitive toxicity and may be more effective than WBRT at preventing relapses, however, at the cost of a higher treatment-related mortality.

Objective Radiation therapy (RT) is the primary treatment of intracranial metastasis (ICM) from lung cancer (LC). Radiation necrosis (RN) has been reported post-RT with an incidence of 5% to 24%. We reviewed the spectrum of imaging changes in patients treated with RT for ICM from LC in an effort to identify potential risk factors for RN. Methods We reviewed 63 patients with LC and ICM who received RT (radiosurgery [stereotactic radiosurgery] with/without whole brain radiation therapy) at our institution between 2013 and 2018. Data evaluated included demographics, tumor type, ICM burden and location, chemotherapy, surgery, and RT details as well as treatment choices and outcomes. Results Of the 63 patients, clinical and radiographic criteria for RN were noted in 24 (38%) as early as 2 months and as late as 5 years posttreatment. Six patients required surgical resection due to refractory symptoms revealing pathology-proven RN and occasionally tumor. Patients were significantly more likely to develop RN if they had surgical resection of an ICM (45.8% vs. 20.5%, P=0.05). No differences were found in location, size, or genetic profile of lesions. In total, 80% of patients received treatment for symptoms and/or radiographic change. This was generally a combination of steroids, bevacizumab, laser interstitial thermal treatment, or surgical resection. Most patients required >1 treatment modality. Conclusions This review of outcomes of RT for ICM in LC demonstrates a higher rate of RN than previously reported in the literature in those having had a surgical resection plus stereotactic radiosurgery. Our observation of RN as late as 5 years post-RT for ICM necessitates clinician awareness.

Metastatic breast cancer frequently leads to brain metastases and, less commonly, leptomeningeal carcinomatosis (LC). Once cerebrospinal fluid involvement occurs, the prognosis is poor. There are limited treatment options available, but none offer significant survival benefit. Methotrexate, given systemically at high doses (3.5-8 gm/m2), achieves cytotoxic concentrations in the CSF and has been shown to prolong survival in patients with LC. Intrathecal liposomal cytarabine has been shown to increase time to neurologic progression in patients with breast cancer and LC. The combination of these 2 agents in LC has not been studied extensively. Here, we present the results of the phase II study with this combination showing promising efficacy and very good tolerability.

Background Guidelines to provide recommendations about driving restrictions for patients with brain metastases are lacking. We aim to determine whether clinical neurologic examination is sufficient to predict suitability to drive in these patients by comparison with an occupational therapy driving assessment (OTDA). Methods We prospectively evaluated the concordance between neurology assessment of suitability to drive (pass/fail) and OTDA in 41 individuals with brain metastases. Neuro-oncology evaluation included an interview and neurological examination. Participants subsequently underwent OTDA during which a battery of objective measures of visual, cognitive, and motor skills related to driving was administered. Results The mean age of patients who failed OTDA was age 68.9 years vs 59.3 years in the group members who passed (P = .0046). The sensitivity of the neurology assessment to predict driving fitness compared with OTDA was 16.1% and the specificity 90%. The 31 patients who failed OTDA were more likely to fail Vision Coach, Montreal Cognitive Assessment, and Trail Making B tests. Conclusions There was poor association between the assessment of suitability to drive by neurologists and the outcome of the OTDA in patients with brain metastases. Subtle deficits that may impair the ability to drive safely may not be evident on neurologic examination. The positive predictive value was high to predict OTDA failure. Age could be a factor affecting OTDA performance. The results raise questions about the choice of assessments in making recommendations about driving fitness in people with brain metastases. OTDA should be strongly considered in patients with brain metastases who wish to continue driving.

PURPOSE The Congress of Neurological Surgeons (CNS) has developed a series of guidelines for the treatment of adults with metastatic brain tumors, including systemic therapy and supportive care topics. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS Two CNS guidelines were reviewed for developmental rigor by methodologists, and an independent multidisciplinary Expert Panel was formed to review the content and assess agreement with the recommendations. The Expert Panel voted to endorse the two guidelines, and ASCO and Society for Neuro-Oncology (SNO) independently reviewed and approved the ASCO/SNO guideline endorsement. RESULTS The ASCO/SNO Expert Panel determined that the recommendations from the CNS anticonvulsants and steroids guidelines, published January 9, 2019, are clear, thorough, and based on the most relevant scientific evidence. ASCO/SNO endorsed these two CNS guidelines with minor alterations. RECOMMENDATIONS Key recommendations include the following: prophylactic antiepileptic drugs were not recommended for routine use; and corticosteroids, specifically dexamethasone, were recommended for temporary symptomatic relief in patients with neurologic symptoms and signs related to mass effect from brain metastases. Additional information is available at www.asco.org/neurooncology-guidelines .

Background. The Congress of Neurological Surgeons (CNS) has developed a series of guidelines on the treatment of adults with metastatic brain tumors, including systemic therapy and supportive care topics. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. Methods. Two CNS Guidelines were reviewed for developmental rigor by methodologists and an independent multi-disciplinary Expert Panel was formed to review the content and assess agreement with the recommendations. The expert panel voted to endorse the two guidelines and ASCO and SNO independently reviewed and approved the ASCO/SNO guideline endorsement. Results. The ASCO/SNO Expert Panel determined that the recommendations from the CNS anticonvulsants and steroids guidelines, published January 9, 2019, are clear, thorough, and based upon the most relevant scientific evidence. ASCO/SNO endorsed these two CNS guidelines, with minor alterations. Conclusions. Key recommendations include: prophylactic anti-epileptic drugs were not recommended for routine use; corticosteroids (specifically dexamethasone) were recommended for temporary symptomatic relief in patients with neurologic symptoms and signs related to mass effect from brain metastases.

Lung cancer is the most common cause of intracranial metastases (ICM). Metastases in the brain can result in a broad range of uncomfortable symptoms and significant morbidity secondary to neurological disability. Treatment options can range from surgical resection of solitary metastases to radiotherapy and more recently systemic targeted therapies and immunotherapy. Patient survival continues to improve with innovations made in treatments for this condition, but each of these treatments carry their own adverse effects that must be appropriately managed. These patients can benefit greatly from multidisciplinary care throughout the course of their disease. Clinicians involved in their care must be equipped with the ability to communicate skillfully and compassionately and set expectations for the road ahead, including symptoms, treatment plans, and prognosis. Involvement of a palliative care team can be very helpful, especially for patients who are nearing the terminal stages of the disease. Palliative care skills may be invaluable in the management of symptoms and can ease suffering for patients and their caregivers, thus allowing for maximum quality of life for as long as possible. End of life may bring its own complications and challenges; and opinion of an experienced and knowledgeable clinician can alleviate the pain and distress of the patient and also bring peace to the caregivers and loved ones.

Morphological characteristics have been linked to outcomes across a variety of cancers. Lacunarity is a quantitative morphological measure of how shapes fill space while fractal dimension is a morphological measure of the complexity of pixel arrangement. Glioblastoma is the most aggressive primary brain tumor with a short expected survival given the current standard-of-care treatment. Due to the sensitive location of the tumor, there is a heavy reliance on imaging to assess the state of the disease in the clinic. In this project, we computed lacunarity and fractal dimension values for glioblastoma-induced abnormalities on gadolinium-enhanced T1-weighted magnetic resonance imaging (T1Gd MRI) as well as T2-weighted (T2) and fluid-attenuated inversion recovery (FLAIR) MRIs. In our patient cohort (n=402), we aim to connect these morphological metrics calculated on pretreatment MRI with the survival of patients with GBM. We calculated lacunarity and fractal dimension across all MRI slices on necrotic regions (n=390) and abnormalities on T1Gd MRI (n=402), as well as on enhancing abnormalities present on T2/FLAIR MRI (n=257). We also explored the relationship between these metrics and age at diagnosis, as well as abnormality volume. We found statistically significant relationships to outcome across all three imaging subtypes, with the shape of T2/FLAIR abnormalities showing the strongest relationship with overall survival. The link between morphological and survival metrics could be driven by underlying biological phenomena, tumor location or microenvironmental factors that should be further explored.

Background Advanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDHwt GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDHwt GBM have a median age of diagnosis at 68–70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM. Methods The Surveillance, Epidemiology, and End Results, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas databases were analyzed for mortality indices. Meta-analysis of 80 clinical trials was evaluated for log hazard ratio for aging to tumor survivorship. Results Despite significant advances in the understanding of intratumoral genetic alterations, molecular characteristics of tumor microenvironments, and relationships between tumor molecular characteristics and the use of targeted therapeutics, life expectancy for older adults with GBM has yet to improve. Conclusions Based upon the results of our analysis, we propose that age-dependent factors that are yet to be fully elucidated, contribute to IDHwt GBM patient outcomes.

BackgroundIt remains unknown how the COVID-19 pandemic has changed neuro-oncology clinical practice, training, and research efforts.MethodsWe performed an international survey of practitioners, scientists, and trainees from 21 neuro-oncology organizations across 6 continents, April 24–May 17, 2020. We assessed clinical practice and research environments, institutional preparedness and support, and perceived impact on patients.ResultsOf 582 respondents, 258 (45%) were US-based and 314 (55%) international. Ninety-four percent of participants reported changes in their clinical practice. Ninety-five percent of respondents converted at least some practice to telemedicine. Ten percent of practitioners felt the need to see patients in person, specifically because of billing concerns and pressure from their institutions. Sixty-seven percent of practitioners suspended enrollment for at least one clinical trial, including 62% suspending phase III trial enrollments. More than 50% believed neuro-oncology patients were at increased risk for COVID-19. Seventy-one percent of clinicians feared for their own personal safety or that of their families, specifically because of their clinical duties; 20% had inadequate personal protective equipment. While 69% reported increased stress, 44% received no psychosocial support from their institutions. Thirty-seven percent had salary reductions and 63% of researchers temporarily closed their laboratories. However, the pandemic created positive changes in perceived patient satisfaction, communication quality, and technology use to deliver care and mediate interactions with other practitioners.ConclusionsThe pandemic has changed treatment schedules and limited investigational treatment options. Institutional lack of support created clinician and researcher anxiety. Communication with patients was satisfactory. We make recommendations to guide clinical and scientific infrastructure moving forward and address the personal challenges of providers and researchers.

Background Dual diagnoses in genetics practice are not uncommon and patients with dual diagnosis often present with complex and challenging phenotypes. A combination of meticulous phenotyping and molecular genetic techniques are essential in solving these diagnostic odysseys. Methods Clinical features and genetic workup of a patient presenting with incidental schwannomatosis. Results A 19‐year‐old male presented with incidental painless schwannomatosis in the background of macrocephaly, distinctive facies, and learning disability. Comprehensive genetic testing with gene panel and chromosomal microarray led to a dual diagnosis of LZTR1‐related schwannomatosis and 7q11.23 duplication syndrome. Conclusion We emphasize the need for high index of suspicion and comprehensive genetic testing in complex phenotypes. Interrogation of the interplay between the pathogenic variants in multiple genes could improve our understanding of the pathophysiologic pathways and contribute to therapeutic discoveries., A nineteen year old male presented with incidental painless schwannomatosis in the background of macrocephaly, distinctive facies and learning disability. Comprehensive genetic testing with gene panel and chromosomal microarray led to a dual diagnosis of LZTR1 related schwannomatosis and 7q11.23 duplication syndrome. We emphasize the need for high index of suspicion and comprehensive genetic testing in complex phenotypes. Interrogation of the interplay between the pathogenic variants in multiple genes could improve our understanding of the pathophysiologic pathways and contribute to therapeutic discoveries.