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Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that involves the central and peripheral nervous systems. Accurate detection and segmentation of neurofibromas are essential for assessing tumor burden and longitudinal tumor size changes. Automatic convolutional neural networks (CNNs) are sensitive and vulnerable as tumors' variable anatomical location and heterogeneous appearance on MRI. In this study, we propose deep interactive networks (DINs) to address the above limitations. User interactions guide the model to recognize complicated tumors and quickly adapt to heterogeneous tumors. We introduce a simple but effective Exponential Distance Transform (ExpDT) that converts user interactions into guide maps regarded as the spatial and appearance prior. Comparing with popular Euclidean and geodesic distances, ExpDT is more robust to various image sizes, which reserves the distribution of interactive inputs. Furthermore, to enhance the tumor-related features, we design a deep interactive module to propagate the guides into deeper layers. We train and evaluate DINs on three MRI data sets from NF1 patients. The experiment results yield significant improvements of 44% and 14% in DSC comparing with automated and other interactive methods, respectively. We also experimentally demonstrate the efficiency of DINs in reducing user burden when comparing with conventional interactive methods. The source code of our method is available at \url{https://github.com/Jarvis73/DINs}., Accepted by IEEE Journal of Biomedical and Health Informatics (JBHI)

Early‐phase clinical trials using oral inhibitors of MEK, the mitogen‐activated protein kinase kinase, have demonstrated benefit for patients with neurofibromatosis type 1 (NF1)‐associated tumors, particularly progressive low‐grade gliomas and plexiform neurofibromas. Given this potential of MEK inhibition as an effective medical therapy, the use of targeted agents in the NF1 population is likely to increase substantially. For clinicians with limited experience prescribing MEK inhibitors, concern about managing these treatments may be a barrier to use. In this manuscript, the Clinical Care Advisory Board of the Children's Tumor Foundation reviews the published experience with MEK inhibitors in NF1 and outlines recommendations for side‐effect management, as well as monitoring guidelines. These recommendations can serve as a beginning framework for NF providers seeking to provide the most effective treatments for their patients. Implications for Practice Neurofibromatosis type 1 (NF1) clinical care is on the cusp of a transformative shift. With the success of recent clinical trials using MEK inhibitors, an increasing number of NF1 patients are being treated with MEK inhibitors for both plexiform neurofibromas and low‐grade gliomas. The use of MEK inhibitors is likely to increase substantially in NF1. Given these changes, the Clinical Care Advisory Board of the Children's Tumor Foundation has identified a need within the NF1 clinical community for guidance for the safe and effective use of MEK inhibitors for NF1‐related tumors. This article provides a review of the published experience of MEK inhibitors in NF1 and provides recommendations for monitoring and management of side effects., As treatment for neurofibromatosis type 1 (NF1)‐associated complex and inoperable tumors, MEK inhibitor therapy is likely to become more widely used. To aid clinicians who may not have experience with the use of this class of agents, the Clinical Care Advisory Board of the Children's Tumor Foundation presents an overview of the use of MEK inhibitors in the NF1 population, covering relevant clinical trial results, common side effects, basic symptom management, recommended screening guidelines, and patient counseling approaches.

BACKGROUND Several MRI features are proposed to distinguish between plexiform neurofibromas (PNF) and malignant peripheral nerve sheath tumors (MPNST) in neurofibromatosis type 1 (NF1), including tumor size, margins, and degree of heterogeneity. However, most of these features are descriptive in nature, subject to intra-/interrater variability, and based on small single-institution studies. The goal of this study was to identify radiomic features that can differentiate between NF1-associated PNF and MPNST. METHODS 31 MPNSTs and 24 PNFs from five centers were segmented on short TI inversion recovery sequences using a semi-automated segmentation software (3DQI). Standard pre-processing was performed, including N4 bias field correction, intensity normalization (using a mean of 120 SI and standard deviation of 80 SI), and resampling to 1 mm3 voxel resolution. 1688 radiomic features were extracted from the tumor region of interest using PyRadiomics, an open-source Python radiomics package. To classify tumors as PNF or MPNST, we implemented the Boruta algorithm and correlation removal for selection of important features. A Random Forest model was built using the top ten selected features. Five-fold cross-validation was performed and repeated 100 times. Model performance was evaluated using the area under the ROC curve (AUC), sensitivity, specificity, accuracy, and confidence intervals. RESULTS The top ten features included in the model were five intensity features, two shape features, and three texture features. The model demonstrated an AUC of 0.891 (95% CI 0.882-0.899), sensitivity of 0.744, specificity of 0.847, and accuracy of 0.802 (95% CI 0.792-0.813). CONCLUSIONS Our machine learning model demonstrated high performance in classifying tumors as either PNF or MPNST in NF1 individuals. Inclusion of additional tumors for model training and testing on an independent dataset are underway. Ultimately, our model may enable improved differentiation between PNF and MPNST compared to descriptive MRI features, permit early patient risk stratification, and improve patient outcomes.

A diverse workforce is critical to providing high-quality, equitable neurologic care. Many neurologic conditions disproportionately affect Black and Latinx people, but these populations have limited access to neurologic care.1,2 Although healthcare disparities can be reduced with a diverse workforce,3-7 just 2.8% of neurologists are Black and 7.2% are Latinx, compared with the most recent US census with 12.8% of individuals identifying as Black and 18.4% as Latinx.8,9 The gap also exists at the trainee level; 4.4% of neurology residents are Black and 7.2% are Latinx.10 Recruitment of an inclusive residency class is paramount to addressing these inequities.3,5,7,11 A record of 42,508 medical students and physicians applied for residency positions in the United States in 2020–2021, as the application season moved to a virtual format because of the COVID-1912 pandemic. Future residency application seasons will likely be a hybrid of in-person and virtual recruitment. This change presents both unique opportunities and challenges for the recruitment of a diverse and inclusive residency class.13

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.

BACKGROUND Individuals with neurofibromatosis type 1 (NF1) frequently have peripheral nerve sheath tumors (PNST), including plexiform neurofibromas (PNF), atypical neurofibromas (ANF), and malignant peripheral nerve sheath tumors (MPNST). These tumors reflect a histologic spectrum from benign to malignant. Various clinical and MRI-based features are proposed as risk factors for MPNST development based on small single-institution studies. A major barrier to study these risk factors is collation and annotation of multi-center serial MRIs. To address this, we created a standardized database of clinical data and longitudinal MRIs from NF1-associated PNST from nine international NF1 referral centers. METHODS Clinical data from NF1 patients are collected in Research Electronic Data Capture databases housed at Massachusetts General Hospital and Washington University, including demographic information, genotype, disease course, treatment history, and survival. ANF and MPNST require histologic confirmation whereas a diagnosis of PNF can also be made based on clinical/radiographic stability. Longitudinal MRIs predating the histologic diagnosis are uploaded to a HIPAA-compliant cloud-based system. RESULTS Data from 200 patients (87 females, 113 males) with 217 tumors (75 PNF, 40 ANF, 102 MPNST) have been collected. 280 regional and 108 whole-body MRIs have been identified. Median age at the time of histologic diagnosis is 30 years (range 5-64). All tumors are histologically confirmed except for 6 PNF which remained stable over time. Median follow-up time is 32 months. Of 147 patients with available survival data, 32 (21.7%) have died from MPNST progression; estimated median overall survival is 20 months. CONCLUSIONS In this ongoing work, we have assembled one of the largest systematically annotated clinical and MRI repositories of NF1-associated PNST from pediatric and adult NF1 patients. The data will be accessible to outside researchers which will promote interdisciplinary and multi-center collaborations. Active efforts include the identification of radiomic MRI features to differentiate between PNF and MPNST.

PurposeThe coronavirus disease 2019 (COVID-19) pandemic has had unprecedented impact on the provision of medical care for genetic disorders. The purpose of this study was to assess the effects of the pandemic on neurofibromatosis (NF) care and research.MethodsSixty-three United States NF clinics were surveyed to identify the impact of the pandemic on clinician role, patient volume, continuity of guideline-driven surveillance, research protocols, and use of (and satisfaction with) telehealth for the delivery of NF care.ResultsFifty-two clinic directors or their representatives completed the survey (83% response rate). About 2/3 of the clinics reported a greater than 50% decrease in the number of available patient appointments, and modified clinical surveillance and research protocols. Fifty-one clinics (98%) newly instituted telehealth during the pandemic. Barriers to telehealth prior to the pandemic were insurance reimbursement concerns and lack of infrastructure. Since telehealth was initiated, high provider satisfaction was reported with ease of use. The most common area of concern was related to inability to perform a physical examination.ConclusionResults show marked impacts on NF care and research since the beginning of the pandemic, with potential long-term changes related to the introduction (or adoption) of telehealth for clinical care.

PURPOSE: Although uncommon, detection of BRAF V600E mutations in adult patients with glioblastoma has become increasingly relevant given the widespread application of molecular diagnostics and encouraging therapeutic activity of BRAF/MEK inhibitors. METHODS: We performed a retrospective study of adult glioblastoma patients treated at Dana-Farber Cancer Institute/Brigham and Women’s Hospital or Massachusetts General Hospital from January 2011 to July 2019 with an identified BRAF V600E mutation by either immunohistochemistry or molecular testing. Patient characteristics, molecular genomics, and preoperative MRI were analyzed. RESULTS: Nineteen glioblastoma patients were included, with median age at diagnosis of 41-years-old (range 22–69). Only 1/18 was IDH1/2-mutant; 10/17 had MGMT unmethylated tumors. The most common additional molecular alterations were CDKN2A/2B biallelic loss/loss-of-function (10/13, 76.9%), polysomy 7 (8/12, 66.7%), monosomy 10 (5/12, 41.7%), PTEN biallelic loss/loss-of-function (5/13, 38.5%) and TERT promoter mutations (5/15, 33.3%). Most tumors were well-circumscribed (11/14) and all were contrast-enhancing on MRI. Twelve patients eventually developed subependymal or leptomeningeal dissemination. Six patients were treated with BRAF/MEK inhibition following disease progression after standard of care therapy, with 4/6 patients showing partial response or stable disease as best response. Median time to progression after BRAF/MEK inhibition was 6.0 months (95% CI 1.2–11.8). Grade 1 skin rash was present in 2 patients, but no other adverse events were reported. Median OS for the entire cohort was 24.1 months (95% CI 15.7–38.9). CONCLUSION: Understanding the natural history and features of BRAF V600E glioblastoma may help better identify patients for BRAF/MEK inhibition and select therapeutic strategies.

PURPOSE Vascular endothelial growth factor (VEGF) is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase 2 study of pembrolizumab, a programmed death-1 (PD-1) blocking antibody alone or with the anti-VEGF antibody bevacizumab in recurrent glioblastoma with detailed analyses of biomarkers and patient neurologic function. METHODS Eighty bevacizumab-naive, recurrent glioblastoma patients were randomized to receive pembrolizumab with bevacizumab (cohort A, n=50) or pembrolizumab monotherapy (cohort B, n=30). The primary endpoint was six-month progression-free survival (PFS-6). Exploratory endpoints included evaluation of tumor PD-L1 expression, TIL density, immune activation gene expression signature and plasma cytokines with outcome. Changes in neurologic function were prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale. RESULTS Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% (95% CI: 16.3, 41.5), median OS was 8.8 months (95% CI: 7.7, 14.2), ORR was 20% and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI: 1.7, 25.4), median OS was 10.3 months (95% CI: 8.5, 12.5) and ORR was 0%. Factors associated with worsened OS included baseline dexamethasone use and increased post-therapy plasma VEGF (cohort A) and wild-type IDH1, unmethylated MGMT and increased baseline PlGF and sVEGFR1 levels (cohort B), but tumor immune markers were not informative. The NANO scale effectively predicted neurologic function. CONCLUSIONS Although well tolerated, pembrolizumab was ineffective both as monotherapy and with bevacizumab for recurrent glioblastoma. Nonetheless, radiographic responses to combinatorial therapy were durable. Baseline dexamethasone use and plasma cytokines but not tumor immunologic biomarkers were associated with outcome. Neurologic function evaluated by the NANO scale contributed to outcome assessment.

ObjectiveTo assess the reliability and variability of digital calipers, 3D photography, and high-frequency ultrasound (HFUS) for measurement of cutaneous neurofibromas (cNF) in patients with neurofibromatosis type 1 (NF1).BackgroundcNF affect virtually all patients with NF1 and are a major source of morbidity. Reliable techniques for measuring cNF are needed to develop therapies for these tumors.MethodsAdults with NF1 were recruited. For each participant, 6 cNF were assessed independently by 3 different examiners at 5 different time points using digital calipers, 3D photography, and HFUS. The intraclass correlation coefficient (ICC) was used to assess intrarater and interrater reliability of linear and volumetric measurements for each technique, with ICC values >0.90 defined as excellent reliability. The coefficient of variation (CV) was used to estimate the minimal detectable difference (MDD) for each technique.ResultsFifty-seven cNF across 10 participants were evaluated. The ICC for image acquisition and measurement was >0.97 within and across examiners for HFUS and 3D photography. ICC for digital calipers was 0.62–0.88. CV varied by measurement tool, linear vs volumetric measurement, and tumor size.ConclusionsHFUS and 3D photography demonstrate excellent reliability whereas digital calipers have good to excellent reliability in measuring cNF. The MDD for each technique was used to create tables of proposed thresholds for investigators to use as guides for clinical trials focused on cNF size. These criteria should be updated as the performance of these end points is evaluated.

Objective To understand diagnostic communication preferences of patients with schwannomatosis, a rare disease. Methods Eighteen adults with schwannomatosis from across the United States participated in semi-structured phone interviews about their diagnostic experiences. Interview transcripts were inductively coded using thematic analysis. Results We identified three elements of effective diagnostic communication: education (particularly about etiology, prognosis, and treatment options); psychological support (to cope with the new diagnosis and any prior diagnostic harms); and efforts to develop therapeutic alliance (i.e. feelings of collaboration, trust, and social-emotional rapport). Poor communication was characterized by inadequate or jargon-heavy explanations, perceived disinterest in or disbelief of symptoms, and lack of partnership. Effective communication helped people feel informed and cope with their condition; poor communication could cause significant psychological distress. Conclusions During diagnosis, patients need education and psychosocial support; the presence of therapeutic alliance between clinicians and patients facilitates this assistance. Diagnostic communication that includes these elements helps patients proactively engage in healthcare decision-making and connect with appropriate treatments. Practice Implications When disclosing a rare disease diagnosis, clinicians should meaningfully educate patients about the disorder and acknowledge diagnosis-related psychosocial stressors. Approaching diagnosis empathetically and collaboratively helps foster therapeutic alliance. Referrals for psychological and genetic counseling are often warranted.

Purpose: VEGF is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase II study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma. Patients and Methods: Eighty bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A, n = 50) or pembrolizumab monotherapy (cohort B, n = 30). The primary endpoint was 6-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor programmed death-ligand 1 expression, tumor-infiltrating lymphocyte density, immune activation gene expression signature, and plasma cytokines. The neurologic assessment in neuro-oncology (NANO) scale was used to prospectively assess neurologic function. Results: Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% [95% confidence interval (CI), 16.3–41.5], median overall survival (OS) was 8.8 months (95% CI, 7.7–14.2), objective response rate (ORR) was 20%, and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI, 1.7–25.4), median OS was 10.3 months (95% CI, 8.5–12.5), and ORR was 0%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased posttherapy plasma VEGF (cohort A) and mutant IDH1, unmethylated MGMT, and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment. Conclusions: Pembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in glioblastoma immunotherapy trials.

BackgroundHypoxia is a driver of treatment resistance in glioblastoma. Antiangiogenic agents may transiently normalize blood vessels and decrease hypoxia before excessive pruning of vessels increases hypoxia. The time window of normalization is dose and time dependent. We sought to determine how VEGF blockade with bevacizumab modulates tumor vasculature and the impact that those vascular changes have on hypoxia in recurrent glioblastoma patients.MethodsWe measured tumor volume, vascular permeability (Ktrans), perfusion parameters (cerebral blood flow/volume, vessel caliber, and mean transit time), and regions of hypoxia in patients with recurrent glioblastoma before and after treatment with bevacizumab alone or with lomustine using [18F]FMISO PET-MRI. We also examined serial changes in plasma biomarkers of angiogenesis and inflammation.ResultsEleven patients were studied. The magnitude of global tumor hypoxia was variable across these 11 patients prior to treatment and it did not significantly change after bevacizumab. The hypoxic regions had an inefficient vasculature characterized by elevated cerebral blood flow/volume and increased vessel caliber. In a subset of patients, there were tumor subregions with decreased mean transit times and a decrease in hypoxia, suggesting heterogeneous improvement in vascular efficiency. Bevacizumab significantly changed known pharmacodynamic biomarkers such as plasma VEGF and PlGF.ConclusionsThe vascular signature in hypoxic tumor regions indicates a disorganized vasculature which, in most tumors, does not significantly change after bevacizumab treatment. While some tumor regions showed improved vascular efficiency following treatment, bevacizumab did not globally alter hypoxia or normalize tumor vasculature in glioblastoma.

Background Update 3 of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recognizes amplification of epidermal growth factor receptor (EGFR) as one important aberration in diffuse gliomas (World Health Organization [WHO] grade II/III). While these recommendations endorse testing, a cost-effective, clinically relevant testing paradigm is currently lacking. Here, we use real-world clinical data to propose a financially effective diagnostic test algorithm in the context of new guidelines. Methods To determine the prevalence, distribution, neuroradiographic features (Visually Accessible REMBRANDT Images [VASARI]), and prognostic relevance of EGFR amplification in lower-grade gliomas, we assembled a consecutive series of diffuse gliomas. For validation we included publicly available data from The Cancer Genome Atlas. For a cost-utility analysis we compared combined EGFR and isocitrate dehydrogenase (IDH) testing, EGFR testing based on IDH results, and no EGFR testing. Results In n = 71 WHO grade II/III gliomas, we identified EGFR amplification in 28.2%. With one exception, all EGFR amplifications occurred in IDH-wildtype gliomas. Comparison of overall survival showed that EGFR amplification denotes a significantly more aggressive subset of tumors (P 5% tumor contrast enhancement (75%, P = 0.016), and mild (not avid) enhancement (P = 0.016). The proposed testing algorithm reserves EGFR fluorescence in situ hybridization (FISH) testing for IDH-wildtype cases. Implementation would result in ~37.9% cost reduction at our institution, or about $1.3-4 million nationally. Conclusion EGFR-amplified diffuse gliomas are "glioblastoma-like" in their behavior and may represent undersampled glioblastomas, or subsets of IDH-wildtype diffuse gliomas with inherently aggressive biology. EGFR FISH after IDH testing is a financially effective and clinically relevant test algorithm for routine clinical practice.

Background Meningiomas are the most common primary brain tumor in adults, and somatic loss of the neurofibromatosis 2 (NF2) tumor suppressor gene is a frequent genetic event. There is no effective treatment for tumors that recur or continue to grow despite surgery and/or radiation. Therefore, targeted therapies that either delay tumor progression or cause tumor shrinkage are much needed. Our earlier work established mammalian target of rapamycin complex mTORC1/mTORC2 activation in NF2-deficient meningiomas. Methods High-throughput kinome analyses were performed in NF2-null human arachnoidal and meningioma cell lines to identify functional kinome changes upon NF2 loss. Immunoblotting confirmed the activation of kinases and demonstrated effectiveness of drugs to block the activation. Drugs, singly and in combination, were screened in cells for their growth inhibitory activity. Antitumor drug efficacy was tested in an orthotopic meningioma model. Results Erythropoietin-producing hepatocellular receptor tyrosine kinases (EPH RTKs), c-KIT, and Src family kinase (SFK) members, which are biological targets of dasatinib, were among the top candidates activated in NF2-null cells. Dasatinib significantly inhibited phospho-EPH receptor A2 (pEPHA2), pEPHB1, c-KIT, and Src/SFK in NF2-null cells, showing no cross-talk with mTORC1/2 signaling. Posttreatment kinome analyses showed minimal adaptive changes. While dasatinib treatment showed some activity, dual mTORC1/2 inhibitor and its combination with dasatinib elicited stronger growth inhibition in meningiomas. Conclusion Co-targeting mTORC1/2 and EPH RTK/SFK pathways could be a novel effective treatment strategy for NF2-deficient meningiomas.

Background: Three CD19 directed CAR-T products have gained FDA approval for systemic large B-cell lymphoma. Due to heightened concerns of immune cell associated neurotoxicity syndrome (ICANS), patients with primary CNS lymphoma (PCNSL) were excluded from all pivotal CAR-T studies. Consequently, all three products carry a limitation of use in the PCNSL patient population per their FDA labels . Due to these exclusions, little is known about the treatment-related toxicities and therapeutic potential of the currently available CD19 directed CAR-T products in this challenging patient population with significant unmet need. Methods: Based on our prior experience of tisagenlecleucel in secondary CNS lymphoma (PMID: 31320380) we conducted a pilot study with expansion of tisagenlecleucel in adults with relapsed or refractory PCNSL (NCT04134117). Patients had to be 18 years of age or older and have had progression or relapse following methotrexate-based therapy. All patients needed a confirmed diagnosis of PCNSL without evidence of systemic disease. Patients received a standard regimen of fludarabine (25 mg/m 2) and cyclophosphamide (250 mg/m 2) daily on days -5, -4, and -3 of infusion and a dose of 0.6-6.0 x 10 8 tisagenlecleucel CAR+ T-cells. Patients who had progressed on prior BTKi were allowed to continue given its beneficial effect on CAR-T expansion and function with cessation by month 3. The primary endpoint of this study was tolerability and toxicity including the rate and grade of CRS and ICANS per the 2019 ASTCT (American Society of Transplantation and Cellular Therapy) consensus criteria. Secondary endpoints included overall response rate and complete response rate to tisagenlecleucel per the international PCNSL Collaborative Group (IPCG) criteria which included MRI and CSF assessments. Exploratory endpoints included long-term efficacy, expansion, persistence and phenotype of tisagenlecleucel, cytokine profiling of the blood and CSF and CNS trafficking of CAR-T cells. Results: As of April 1, 2021, 10 subjects (ages 35-70 years) were enrolled and 9 were infused with a median age of 67 years (range, 34-81). Of the 9 infused patients, the median time from leukapheresis to infusion was 30 days (range, 27-37). Patients were heavily pretreated prior to study enrollment and received a median of 4 prior lines of anti-neoplastic therapy. All patients had progressed or failed first line high-dose methotrexate (HD-MTX); two had a history of prior thiotepa based autologous stem cell transplant (ASCT). Eight out of 9 patients had progressed following a prior BTKi and/or an immunomodulatory drug (IMiD) as part of TEDDI-R (temozolomide, etoposide, doxil, dexamethasone, ibrutinib and rituximab, n = 3), ViPOR (venetoclax, ibrutinib, prednisone, obinutuzumab and Revlimid, n = 3), or as monotherapy (n = 5) and 2 patients had received prior stereotactic radiotherapy. All patients had measurable disease at time of lymphodepletion (pre-infusion). Grade 1 CRS was observed in 6 patients with a median onset of 4 days (range, 1-5) following tisagenlecleucel and no patients required intervention for CRS. ICANS developed in 5 out of the 9 patients, only a single case of grade 3 ICANS, with a median time of onset was 5 days (range, 3-11). With a median follow-up of 7.43 months for survivors, 6/9 patients were alive with 4/9 showing ongoing responses (Figure 1). Expansion of tisagenlecleucel was demonstrated in the peripheral blood and CSF. Nanostring and RNA pathway analysis of CSF infiltrates demonstrated higher degrees of CNS CAR-T penetration in responding patients and increased T-cell and macrophage gene signatures. Peripheral and CSF cytokines were assessed. Conclusion: Tisagenlecleucel in r/r PCNSL was safe and efficacious in a highly refractory group of patients with significant unmet need. The majority of patients demonstrated a response per IPCG, including responses beyond 12 months. Tisagenlecleucel was found to expand in the peripheral blood and CNS with CSF gene signatures suggestive of higher CAR-T cell infiltrates in responding patients. Full trial safety data as well as additional follow-up and correlative studies will be presented. Figure 1 Figure 1. Disclosures Frigault: Editas: Consultancy; Iovance: Consultancy; Arcellx: Consultancy; Kite: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy, Research Funding; BMS: Consultancy. Dietrich: Unum: Consultancy; Blue Earth Diagnostics: Consultancy; Magnolia: Consultancy; Gamaka Bio: Consultancy; Beacon Biosignals: Research Funding; Boehringer Ingelheim: Research Funding; BMS: Research Funding; Medimmune: Research Funding; Acerta: Research Funding; Orbus: Research Funding. Jordan: CereXis: Consultancy; Recursion: Consultancy; Navio Theragnostics: Consultancy. Forst: Eli Lilly: Current holder of individual stocks in a privately-held company. Plotkin: AstraZeneca: Consultancy; Akuous: Consultancy; NFlection Therapeutics: Other: Co-founder; NF2 Therapeutics: Other: Co-founder. Spitzer: Qihan Bio: Consultancy; Bluebird Bio: Consultancy; Jazz Pharmaceuticals: Consultancy; Syneos Health: Consultancy. Defilipp: Omeros, Corp.: Consultancy; Incyte Corp.: Research Funding; Regimmune Corp.: Research Funding; Syndax Pharmaceuticals, Inc: Consultancy. Maus: Tmunity: Consultancy; Novartis: Consultancy; Micromedicine: Consultancy, Current holder of stock options in a privately-held company; Kite Pharma: Consultancy, Research Funding; GSK: Consultancy; Intellia: Consultancy; In8bio (SAB): Consultancy; CRISPR therapeutics: Consultancy; Cabaletta Bio (SAB): Consultancy; BMS: Consultancy; Bayer: Consultancy; Atara: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy; Arcellx: Consultancy; Agenus: Consultancy; Adaptimmune: Consultancy; tcr2: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; century: Current equity holder in publicly-traded company; ichnos biosciences: Consultancy, Current holder of stock options in a privately-held company; Torque: Consultancy, Current holder of stock options in a privately-held company; WindMIL: Consultancy. Chen: Gamida: Consultancy; Incyte: Consultancy.

Grade II/III meningiomas have increased rates of recurrence with no approved medical therapies. The historical progression-free survival at 6 months (PFS-6) is 25% with rates >35% declared of interest for drug development. NF2 gene inactivation occurs in about half of meningiomas. Based on our studies showing mTORC1 and mTORC2/SGK1 pathway activation in NF2-deficient meningiomas and the paradoxical activation of the mTORC2/AKT pathway, we hypothesized that mTORC1/mTORC2 inhibitors would be active in meningiomas. We studied the effect of vistusertib in patients with progressive/recurrent grade II/III meningiomas (NCT03071874). Vistusertib was administered orally at 125mg twice daily on two consecutive days each week. MRIs were obtained every 56 days. Tumor size was defined as the largest cross-sectional area. Progression was defined as ≥ 25% increase in the sum of products of all measurable lesions over smallest sum observed. The primary endpoint was PFS-6. Secondary endpoints included toxicity, radiographic response, and correlative studies including immunohistochemistry for mTORC1/2 pathway activation and genetic biomarkers. Twenty-eight patients (13 female, median age 58 years, median KPS 80%) were enrolled. Median tumor size was 4.4cm; 71% were grade II and 50% harbored pathogenic NF2 variants. Four patients discontinued treatment voluntarily and 1 each withdrew for intercurrent illness and non-compliance. PFS-6 is 47% (CI, 26%-65%) and OS-12 is 72% (95%CI, 48%-86%). PFS but not OS was shorter for patients with grade 3 meningiomas; there was no difference in PFS/OS between genetic groups. Adverse events at least possibly related to vistusertib with frequency >10% include nausea, fatigue, hypophosphatemia, diarrhea, anorexia, dry mouth, hypertriglyceridemia, hypertension, vomiting, increased ALT, constipation, and weight loss. Vistusertib treatment was associated with a PFS-6 rate exceeding the target of 35% for recurrent high-grade meningioma. Adverse events were tolerable in this patient population. These data support the continued development of mTORC1/2 inhibitors in this setting.

PURPOSE The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in brain tumor patients to complement radiographic assessment in defining overall outcome. A multicenter, phase 2 study of pembrolizumab with or without bevacizumab in patients with recurrent glioblastoma incorporated the NANO scale as an exploratory endpoint. METHODS Neurologic examination was evaluated at baseline and MRI assessments using the NANO scale until patients came off study. Statistical descriptive data analysis was performed using R (version 3.4.3). Correlation analysis utilized Fisher’s exact test. RESULTS NANO compliance rate was 94% in 80 patients accrued on the study. Of the 80 patients, 7 were missing NANO at baseline visit and were excluded from analysis for NANO response criteria. Fifteen patients did not have end of treatment NANO evaluation. Of 73 patients, 35 (48%) had a normal neurologic examination at baseline by NANO. Strength and language accounted for the majority of changes in neurologic function over the course of study treatment. Eighteen patients (25%) had neurologic progression by NANO, of whom 2 did not have concurrent radiographic progression. Three patients (pembrolizumab plus bevacizumab cohort) had a neurologic response associated with stable disease on MRI. NANO assessment prior to initiation of cycle 3 correlated with RANO response (p=0.011), change in KPS (p=0.002) and dexamethasone requirement (p=0.007) while those with NANO progression at this assessment had worse overall survival (291 vs 324 days), but this trend did not achieve statistical significance (p=0.2). CONCLUSIONS Evaluation of neurologic function by NANO scale was feasible in a multicenter prospective study in patients with GBM with a high compliance rate. The NANO scale objectively tracked stable neurologic function in most patients throughout the trial period and was associated with a trend for survival.

Background Clinical experience is limited for primary central nervous system (CNS) lymphoma that arises from the dura mater, which is denoted with the term primary dural lymphoma (PDL). This study was aimed at determining the relative incidence, presentation, and outcomes of PDL. Methods The institutional databases of the Divisions of Neuro-Oncology at the Massachusetts General Hospital and the Yale School of Medicine were retrospectively searched for patients with primary CNS lymphoma. Patients with pathologically confirmed dural lymphoma and no evidence of primary cerebral or systemic involvement were identified. Clinical data, diagnostic findings, treatments, and outcomes were recorded. Results A total of 20 patients with PDL were identified, and they represented 6.3% of the individuals with primary CNS lymphomas (20 of 316). Histopathological examination of PDL revealed the following underlying subtypes: diffuse large B-cell lymphoma (10 of 20 patients), marginal zone lymphoma (6 of 20), follicular lymphoma (2 of 20), undefined B-cell non-Hodgkin lymphoma (1 of 20), and T-cell non-Hodgkin lymphoma (1 of 20). On imaging, all tumors appeared as extra-axial masses with avid contrast enhancement and mostly mimicked meningioma. The median apparent diffusion coefficient value was 667 ± 26 mm2 /s. Cerebrospinal fluid analyses and symptoms were nonspecific, and the diagnosis rested on tissue analysis. Therapeutic approaches included surgery, radiotherapy, and chemotherapy. The median overall survival was not reached after 5 years. Three patients were deceased at database closure because of tumor progression. The extent of tumor resection correlated positively with overall survival (P = .044). Conclusions PDL is a rare variant of primary CNS lymphoma that can be radiographically mistaken for meningioma. The outcome is excellent with multimodality treatment, and aggressive surgery may convey a survival advantage in select cases.

To test the feasibility, acceptability, and preliminary efficacy of a mind–body program for patients with neurofibromatosis 2 (NF2) who are deaf or have significant hearing loss (d3RP-NF2) against an attention placebo control (dHEP-NF2) in a single-blind randomized control trial. Both were delivered using Communication Access Real-Time Translation and live group videoconferencing. Forty-five adults with NF2 were randomized. Co-primary outcomes were physical quality of life (QoL) and psychological QoL and secondary outcomes were social QoL and environmental QoL, all measured with the World Health Organization Quality of Life Abbreviated Instrument (WHOQOL-BREF). Assessments were conducted at baseline, post-treatment, and six-month follow-up. Forty-one participants (91%) completed the intervention, and 29 (64%) completed the six-month follow up. Participants in the d3RP-NF2 showed significantly greater improvements from baseline to post-treatment on physical QoL (14.79, 95% CI 5.41–24.18; p ≤ 0.001), psychological QoL (18.77, 95% CI 7.09–30.44, p ≤ 0.001), and environmental QoL (13.25, 95% CI 1.10–25.39, p = 0.03) compared to the dHEP-NF2. Social QoL also significantly increased in the d3RP-NF2 (16.32, 95% CI 6.66–25.97, p = 0.001), but improvement was not beyond the dHEP-NF2. Gains in QoL were clinically meaningful and maintained at the 6-month follow-up for d3RP-NF2 participants across all QoL domains. There were more treatment responders in the d3RP-NF2 compared to the dHEP-NF2. The d3RP-NF2 was well accepted, highly feasible, and resulted in sustained improvements in QoL in patients with NF2 who are deaf or have significant hearing loss.

WHAT WE FOUND: Length of stay and time to surgery were significantly reduced after implementation of this admission pathway. Readmission rate was not adversely affected by this change. The protocol also significantly reduced the number of unnecessary body computed tomography imaging studies obtained in this patient population. CONFOUNDING FACTORS/REAL-LIFE IMPLICATIONS: The results of this study should be interpreted with their retrospective nature in mind. Further, analysis of this admission pathway did not take into consideration patient perspective or cost implications. Finally, the authors recognize that the resources for such an operational shift may only be found in large, tertiary, referral centers. Optimized specialized care for patients with new single brain masses promotes improved health care outcomes. It may also predictively reduce health care costs and improve patient satisfaction. More research is needed in this field. Limitations to our study included the inherent limitations of a retrospective pre-post design that can make it difficult to separate the effect of a specific intervention from other factors that change over time. In addition, assessment of patient satisfaction, use of diagnostic tests beyond body imaging, and advanced cost analysis could have strengthened this study. Lastly, it should be noted that the applicability of our approach may be limited to major tertiary centers with enough resources to implement such a pathway.

Chimeric antigen receptor (CAR) T cells have emerged as a promising class of cell-based immunotherapy in refractory malignancies. Neurotoxicity represents a common and potentially life-threatening adverse effect of CAR T cells, and clinical experience is limited. Here, we describe the clinical presentation and management of 25 adult patients who presented with neurotoxic syndromes after CAR T-cell therapy at the Massachusetts General Hospital. This cohort includes 24 patients treated with CD19-directed CAR T cells for non-Hodgkin lymphoma (n = 23) and acute lymphoblastic leukemia (n = 1), and 1 patient treated with α-fetoprotein–directed CAR T cells for hepatocellular carcinoma (n = 1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and 13 patients (52%) presented with grade 3-4 neurotoxicity. We found that lower platelet counts at time of CAR T-cell infusion were associated with more severe neurotoxicity (P = .030). Cytokine release syndrome occurred in 24 of 25 patients (96%). Serum levels of ferritin peaked with onset of neurologic symptoms, and higher ferritin levels were associated with higher neurotoxicity grade. Grade 3-4 neurotoxicity correlated negatively with overall survival (OS) (P = .013). Median OS of the entire cohort was 54.7 weeks. Eight patients (32%) with grade 3-4 neurotoxicity were deceased at database closure, whereas none died with neurotoxicity grade 1-2. High pretreatment lactate dehydrogenase was frequently encountered in lymphoma patients with grade 3-4 neurotoxicity and correlated negatively with progression-free survival (P = .048). We did not find evidence that steroid use ≥7 days altered the patient’s outcome when compared with

2024 Background: Grade II/III meningiomas represent about 20% of tumors and have increased rates of recurrence with no approved medical therapies. Historically, the progression-free survival at 6 months (PFS-6) for these tumors is 25%. The Response Assessment in Neuro-Oncology (RANO) group identified a PFS-6 rate of > 35% to be of interest for trials of grade II/III meningioma. Methods : NF2 gene inactivation occurs in the majority of meningiomas and is associated with mTORC1 activation. Human studies of everolimus for neurofibromatosis 2 patients documented growth arrest in only a minority of tumors. Based on our studies showing mTORC2/SGK1 pathway activation in NF2-deficient meningiomas and the known paradoxical activation of the mTORC2/AKT pathway in meningiomas, we hypothesized that dual inhibition of mTORC1/2 would be superior in meningiomas. Treatment of primary meningioma cells with vistusertib led to decreased cell proliferation and showed greater efficacy than rapamycin, regardless of NF2 expression. We studied the effect of vistusertib in patients with progressive or recurrent grade II/III meningiomas (NCT03071874). Vistusertib was administered orally at 125mg twice daily on two consecutive days each week. MRIs were obtained every 2 cycles (1 cycle = 28 days). Tumor size was defined as the largest cross-sectional area. Progression was defined as ≥25% increase in the sum of products of all measurable lesions over smallest sum observed. The primary endpoint was PFS-6. Secondary endpoints included toxicity, radiographic response, and correlative studies including immunohistochemistry for mTORC1/2 pathway activation and genetic biomarkers. Results: Twenty-eight patients (13 female), with a median age of 58 years (range, 32 to 77 years), were enrolled in this multicenter study. The median Karnofsky performance status was 80. Twenty-five patients have been followed to six months or to tumor progression. The median duration of treatment was 6.5 month (range, 1-18 months). Four patients chose to discontinue treatment, 1 withdrew to intercurrent illness, and 1 was withdrawn due to non-compliance. PFS-6 is 51.5% (CI, 29.3% - 70.0%). Adverse events at least possibly related to vistusertib with frequency > 10% include nausea (54%); fatigue (36%); hypophosphatemia (29%); diarrhea, anorexia, dry mouth, and hypertriglyceridemia (all 14%); hypertension, vomiting, increased ALT, constipation, and weight loss (all 11%). Conclusions: Vistusertib treatment was associated with a PFS-6 rate that exceeds the RANO target of 35% for recurrent high-grade meningioma. The follow-up data continue to mature. Adverse events were tolerable in this patient population. Correlative studies to identify biological factors that correlate with response are under way. These data support the initiation of larger randomized studies of vistusertib in this setting. Clinical trial information: NCT03071874.

The patient reported outcomes measurement information system (PROMIS) provides clinicians and researchers access to reliable, validated measures of physical, mental, and social well-being. The use of PROMIS can facilitate comparisons among clinical subpopulations and with the U.S. general population. We report on the first study using PROMIS measures in patients with neurofibromatosis (NF). Eighty-six adult patients (mean age = 44; 55% female; 87% white; 50% NF1, 41% NF2 and 9% schwannomatosis) completed a battery of PROMIS computerized adaptive tests (CATs). Across all PROMIS instruments, mean scores for each CAT were between 48.97 and 52.60, which is within ±0.5 SD of the U.S. general population norms. However, scores were distributed across a broad range for each PROMIS measure (±3 SDs). Clinically meaningful scores (defined >1 SD impairment) were observed in 20% (pain interference), 17% (pain behavior), 16% (physical function), 16% (anxiety), 16% (depression), 15% (satisfaction with social roles), 13% (fatigue), 6% (anger), and 5% (satisfaction with discretionary social activities) of the sample. All PROMIS measures were highly interrelated in bivariate analysis (P ≤ .001). There were no differences in PROMIS scores by disease type (NF1, NF2 and schwannomatosis), or self reported learning disabilities, or compared with the US population. Scores suggest a broad continuum of symptoms and functioning in patients with NF that is not affected by NF type, as well as interrelation among the physical and psychosocial domains as measured by PROMIS. PROMIS measures may be useful in clinical practice to monitor changes in symptoms and functioning over time, as well as in clinical trials to determine patient reported changes during drug and psychosocial clinical trials.

Objective: To survey US-trained graduating neurology residents who are American Academy of Neurology members, in an effort to trend perceived quality and completeness of graduate neurology education. Methods: An electronic survey was sent to all American Academy of Neurology members graduating from US neurology residency programs in the Spring of 2014. Results: Of 805 eligible respondents, 24% completed the survey. Ninety-three percent of adult neurology residents and 56% of child neurology residents reported plans to pursue fellowship training after residency. Respondents reported a desire for additional training in neurocritical care, neuro-oncology, neuromuscular diseases, botulinum toxin injection, and nerve blocks. There remains a clear deficit in business training of neurology residents, although there was notable improvement in knowledge of coding and office management compared to previous surveys. Discussion: Although there are still areas of perceived weakness in neurology training, graduating neurology residents feel generally well prepared for their chosen careers. However, most still pursue fellowship training for reasons that are little understood. In addition to certain subspecialties and procedures, practice management remains deficient in neurology training and is a point of future insecurity for most residents. Future curriculum changes should consider resident-reported gaps in knowledge, with careful consideration of improving business training.

Background and Purpose— Although neurofibromatosis type 1 (NF1) may be associated with an incompletely understood vasculopathy, relative odds of stroke in this population is not known. Methods— Using the 1998 to 2009 US Nationwide Inpatient Sample, we performed a case–control study matching cases of NF1 to controls without such a diagnosis. We then compared the odds of stroke between the 2 groups. We used multivariable logistic regression to adjust for known or suspected confounders. Results— NF1 was associated with younger mean age at the time of stroke (41 versus 48) and a lower prevalence of stroke risk factors among adult patients. Pediatric patients with NF1, however, were more likely to have hypertension. Patients with NF1 were significantly more likely to be diagnosed with any stroke (odds ratio, 1.2; P P P P Conclusions— When compared with the general population, the odds of any type of stroke are significantly increased for patients with NF1, both adult and pediatric. This risk is most notable for hemorrhagic strokes although it is also increased for ischemic strokes in children. Physicians should be aware of the increased risk of stroke in this population, and consider stroke as a potential cause of new neurological symptoms.

BACKGROUND Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are related genetic tumor predisposition syndromes caused by distinct germline pathogenic variants on chromosome 22. Both conditions are characterized by the presence of cranial, peripheral, and/or spinal nerve schwannomas. The long-term growth behavior of schwannomas is unknown but knowledge thereof would help guide patient surveillance and selection for treatment and improvement of clinical trial design. Whole-body MRI (WBMRI) can detect whole-body schwannoma burden in a single image acquisition session. METHODS 12 NF2 and 10 SWN patients who underwent a WBMRI between 2007-2010 underwent a repeat WBMRI between 2018-2019. Schwannomas were segmented on short tau inversion recovery (STIR) sequences. Tumor volume was calculated using a three-dimensional tumor quantification software (3DQI). Tumor growth and shrinkage were defined as a volume change ≥ 20% over the entire study period. RESULTS Median time between scans was 10 years. A total of 103 schwannomas (46 NF2-associated, 57 SWN-associated) were analyzed. In both NF2 and SWN, 50% of tumors grew. Median growth was 88.3% in NF2 and 100.4% in SWN. All growing NF2-associated schwannomas grew in the setting of exposure to systemic therapy whereas only one growing SWN-associated tumor had been treated systemically. Excluding resected tumors, 19.4% of schwannomas shrank. Median shrinkage was 48.5% in NF2 and 37.4% in SWN. All shrinking NF2-associated tumors had been treated with systemic therapy whereas none of the shrinking SWN-associated tumors had been. 19 new tumors (7 NF2-associated, 12 SWN-associated) developed in 8 patients. CONCLUSIONS Half of NF2- and SWN-associated schwannomas grow significantly over a decade. In NF2 patients, growth occurs despite systemic treatment whereas, in SWN patients, schwannomas may shrink spontaneously without treatment. These findings may suggest a more aggressive tumor phenotype in NF2. Continued patient enrollment and correlation of MRI findings with functional outcomes and hormone exposure history are ongoing.

2546 Background: Glioblastoma and tumor endothelial cells express phosphatidylserine (PS), a highly immunosuppressive membrane phospholipid. Bavituximab – a chimeric monoclonal antibody – binds to β2-glycoprotein 1 (β2-GP1) to form a complex of β2-GP1 with PS, resulting in immune activation against tumor cells and anti-angiogenic effects. Phase I/II trials in other solid cancers demonstrated response rates up to 75% when bavituximab was given with cytotoxic chemotherapy. Pre-clinical data in glioblastoma models suggested synergistic effects of PS blockade, radiation, and temozolomide. Methods: 33 adult patients with IDH-wild-type, MGMT-methylated or -unmethylated newly diagnosed glioblastoma were enrolled in this phase II trial (NCT03139916) and received 6 weeks of chemoradiation, followed by 6 cycles of adjuvant temozolomide (C1-C6 aTMZ). Bavituximab (3 mg/kg) was given weekly, starting week 1 of chemoradiation, for 18 weeks with the option to continue if tolerated. Physiologic MRIs were performed pre-treatment, pre-C1, pre-C3, and pre-C5 aTMZ. Within the enhancing tumor region, median tumor Ktrans (reflecting vascular permeability) and relative cerebral blood flow (rCBF) were measured. Median percent changes during treatment were compared to pre-treatment values. Results: Median progression-free survival (mPFS) was 8 months. Based on a median overall survival (mOS) of 17.1 months, patients were categorized into above-median survivors (AMS) and below-median survivors (BMS). All patients had pre-treatment scans. 31 had evaluable pre-C1, 25 had pre-C3, and 7 had pre-C5 scans. Compared to BMS, AMS had a greater reuction in enhancing tumor volume and rCBF, and a greater increase in Ktrans during treatment (table). One patient remains on study; 23 patients have died. Bavituximab was well tolerated. Conclusions: mPFS and mOS in patients treated with bavituximab, radiation and temozolomide were comparable to standard chemoradiation and aTMZ. Lower rCBF in AMS may reflect decreased tumor perfusion while higher Ktrans could imply enhanced drug delivery to the tumor. Bavituximab induces changes in tumor vasculature that may improve survival in a subset of patients. Clinical trial information: NCT03139916 . [Table: see text]

BACKGROUND: Telehealth allows for evaluation and management to be delivered over long distances, which may particularly benefit patients with rare neurological diseases. METHODS: We performed a retrospective cohort study of patients receiving telehealth-based care in our NF clinic, and used ArcGIS to calculate driving distance and time from patients home to clinic. RESULTS: 109 patients (70 female, median age: 37 years) had telehealth visits from May 2016-March 2018, eighteen (17%) of whom had multiple telehealth visits. Patient diagnosis was 33% NF1, 42% NF2, 8% Schwannomatosis, and 17% other, compared to our clinic population of 58% NF1, 31% NF2, 6% Schwannomatosis and 5% other. Only 7 patients (6%) were pediatric, compared to 15% pediatric population in our NF clinic. Telehealth visit indication was 62% routine follow up, 26% new test result follow up, 6% evaluation of a new problem, and 6% on-therapy follow up. The plan developed by telehealth visits included 24% new radiology ordered, 7% new medication ordered, 18% new specialty consultation ordered, and 51% no change in previous plan. Telehealth saved patients a median round trip drive of 108 miles (IQR 388 miles) and a median driving time of 170 minutes (IQR 292 minutes). CONCLUSIONS: Telehealth improved NF specialty care through more accessible routine follow up, and urgent evaluation of new symptoms in 6% of patients. Telehealth visits led to new testing, referrals, or medications in 49% of cases, showing that telehealth fulfills a distinct need for services while saving patients time and travel. Adult patients were overrepresented among telehealth cases compared to our general clinic volume, suggesting that in-person examination of children may be preferred by NF providers or families. Given difficulties in access to specialty care, telehealth offers an opportunity to extend care for patients with rare neurological diseases who live at a distance from specialty centers.

Meningiomas (MN), the most common adult primary intracranial tumor, arise from the arachnoid/meninges and are non-responsive to chemotherapies with a high recurrence rate despite surgery, necessitating effective non-invasive therapies. Our previous work showed that NF2 loss activates mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2 signaling, which led to past NF2 clinical trials using rapalogs (RAD001/everolimus), and current meningioma clinical trials with dual mTORC1/mTORC2 inhibitor (mTORi) AZD2014. To understand additional dysregulated, potentially druggable pathways, we undertook an ‘omics approach of large-scale kinomics and RNA-sequencing employing CRISPR-modified human arachnoidal cells (ACs), NF2-expressing vs NF2-null. In NF2-null ACs, several kinases were elevated including erythropoietin-producing hepatocellular (EPH)-receptor tyrosine kinase (RTK) family members, Src family kinase (SFK) members, and c-KIT, all targets of dasatinib. In vitro treatment of MN cells using mTORi (AZD2014 or INK128) and dasatinib enhanced growth inhibition upon combination mTORi+dasatinib. In vivo treatment of an orthotopic mouse MN model showed moderate response to dasatinib with stronger response using INK128 or INK128+dasatinib (e-published in Neuro-Oncology). Our transcriptomic data also revealed increased expression of several ligands/growth factors, particularly NRG1/neuregulin. Expanding these results, we have confirmed increased expression of NRG1 in human NF2-null ACs. We also find NF2-null ACs secrete NRG1, and in conditioned-media experiments we observe stimulation of ErbB3, EPHA2 and mTOR pathways, suggesting an autocrine signaling mechanism. NF2-null AC or MN cells, when stimulated with exogenous NRG1, show enhanced activation of mTOR and EPH pathways besides ErbB3 signaling. Further, lapatinib (multi-ErbB inhibitor) but not erlotinib (EGFR inhibitor) attenuates the NRG1-stimulated activation of ErbB3, EPHA2 and mTOR, suggesting that NRG1-induced activation is EGFR-independent. Taken together, our results support a mechanistic link where NF2 loss increases NRG1/ErbB signaling to EPH/SFK and mTOR pathways, which may be a critical driver of tumorigenesis, thus providing a therapeutic opportunity to co-target these pathways in NF2-deficient meningiomas.

Background: Neurofibromatoses (NF) are rare genetic conditions associated with substantial psychosocial burden and impaired quality of life (QoL). We developed the first NF-tailored mind-body program (the Relaxation Response Resiliency Program for NF) and adapted it for delivery via live videoconferencing to decrease participation barriers and increase its reach. In a pilot randomized controlled trial (RCT), we found that the Relaxation Response Resiliency Program for NF had excellent feasibility and acceptability when delivered via live videoconferencing; furthermore, the Relaxation Response Resiliency Program for NF showed proof of concept in improving QoL compared with an NF-tailored health education control program (the Health Enhancement Program for NF). A fully powered trial is needed to ascertain the efficacy and durability of the Relaxation Response Resiliency Program for NF delivered via secure live videoconferencing among geographically diverse patients. Objective: The objective of this study is to evaluate the efficacy of the Relaxation Response Resiliency Program for NF versus the Health Enhancement Program for NF, both delivered in groups via secure live videoconferencing, among geographically diverse patients with NF across the United States and internationally. Here we describe the protocol, manualized treatments, evaluation plan, and study design. Methods: This is a single-blind RCT. Patients are told that they will be randomized to one of the two stress management programs (stress management program 1: the Relaxation Response Resiliency Program for NF and stress management program 2: the Health Enhancement Program for NF). Patients are recruited from NF-specific national and international foundations and NF clinics across the United States through study ads and a video of participants who have completed the program as part of the pilot study or ongoing trial. Interested participants are screened for eligibility via secure live videoconferencing (self-reported stress and difficulties coping, no change in antidepressant medication within the past 3 months, no psychotherapy within the past 3 months, no major upcoming surgeries within the next 12 months, English speaking, and able to complete questionnaires online and participate in live video interventions) and consent obtained before participation. Both programs are manualized comprising 8 sessions delivered via secure live videoconferencing by trained clinical psychologists. Primary outcomes are physical health QoL and psychological health QoL. Secondary outcomes are social relationship QoL, environment QoL, and psychosocial and resiliency variables. Outcomes are assessed at baseline, posttraining, and 6- and 12-month follow-ups. Results: The trial is ongoing. Thus far, we have recruited 55 patients and aim to recruit a total of 224. Recruitment will close in May 2020; we plan to complete data analyses by June 2021. Conclusions: This trial will answer key questions about the efficacy and durability of the Relaxation Response Resiliency Program for NF via live videoconferencing with English-speaking adults with NF worldwide. If found efficacious, this program can be readily implemented through national and international NF foundations and NF-specific clinics. The virtual model of delivery has extensive applications for patients in rural areas, those with disability or illness that precludes travel to clinics, and those with rare diseases. Trial Registration: ClinicalTrials.gov NCT03406208; https://clinicaltrials.gov/ct2/show/NCT03406208 (Archived by WebCite at http://www.webcitation.org/72ZoTDQ6h) International Registered Report Identifier (IRRID): RR1-10.2196/11008

Aggressive neurosurgical resection to achieve sustained local control is essential for prolonging survival in patients with lower-grade glioma. However, progression in many of these patients is characterized by local regrowth. Most lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations, which sensitize to metabolism-altering agents. To improve local control of IDH mutant gliomas while avoiding systemic toxicity associated with metabolic therapies, we developed a precision intraoperative treatment that couples a rapid multiplexed genotyping tool with a sustained release microparticle (MP) drug delivery system containing an IDH-directed nicotinamide phosphoribosyltransferase (NAMPT) inhibitor (GMX-1778). We validated our genetic diagnostic tool on clinically annotated tumor specimens. GMX-1778 MPs showed mutant IDH genotype-specific toxicity in vitro and in vivo, inducing regression of orthotopic IDH mutant glioma murine models. Our strategy enables immediate intraoperative genotyping and local application of a genotype-specific treatment in surgical scenarios where local tumor control is paramount and systemic toxicity is therapeutically limiting.

Meningiomas are the most common primary intracranial tumor in adults. With schwannomas, these tumors account for almost all intracranial benign tumors. Despite the benign histologic nature, patients suffer from neurologic symptoms and require treatment. Surgery remains the primary treatment for many such tumors, though radiation may be used either as a primary treatment or, commonly, for surgically inaccessible or recurrent lesions. The epidemiology, risk factors, and current data for local and systemic therapy options are reviewed. Active areas of research include exploration of the genetic landscape, identification of signaling pathway aberrations, and investigation of targeted systemic therapies.

Schwannomatosis has been linked to germline mutations in the SMARCB1 and LZTR1 genes, and is frequently associated with pain. In a cohort study, we assessed the mutation status of 37 patients with clinically diagnosed schwannomatosis and compared to clinical data, whole body MRI (WBMRI), visual analog pain scale, and Short Form 36 (SF-36) bodily pain subscale. We identified a germline mutation in LZTR1 in 5 patients (13.5%) and SMARCB1 in 15 patients (40.5%), but found no germline mutation in 17 patients (45.9%). Peripheral schwannomas were detected in 3 LZTR1-mutant (60%) and 10 SMARCB1-mutant subjects (66.7%). Among those with peripheral tumors, the median tumor number was 4 in the LZTR1 group (median total body tumor volume 30 cc) and 10 in the SMARCB1 group (median volume 85cc), (P=.2915 for tumor number and P = .2289 for volume). mutation was associated with an increased prevalence of spinal schwannomas (100% vs 41%, P = .0197). The median pain score was 3.9/10 in the LZTR1 group and 0.5/10 in the SMARCB1 group (P = .0414), and SF-36 pain-associated quality of life was significantly worse in the LZTR1 group (P = .0106). Pain scores correlated with total body tumor volume (rho = 0.32471, P = .0499), but not with number of tumors (rho = 0.23065, P = .1696). We found no significant difference in quantitative tumor burden between mutational groups, but spinal schwannomas were more common in LZTR1-mutant patients. Pain was significantly higher in LZTR1-mutant than in SMARCB1-mutant patients, though spinal tumor location did not significantly correlate with pain. This suggests a possible genetic association with schwannomatosis-associated pain.

Background Our primary aim was to assess the ability of a non-profit foundation-sponsored clinic network to facilitate access to specialized care for patients with neurofibromatoses (NF), a group of neurogenetic disorders including NF1, NF2, and schwannomatosis (SWN). Our secondary aim was to identify how our findings in NF could be applied more broadly to other rare diseases. Methods We retrospectively reviewed aggregate data on patient volume reported by specialty NF clinics in a nonprofit network from 2008 to 2015. We classified clinics as high or low volume for disease type (NF1 and NF2/schwannomatosis) and pediatric/adult care. We compared clinic-level data to self-reported patient-level data from a large online patient registry. Results Between 2008 and 2015, the number of certified NF clinics grew from 32 to 50, and annual patient volume rose from 6776 to 10,245 patients (13% of the total estimated U.S. NF patient population). For patient registry participants (n = 4476), the median driving distance to the nearest network clinic was 51.3 miles. Driving distances to reach high-volume centers were elevated for adults compared to children (295.8 vs. 67.9 miles), and schwannomatosis and NF2 patients compared to NF1 patients (310.9 vs. 368.1 vs. 161.7 miles). Of registry participants reporting their location of care (n = 2271), only 43.2% received care in a network specialty clinic, with especially low rates of attendance in the Southwest and Far West. Conclusions While the number of certified NF clinics and volume of patients seen in these clinics has increased, many NF patients still do not attend specialty clinics and/or travel a significant distance for care. Geographic access to care is more limited for adults, patients with rarer conditions, and patients in the Western U.S. Potential measures to improve access to specialty care for people living with NF and other rare diseases are discussed.

Background Despite recommendations from professional organizations supporting early hospice enrollment for patients with cancer, little research exists regarding end-of-life (EOL) practices for patients with malignant glioma (MG). We evaluated rates and correlates of hospice enrollment and hospice length of stay (LOS) among patients with MG. Methods Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database, we identified adult patients who were diagnosed with MG from January 1, 2002 to December 31, 2011 and who died before December 31, 2012. We extracted sociodemographic and clinical data and used univariate logistic regression analyses to compare characteristics of hospice recipients versus nonrecipients. We performed multivariable logistic regression analyses to examine predictors of hospice enrollment >3 or >7 days prior to death. Results We identified 12437 eligible patients (46% female), of whom 7849 (63%) were enrolled in hospice before death. On multivariable regression analysis, older age, female sex, higher level of education, white race, and lower median household income predicted hospice enrollment. Of those enrolled in hospice, 6996 (89%) were enrolled for >3 days, and 6047 (77%) were enrolled for >7 days. Older age, female sex, and urban residence were predictors of longer LOS (3- or 7-day minimum) on multivariable analysis. Median LOS on hospice for all enrolled patients was 21 days (interquartile range, 8-45 days). Conclusions We identified important disparities in hospice utilization among patients with MG, with differences by race, sex, age, level of education, and rural versus urban residence. Further investigation of these barriers to earlier and more widespread hospice utilization is needed.

Background Due to the decreasing prevalence of IDH1 mutations in older patients, the 2016 World Health Organization (WHO) classification of brain tumors proposed not to perform sequencing for isocitrate dehydrogenase (IDH) in glioblastoma patients ≥55 years old. We present a cost-effectiveness analysis to estimate the financial impact of these guidelines. Methods From 2010 to 2015 we performed 1023 IDH tests in gliomas, amounting to ~$1.09 million in direct laboratory test costs. Samples were tested using R132H-specific immunohistochemistry, DNA sequencing validated for detection of noncanonical IDH1/2 mutations, or both methods. Results In cases tested by DNA sequencing, the fraction of non-R132H mutations was 5.4%, which included only 2 high-grade gliomas in patients ≥55 years (0.9%). When remodeling the optimal age cutoff in our patient population using 5-year age-binning, we found a 10-times higher pretest probability for the presence of a noncanonical IDH1 mutation in the setting of a negative IDH1-R132H immunohistochemistry result in patients

Background Treatment of aggressive pituitary adenomas typically involves a multimodality approach based on histopathological features and may include pharmacotherapy, surgery, and occasionally radiation therapy. In cases of treatment-refractory tumor progression, chemotherapy may be considered; however, no standard chemotherapeutic regimen has been established. Literature review suggests that temozolomide may have a beneficial role in a subset of cases. To understand the efficacy of temozolomide in progressive pituitary tumors, we reviewed the outcomes of cases at our center. Methods We performed a retrospective chart review to report the outcome and unique features of 7 patients with aggressive functioning pituitary adenomas or carcinomas treated with temozolomide. Tumor pathology included somatotroph (n = 1), corticotroph (n = 3), and lactotroph (n = 3) tumors. Results Four of the 7 patients had at least 2 prior resections, and all had prior radiation and surgery before treatment with temozolomide. Notably, all patients showed response to therapy, defined as either stable disease (43%) or partial response (57%). Median progression-free survival was 1.66 years, and median overall survival was 4 years. Conclusion Our data suggest that temozolomide has an important role in the management of aggressive functioning pituitary tumors that are resistant to standard therapies, and that optimization of therapy with temozolomide may involve individualized regimens. Future prospective clinical trials should be considered.

Determining health literacy level is an important prerequisite for effective patient education. We assessed multiple dimensions of health literacy and sociodemographic predictors of health literacy in patients with neurofibromatosis. In 86 individuals with a confirmed diagnosis of neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), or schwannomatosis, we assessed health literacy status using two HL tools-the adapted functional, communicative, and critical health literacy scale (adapted FCCHL) and health literacy assessment using talking touchscreen technology (Health LiTT). Factor analyses of the adapted FCCHL in NF patients showed factor structure and psychometric properties similar to pilot work in other patient populations. As a group, patients with NF had moderate scores on the Health LiTT and moderate to high scores on the adapted FCCHL, with the highest score on the functional health literacy subscale. Patients with NF1, those with lower education and those with learning disabilities had lower scores on Health LiTT; in multivariate analysis, learning disability and education remained significant predictors of HealthLiTT scores. Only lower education was associated with lower adapted FCCHL scores. Results suggest utilizing health literacy tools in NF patients is feasible and could provide physicians with valuable information to tailor health communication to subpopulations with lower health literacy levels.

Anti-angiogenic therapy for glioblastoma has been in the spotlight for several years, as researchers and clinicians strive to find agents with meaningful efficacy against glioblastoma. Bevacizumab in particular, in the second half of the last decade, became the most significant breakthrough in anti-glioblastoma therapy since temozolomide. Optimism for bevacizumab has been somewhat challenged given recent clinical trials that have raised questions regarding its clinical effectiveness, the optimal timing of its use and the validity of endpoints, among other issues. In addition, uncertainty has recently arisen regarding the effects of bevacizumab on quality of life and neurocognitive function, two key clinical endpoints of unquestionable significance among glioblastoma patients. In this review, we highlight these controversies and other recent work related to bevacizumab for glioblastoma.

A 62-year-old previously healthy man was diagnosed with a deep vein thrombosis, a suspicious nevus, and macrocytic anemia. Otherwise, his hematogram and coagulation indices were normal. His vitamin B12 level was 52 pg/mL (reference 211–911 pg/mL), iron level was 58 mcg/dL (reference 59–158 mcg/dL), and folate level was normal. His nevus pathology revealed an in situ melanoma. Assuming his anemia and hypercoagulable state were related to newfound melanoma, and given his lack of neurologic complaints, his physician regarded the vitamin B12 level as incidental and asymptomatic. He went home on anticoagulation and iron supplementation.

BACKGROUND Neurofibromas affect 40–50% of neurofibromatosis type 1 (NF1) patients and can cause significant morbidity and mortality. They grow more rapidly during childhood and adolescence but studies in adults are limited by their retrospective nature and follow-up time < 3 years. The long-term natural history of neurofibromas remains unknown. No guidelines exist on the need and frequency of surveillance imaging for patients. Whole-body MRI (WBMRI) can detect whole-body tumor burden, including internal neurofibromas. METHODS 17 adult NF1 patients who underwent WBMRI between 2007–2010 (Scan 1) underwent repeat WBMRI between 2018–2019 (Scan 2). Internal neurofibromas were segmented on short tau inversion recovery (STIR) sequences and tumor volume was calculated using a computerized volumetry and three-dimensional segmentation software. Circumscribed tumors were defined as discrete; invasive tumors or those involving multiple nerves were defined as plexiform. Tumor growth and shrinkage were defined as volume change ≥ 20% over the entire study period. RESULTS Median patient age was 43 years during Scan 1 and 53 years during Scan 2. Median time between Scan 1 and 2 was 9 years. A total of 140 neurofibromas were assessed. 24% of tumors grew by a median 63% (6.8% per year). 54% of tumors spontaneously decreased in volume by a median 60% (7% per year) without treatment. On a per-patient basis, 18% of patients had overall tumor growth and 41% overall tumor shrinkage. 8 new tumors developed in 7 patients. 16 tumors resolved entirely without medical or surgical intervention. Growth behavior did not correlate with discrete or plexiform morphology. CONCLUSION A subset of internal neurofibromas in adult NF1 patients grow significantly over a long-term period, suggesting that continued monitoring of these patients may be warranted. Surprisingly, more than half of neurofibromas shrink spontaneously without intervention. Continued patient enrollment and correlation of imaging findings with functional outcomes are underway.

Introduction:Treatment of aggressive pituitary adenomas typically involves a multimodality approach based on histopathological features and may include pharmacotherapy, surgery and radiation therapy. In cases of treatment-refractory tumor progression, chemotherapy may be considered. However, no standard chemotherapeutic regimen has been established. Anecdotal reports suggest that temozolomide may have a beneficial role in a subset of cases.Materials and Methods:In this case series and institutional experience we report the outcome and unique clinical characteristics of seven patients with aggressive pituitary tumors treated with temozolomide given at various dose regimens.Results:Tumor pathology included somatotrope (n=1), corticotrope (n=3), and lactotrope (n=3) tumors. Four of the seven patients had at least two prior resections, and all had prior radiation and surgery before treatment with temozolomide was considered. Notably, all patients showed response to therapy, defined as either stable disease (43%) or partial response (57%), using standard tumor response assessment parameters. Excluding the two patients who remain on therapy to date, total duration of therapeutic benefit ranged between 5–15 months. Three patients showed radiographic and clinical benefit beyond one year.Conclusions:Our data suggest that temozolomide may have an important role in the management of aggressive functioning pituitary tumors that are resistant to standard therapies, and that optimization of therapy with temozolomide may involve individualized regimens. Future prospective clinical trials should be considered.

Imaging the central nervous system is an important facet of diagnosing paraneoplastic neurological disorders. Many such disorders have characteristic imaging findings. However, even in syndromes without corollary imaging abnormalities, exclusion of additional or alternative diagnoses by neuraxis imaging is prudent. Here, we discuss the most commonly associated imaging abnormalities in such cases, as well as information on differentiation from common mimicking disorders. We also discuss imaging of the body for identification of a primary tumor in patients with suspected paraneoplastic disorders, including data for the most sensitive imaging modality.

Schwannomatosis is a tumor suppressor syndrome that causes multiple tumors along peripheral nerves. Formal diagnostic criteria were first published in 2005. Variability in clinical presentation and a relative lack of awareness of the syndrome have contributed to difficulty recognizing affected individuals and accurately describing the natural history of the disorder. Many critical questions such as the mutations underlying schwannomatosis, genotype-phenotype correlations, inheritance patterns, pathologic diagnosis of schwannomatosis-associated schwannomas, tumor burden in schwannomatosis, the incidence of malignancy, and the effectiveness of current, or new treatments remain unanswered. A well-curated registry of schwannomatosis patients is needed to facilitate research in field. An international consortium of clinicians and scientists across multiple disciplines with expertise in schwannomatosis was established and charged with the task of designing and populating a schwannomatosis patient registry. The International Schwannomatosis Registry (ISR) was built around key data points that allow confirmation of the diagnosis and identification of potential research subjects to advance research to further the knowledge base for schwannomatosis. A registry with 389 participants enrolled to date has been established. Twenty-three additional subjects are pending review. A formal process has been established for scientific investigators to propose research projects, identify eligible subjects, and seek collaborators from ISR sites. Research collaborations have been created using the information collected by the registry and are currently being conducted. The ISR is a platform from which multiple research endeavors can be launched, facilitating connections between affected individuals interested in participating in research and researchers actively investigating a variety of aspects of schwannomatosis. © 2016 Wiley Periodicals, Inc.