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Background People with NF1 have an increased prevalence of central nervous system malignancy. However, little is known about the clinical course or pathologic features of NF1-associated gliomas in adults, limiting clinical care and research. Methods Adults (≥18 years) with NF1 and histologically confirmed non-optic pathway gliomas (non-OPGs) at Johns Hopkins Hospital, Memorial Sloan Kettering Cancer Center, and Washington University presenting between 1990 and 2020 were identified. Retrospective data were collated, and pathology was reviewed centrally. Results Forty-five patients, comprising 23 females (51%), met eligibility criteria, with a median of age 37 (18–68 years) and performance status of 80% (30%–100%). Tissue was available for 35 patients. Diagnoses included infiltrating (low-grade) astrocytoma (9), glioblastoma (7), high-grade astrocytoma with piloid features (4), pilocytic astrocytoma (4), high-grade astrocytoma (3), WHO diagnosis not reached (4) and one each of gliosarcoma, ganglioglioma, embryonal tumor, and diffuse midline glioma. Seventy-one percent of tumors were midline and underwent biopsy only. All 27 tumors evaluated were IDH1-wild-type, independent of histology. In the 10 cases with molecular testing, the most common genetic variants were NF1, EGFR, ATRX, CDKN2A/B, TP53, TERT, and MSH2/3 mutation. While the treatments provided varied, the median overall survival was 24 months [2–267 months] across all ages, and 38.5 [18–109] months in individuals with grade 1–2 gliomas. Conclusions Non-OPGs in adults with NF1, including low-grade tumors, often have an aggressive clinical course, indicating a need to better understand the pathobiology of these NF1-associated gliomas.

BackgroundIn response to the cancellation of clinical clerkships due to COVID-19, the Johns Hopkins (JH) Neurology Education Team developed a virtual elective to enhance medical students’ clinical telemedicine skills and foster community between academic institutions.MethodsThis two-week clinical elective, entitled “Virtual Patient Rounds in Neurology,” was administered once in April 2020 and once in May 2020. The curriculum included attending/fellow-led Virtual Rounds, Student Presentations, and Asynchronous Educational Activities. We also developed a new lecture series entitledJHNeuroChats, which consisted of live synchronous lectures presented by JH faculty and Virtual Visiting Professors. Trainees and faculty from outside institutions were invited to participate in theJHNeuroChats. Students and faculty completed pre- and post-elective surveys to assess the educational impact of the elective. Student’st-tests were used to compare scores between pre- and post-elective surveys.ResultsSeven JH medical students enrolled in each iteration of the elective, and an additional 337 trainees and faculty, representing 14 different countries, registered for theJHNeuroChats. We hosted 48 uniqueJHNeuroChats, 32 (66.7%) of which were led by invited Virtual Visiting Professors. At the end of the elective, students reported increased confidence in virtually obtaining a history (P P P = 0.15).ConclusionsDespite the constraints imposed by COVID-19, this virtual Neurology elective increased medical students’ confidence in certain telemedicine skills and successfully broadened our learning community to encompass learners from around the world. As virtual medical education becomes more prevalent, it is important that we are intentional in creating opportunities for shared learning across institutions. We believe that this elective can serve as a model for these future educational collaborations.

OBJECTIVE There has been limited research on the efficacy of multidisciplinary tumor boards (MDTBs) in improving the treatment of patients with tumors affecting the nervous system. The objective of the present study was to quantify the utility of MDTBs in providing alternative diagnostic interpretations and treatment plans for this patient population. METHODS The authors performed a prospective study of patients in 4 hospitals whose cases were discussed at MDTBs between July and November 2019. Patient demographic data, diagnoses, treatment plans, and eligibility for clinical trials were recorded, among other variables. RESULTS A total of 176 cases met eligibility criteria for study inclusion. The majority (53%) of patients were male, and the mean patient age was 52 years. The most frequent diagnosis was glioblastoma (32.4%). Among the evaluable cases, MDTBs led to 38 (21.6%) changes in image interpretation and 103 (58.2%) changes in patient management. Additionally, patients whose cases were discussed at MDTBs had significantly shorter referral times than patients whose cases were not discussed (p = 0.024). CONCLUSIONS MDTB discussions led to significant numbers of diagnostic and treatment plan changes as well as shortened referral times, highlighting the potential clinical impact of multidisciplinary care for patients with nervous system tumors.

Tumor treating fields (TTF) is a unique treatment modality that utilizes alternating electric fields to deliver therapy. Treatment effects have been assessed in patients with newly diagnosed and recurrent glioblastoma in clinical trials and retrospective studies. While the results of these studies led to FDA approval for both populations, a portion of the neuro-oncology and neurosurgery community remains skeptical of TTF. Thus, this review aims to systematically summarize and evaluate prior studies investigating the efficacy and safety of TTF in patients with high-grade gliomas. A systematic review of the literature was performed according to PRISMA guidelines from database inception through February 2019. To be included, studies must have investigated the efficacy of TTF in adult high-grade glioma patients. In total, 852 studies were initially identified, 9 of which met final inclusion criteria. In total, 1191 patients were identified who received TTF. Included studies consisted of two pilot clinical trials, two randomized clinical trials, and five retrospective studies. In randomized clinical trials, TTF improved survival for newly diagnosed glioblastoma patients but not for recurrent glioblastoma patients. Adverse skin reactions were the primary adverse effect associated with TTF. While TTF has been evaluated for safety and efficacy in a number of studies, concerns remain regarding study design, quality of life, and cost of therapy. Further investigation is needed regarding the therapy, and ongoing trials are already underway to provide more data regarding therapy outcomes and interactions in combination regimens.

Background and Problem StatementMedical students on their clinical neurology clerkship often encounter ethically challenging situations, yet formal neuroethics training is limited. This study sought to evaluate a case-based small-group workshop that was implemented to introduce students to important neuroethics concepts and resources.Objectives(1) To define decision-making capacity and describe how it is assessed in neurologic illness; (2) to define the legal category of brain death and its evolution over time; (3) to describe the legal process for surrogate decision making in the state of Maryland; (4) to identify barriers to goals-of-care conversations; and (5) to reflect on how personal beliefs of patients and physicians influence delivery of care and medical decision making.Methods and Curriculum DescriptionA 1.5-hour interactive curriculum for medical students on the neurology clerkship covering ethical considerations in brain death, surrogate decision making, and navigating conversations surrounding these topics (with reference to lesbian, gay, bisexual, transgender, queer/questioning, and others' health and health disparities) was designed and implemented over 2 years. Curriculum outcomes were measured by preworkshop and postworkshop self-assessment surveys. Learner reactions were measured by self-reported interest in ethics and perceived utility of the curriculum. Content knowledge was measured through multiple-choice questions on brain death and capacity assessment, which were scored for correctness by the study team, and self-reported confidence in ethical reasoning. Changes in these metrics were analyzed for paired precourse and postcourse responses to determine the effectiveness of the session.Results and AssessmentThe study recruited 234 of 356 rotating students (65.7% response rate). Presurvey data revealed that 36% had encountered a challenging clinical scenario before the intervention. Preintervention and postintervention paired data were available for 184 (79%) respondents. Of these, 66% reported increased confidence in their knowledge of ethics, and 42% reported increased interest in ethics. Presession performance on content questions did not differ significantly based on prior clinical ethics experience. Performance on neuroethics content questions improved significantly after the session as demonstrated by the increase in the percentage of students providing correct answers to content questions between the presurvey and postsurvey (17% increase for capacity assessment, 19% increase for brain death, and 22% increase for surrogate decision making,p< 0.0001).Discussion and Lessons LearnedAn interactive neuroethics workshop using a case-based discussion format integrates ethics and health disparity education into the clinical neurology curriculum and enhanced knowledge and confidence in medical ethics. This curriculum increases student interest in ethics, confidence in their ability to perform ethical reasoning tasks, and content knowledge of brain death and surrogate decision making.

The global transcription inhibitor terameprocol is being evaluated clinically as an oral formulation to treat high-grade glioma. A sensitive, reliable method was developed to quantitate terameprocol using LC-MS/MS to perform detailed pharmacokinetic studies. Sample preparation involved protein precipitation using acetonitrile. Separation of terameprocol and the internal standard, Sorafenib-methyl-d3, was achieved with a Zorbax XDB C18 column (2.1 × 50 mm, 3.5 μm) and gradient elution over a 2-minute total analytical run time. A SCIEX 4500 or SCIEX 5500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for terameprocol detection. The assay range of 5-1,000 ng/mL was demonstrated to be accurate (92.7-107.4%) and precise (CV ≤ 11.3%). A sample diluted 1:10 (v/v) was accurately quantitated. Terameprocol in plasma has been proven stable for at least 20 months when stored at −70°C. The method was applied to the measurement of total plasma concentrations of terameprocol in a patient with a high-grade glioma receiving a 300 mg oral dose.

BACKGROUND There is limited research attempting to measure the efficacy of tumor boards (MDTBs) in the treatment of patients with tumors affecting the nervous system. OBJECTIVE The objective of the present study was to quantify the utility of a MDTB in providing alternative diagnostic interpretations and treatment plans for this patient population. METHODS A prospective study of patient cases discussed at four hospitals’ MDTBs between July and November 2019 was performed. Demographic data, diagnoses, treatment plans, and eligibility for clinical trials were recorded, among other variables. RESULTS A total of 176 patient cases met eligibility criteria. The majority of patients (53%) were male with a mean age of 52 years. The most frequent diagnosis was glioblastoma (32.4%). Among the evaluable cases, MDTBs led to 38 (21.6%) changes in image interpretation and 103 (58.2%) changes in patient management. Additionally, patients whose cases were discussed at MDTBs had significantly shorter referral times compared to patients whose cases were not discussed (p= 0.024). CONCLUSION MDTB discussions led to a significant number of diagnostic and treatment plan changes as well as shortened referral times, highlighting the potential clinical impact of multidisciplinary care for patients with nervous system tumors.

Histone mutations occur in approximately 4% of different cancer types. In 2012, mutations were found in the gene encoding histone variant H3.3 (H3F3A gene) in pediatric diffuse intrinsic pontine gliomas and pediatric hemispheric gliomas. Tumors with mutations in the H3F3A gene are generally characterized as histone mutated gliomas (HMGs) or diffuse midline gliomas. HMGs are a rare subtype of glial tumor that is malignant and fast growing, carrying a poor prognosis. In 2017, the Beau Biden Cancer Moonshot Program appropriated $1.7 billion toward cancer care in 10 select areas. The National Cancer Institute (NCI) was granted support to focus specifically on rare central nervous system (CNS) tumors through NCI-CONNECT. Its mission is to address the challenges and unmet needs in CNS cancer research and treatment by connecting patients, providers, researchers, and advocacy organizations to work in partnership. On September 27, 2018, NCI-CONNECT convened a workshop on histone mutated midline glioma, one of the 12 CNS cancers included in its initial portfolio. Three leaders in the field provided an overview of advances in histone mutated midline glioma research. These experts shared observations and experiences related to common scientific and clinical challenges in studying these tumors. Although the clinical focus of this workshop was on adult patients, one important objective was to start a collaborative dialogue between pediatric and adult clinicians and researchers. Meeting participants identified needs for diagnostic and treatment standards, disease biology and biological targets for this cancer, disease-specific trial designs, and developed a list of action items and future direction.

Tumor treating fields (TTF) is a unique treatment modality that utilizes alternating electric fields to deliver therapy. Treatment effects have been assessed in patients with newly diagnosed and recurrent glioblastoma in clinical trials and retrospective studies. While the results of these studies led to FDA approval for both populations, a portion of the neuro-oncology and neurosurgery community remains skeptical of TTF. Thus, this review aims to systematically summarize and evaluate prior studies investigating the efficacy and safety of TTF in patients with high-grade gliomas.A systematic review of the literature was performed according to PRISMA guidelines from database inception through February 2019. To be included, studies must have investigated the efficacy of TTF in adult high-grade glioma patients.In total, 852 studies were initially identified, 9 of which met final inclusion criteria. In total, 1191 patients were identified who received TTF. Included studies consisted of two pilot clinical trials, two randomized clinical trials, and five retrospective studies. In randomized clinical trials, TTF improved survival for newly diagnosed glioblastoma patients but not for recurrent glioblastoma patients. Adverse skin reactions were the primary adverse effect associated with TTF.While TTF has been evaluated for safety and efficacy in a number of studies, concerns remain regarding study design, quality of life, and cost of therapy. Further investigation is needed regarding the therapy, and ongoing trials are already underway to provide more data regarding therapy outcomes and interactions in combination regimens.

Access to healthcare in Mexico is available to its population via publicly and privately funded institutions. The public sector, administered by both the local and federal government under the jurisdiction of the Department of Health, provides healthcare to the majority of the country's population. Privately funded institutions vary in size and scope of practice, ranging from small clinics focused on family practice, to large tertiary hospitals with capacity for treating patients with complex conditions and performing clinical research. The evaluation and treatment of patients with cancer in Mexico is also available through both sectors. In the country's capital, Mexico City, patients with glioblastoma are primarily treated at the National Institute of Neurology and Neurosurgery and the National Institute of Oncology. Epidemiological data is incomplete due to the lack of a national cancer registry. In the case of neoplasms of the central nervous system, the available information suggests that gliomas represent 33% of all intracranial tumors. The treatment of patients in Mexico diagnosed with glioblastoma has not been standardized owing to the lack of resources in some communities and the expense of antineoplastic agents. Current options range from a biopsy only to maximal safe resection followed by adjuvant treatment with radiation and chemotherapy. Currently, basic science and clinical research is being conducted in academic institutions associated with universities and in private hospitals. Studies include the evaluation of tumor biology, neuroimaging biomarkers and new treatment options such as the use of chloroquine.

BACKGROUND MGMT promoter methylation is associated with longer survival in patients with high-grade gliomas who receive alkylating therapy. Methylation status is commonly determined by methylation-specific PCR and results are reported in two forms: a dichotomization of “present” or “not present,” and as a methylation score (MGMT/beta-actinx1000). The primary objective of this study is to determine the association between the degree of methylation and overall survival (OS) in newly diagnosed patients with glioblastoma. METHODS A retrospective IRB-approved study was conducted of 684 patients treated at Johns Hopkins from 2007–2015. Adults with a histologically confirmed glioblastoma treated with standard therapy were included in the analysis. OS was estimated from the date of diagnosis to time of death or last follow up using the Kaplan–Meier method. Cox regression model was used to assess possible positive association between MGMT score and OS. For purposes of this analysis IDH1-mutated patients were excluded. RESULTS In 100 evaluable patients, median age at diagnosis was 56 years [45–77]. Fifty-two patients were MGMT promoter methylated (score ≥2.00) and 48 were unmethylated. The median OS was 31 months in the methylated patients and 15 months in the unmethylated (p=0.0001). Methylated patients had MGMT scores ranging from 2.53-1278. The methylated scores were classified into 3 groups; #1: 0-25th percentile, #2: 25-75th percentiles, and #3: >75th percentile. mOS was: 30.8 months for group 1 (n=13); 34.8 months for group 2 (n=27); and 20.9 months for group 3 (n=12) (p=0.19). Difference in mOS between groups 1 and 3 was not statistically significant (HR 0.819 [95% CI, 0.3–2.2], p=0.69). DISCUSSION The prognostic value of MGMT promoter methylation in patients with glioblastoma was replicated in our study sample. The degree of methylation reported as a score on routine testing does not appear to be directly related to OS in this patient population.

BACKGROUND Neurofibromatosis type 1 (NF1) is caused by mutations of the tumor suppressor gene NF1 resulting in decreased levels of neurofibromin and dysregulation of the RAS pathway, including MEK/ERK upregulation. Central nervous system malignancies have an overall standardized incidence ratio of 37.5 in population studies, with higher rates of aggressive gliomas in adults with NF1. Further, the response to standard glioma therapies in this population is mixed in published series. MEK1/2 inhibitors have shown activity in both NF1 driven plexiform neurofibromas and low grade gliomas, however, data is lacking about their optimal dose or sequencing relative to standard glioma therapies for adults with NF1 associated aggressive gliomas. We present recent experiences with the MEK1/2 inhibitor trametinib in adults with NF1 and newly diagnosed aggressive gliomas. METHODS A retrospective chart review was conducted on all adult patients with NF1 and astrocytoma treated with trametinib at the Johns Hopkins Brain Cancer Program from 2016 to 2018. RESULTS Four patients met selection criteria. Median age at diagnosis was 37 years [25–43]. Histologic diagnoses were: pilocytic astrocytoma (1), diffuse astrocytomas (2), and anaplastic astrocytoma (1). All tumors were IDH1 wild-type. Three received trametinib as frontline therapy (2 mg daily), one as second line treatment. All achieved a partial radiographic response within 2 months from the start of trametinib. Median overall survival was 15 months [4–19]; three patients are alive at publication, with a median of 12 months from diagnosis. Median progression-free survival was 2.5 months [1–11]. CONCLUSIONS Astrocytomas in adults with NF1, including histologically low-grade tumors, often have a more aggressive course than suggested by histology. These cases demonstrate clinical benefit from single agent MEK inhibition as well as possible synergistic effects with conventional therapies for gliomas in people with NF1, however, prospective investigation is needed.

e13562 Background: Neurofibromatosis type 1 (NF1) is caused by mutations of the tumor suppressor gene NF1 resulting in decreased levels of neurofibromin and dysregulation of the RAS pathway, including MEK/ERK upregulation. NF1 is characterized by multiple benign and malignant tumors. Central nervous system tumors have an overall standardized incidence ratio of 37.5 in population studies with high rates of aggressive gliomas in adults with NF1. The response to standard glioma therapies is mixed. MEK1/2 inhibitors have shown activity in NF1 driven plexiform neurofibromas and low grade gliomas, however, data is lacking about the optimal dose or sequencing of MEK1/2 inhibitors for adults with NF1 associated aggressive gliomas. We present recent experiences with the MEK1/2 inhibitor trametinib in adults with NF1 and aggressive gliomas. Methods: A retrospective chart review was conducted on all adult patients with NF1 and astrocytoma treated with trametinib at the Johns Hopkins Brain Cancer Program between 2016-2018. Results: Three patients met selection criteria. Two received trametinib as initial therapy (2 mg daily). All developed an acneiform rash; one had transient transaminitis requiring temporary discontinuation and subsequent dose reductions. Clinical benefit was achieved associated with two partial radiographic responses. Conclusions: Astrocytomas in adults with NF1 often have a more aggressive course than suggested by histology. The cases presented here demonstrate clinical benefit from single agent MEK inhibition as well as possible synergistic effects with conventional therapies for gliomas in this patient population. These observations highlight the need for further research in this area. [Table: see text]

e13590 Background: As the treatment of non-central nervous system (CNS) malignancies improves, brain metastases (BM) are occurring more often in patients with controlled primary disease. In a retrospective analysis of 1953 patients with BM, 44.7% had a controlled primary tumor at the time of BM diagnosis. Given that prognosis after BM remains dismal, it is necessary to identify groups who might benefit from improved delivery of initial systemic therapy across the blood brain barrier (BBB). Methods: A retrospective literature review was conducted to estimate the proportion of patients with non-small cell lung cancer (NSCLC), breast cancer, and melanoma treated with chemotherapy in whom BM was the initial site of recurrence. Only studies explicitly reporting CNS metastasis with controlled extra-cranial (EC) disease on chemotherapy or reporting the first site of recurrence after chemotherapy were included. Results: Four studies of advanced NSCLC reported an average of 23% of patients who developed BM as an initial site of recurrence. Breast cancer cases varied by subtype with a range of 4 - 19%. In four papers reporting HER-2 status, an average of 14% of patients treated with traztuzumab had CNS metastasis with controlled EC disease. In three papers assessing patients with metastatic melanoma on chemotherapy, 4 – 25% initially progressed in the CNS. Conclusions: Of the 1024 patients treated with chemotherapy and achieving controlled systemic disease in this retrospective review, first recurrence in the brain was common: 23% in NSCLC, 12% in breast cancer, and 12% in melanoma. While chemotherapy controlled non-CNS disease, concentrations of these drugs were clearly subtherapeutic in the CNS. Preventing BM in patients with NSCLC, breast cancer, and melanoma will require novel therapeutic approaches designed to facilitate drug entry through an intact BBB early in the treatment of the primary tumor. [Table: see text]

e13530 Background: Standard therapy for patients with newly diagnosed glioblastoma (GBM) includes concurrent temozolomide (TMZ) and radiation (RT) followed by six monthly cycles of adjuvant TMZ. Although TMZ improves survival for MGMT methylated patients, it is unclear if this benefit is from the TMZ given with the radiation, the adjuvant TMZ, or if both are required. This retrospective study was designed to identify MGMT methylated patients who started treatment with near-normal functional status, completed concurrent RT+TMZ, but did not receive adjuvant TMZ to estimate if their survival was significantly less than expected. Methods: We reviewed charts from 190 adults diagnosed with GBM at Johns Hopkins Hospital from 2013 to 2015 recording their Karnofsky Performance Score (KPS), extent of resection, MGMT-methylation and IDH1 mutation status, and treatment records. We selected patients with MGMT-methylated GBM who received concurrent RT+TMZ without adjuvant TMZ for this study. Patients with a KPS < 70 or severe post-radiation complications were excluded. Results: Six patients met the selection criteria. They had a median age of 65 years, average KPS of 80, 2/6 had a gross total resection, and all were IDH1 wildtype. Their overall survival ranged from 17 to > 46 months. Conclusions: The overall survival of these patients who received no adjuvant TMZ is very similar to the median of 23 months reported in the literature for MGMT methylated patients who received adjuvant TMZ. This preliminary data suggests that a prospective study in MGMT methylated patients comparing concurrent RT+TMZ followed by either standard adjuvant TMZ or observation could be considered without placing patients in the experimental arm at excessive risk.[Table: see text]

2568 Background: Wee1 is a key regulator of the G2/M checkpoint and is frequently overexpressed in glioblastoma (GB). Adavosertib is a first-in-class oral, small molecule inhibitor of Wee1 that acts primarily as a DNA damage sensitizer. A phase I clinical trial was conducted to evaluate its safety and establish the recommended phase II dosing. Studies were undertaken to evaluate whether potentially therapeutic concentrations of the drug are achieved in recurrent tumor and adjacent non-enhancing brain regions with presumed intact blood-brain barrier (BBB). Methods: Twelve patients received five daily doses of adavosertib pre-operatively at either the maximum tolerated dose (MTD) for concurrent radiation or adjuvant temozolomide. Tissue from contrast enhancing (CE) and non-enhancing (NE) brain regions was obtained for analysis during surgical resection. A second stage is being conducted using microdialysis (MD) to facilitate continuous sampling of extracellular fluid (ECF) and measuring free drug concentrations in: normal-appearing brain, contrast enhancing tumor, and a peritumoral T2 hyperintense area. The concentration of total adavosertib in plasma and tissue homogenates and free drug in ECF were determined by validated LC/MS/MS methods. Results: Geometric mean concentrations of adavosertib after a 200 mg dose were 644 ng/mL and 119 ng/mL in CE and NE tissue specimens, respectively (6 patients). At the 425 mg dose, the mean concentrations were 3,576 ng/mL in CE tissue and 885 ng/mL in NE tissue (6 patients). MD was performed in 2 patients. Samples from functional MD catheters were collected from NE brain in patient no. 1 and from two NE areas and a FLAIR hyperintense region in patient no. 2, with the following results in the table. Conclusions: The total drug concentration in tissue samples was notably lower in regions of the brain with a relatively intact BBB as compared to contrast enhancing tissue. Concentrations of adavosertib measured by MD vary markedly depending on catheter location. Free drug levels in ECF within brain with a functional BBB, although considerably lower than total drug levels in tissue, were 2-10 times below the previously reported IC50 for antiproliferative activity against sensitive GB cell lines (127 ng/mL). Whether or not the target of the drug is effectively inhibited at these concentrations remains to be demonstrated. Clinical trial information: NCT01849146 . [Table: see text]