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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 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.

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]

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]