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The standard of care for elderly glioblastoma patients is 40 Gy in 15 fraction radiotherapy with temozolomide (TMZ). However, this regimen has a lower biologic equivalent dose (BED) compared to the Stupp regimen of 60 Gy in 30 fractions. We hypothesize that accelerated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) will have superior survival compared to 40 Gy in 15 fractions.Elderly patients (≥ 65 years old) who received hypofractionated radiation with TMZ from 2010 to 2020 were included in this analysis. Overall survival (OS) and progression free survival were defined as the time elapsed between surgery/biopsy and death from any cause or progression. Baseline characteristics were compared between patients who received 40 and 52.5 Gy. Univariable and multivariable analyses were performed.Sixty-six newly diagnosed patients were eligible for analysis. Thirty-nine patients were treated with 40 Gy in 15 fractions while twenty-seven were treated with 52.5 Gy in 15 fractions. Patients had no significant differences in age, sex, methylation status, or performance status. OS was superior in the 52.5 Gy group (14.1 months) when compared to the 40 Gy group (7.9 months, p = 0.011). Isoeffective dosing to 52.5 Gy was shown to be an independent prognostic factor for improved OS on multivariable analysis.Isoeffective dosing to 52.5 Gy in 15 fractions was associated with superior OS compared to standard of care 40 Gy in 15 fractions. These hypothesis generating data support accelerated hypofractionation in future prospective trials.

ImportanceGlioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed.ObjectiveTo investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma.Design, Setting, and ParticipantsThis phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021.InterventionsThe active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies.Main Outcomes and MeasuresThe primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials.ResultsA total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P P = .03).Conclusions and RelevanceIn this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone.Trial RegistrationClinicalTrials.gov Identifier: NCT00045968

Purpose: FGFR genomic alterations (amplification, mutations, and/or fusions) occur in ∼8% of gliomas, particularly FGFR1 and FGFR3. We conducted a multicenter open-label, single-arm, phase II study of a selective FGFR1–3 inhibitor, infigratinib (BGJ398), in patients with FGFR-altered recurrent gliomas. Patients and Methods: Adults with recurrent/progressive gliomas harboring FGFR alterations received oral infigratinib 125 mg on days 1 to 21 of 28-day cycles. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate by Response Assessment in Neuro-Oncology criteria. Comprehensive genomic profiling was performed on available pretreatment archival tissue to explore additional molecular correlations with efficacy. Results: Among 26 patients, the 6-month PFS rate was 16.0% [95% confidence interval (CI), 5.0–32.5], median PFS was 1.7 months (95% CI, 1.1–2.8), and objective response rate was 3.8%. However, 4 patients had durable disease control lasting longer than 1 year. Among these, 3 had tumors harboring activating point mutations at analogous positions of FGFR1 (K656E; n = 2) or FGFR3 (K650E; n = 1) in pretreatment tissue; an FGFR3-TACC3 fusion was detected in the other. Hyperphosphatemia was the most frequently reported treatment-related adverse event (all-grade, 76.9%; grade 3, 3.8%) and is a known on-target toxicity of FGFR inhibitors. Conclusions: FGFR inhibitor monotherapy with infigratinib had limited efficacy in a population of patients with recurrent gliomas and different FGFR genetic alterations, but durable disease control lasting more than 1 year was observed in patients with tumors harboring FGFR1 or FGFR3 point mutations or FGFR3-TACC3 fusions. A follow-up study with refined biomarker inclusion criteria and centralized FGFR testing is warranted.

Leptomeningeal carcinomatosis (LMC) is a form of CNS cancer metastasis with severe morbidity. Intrathecal chemotherapy (ITC) administration through an implanted ventricular catheter reservoir (IVCR) is often utilized. Additionally, a nuclear imaging flow study can be performed prior to ITC administration to assess cerebrospinal fluid (CSF) flow. The clinical impact of a CSF flow study is unclear. A retrospective chart review identified 31 patients with LMC that underwent IVCR placement between 2011 and 2019. Data extracted included patient demographics, nuclear imaging flow study, surgical complications, ITC toxicities and outcomes. Potential drug-induced neurologic toxicities (headache, nausea/vomiting, altered mental status, etc.) were noted in (n = 4/16) 25% of patients who underwent a flow study prior to initiation of ITC, compared to (n = 1/15) 6.6% of patients who did not undergo a flow study. Median overall survival (OS) was 4.0 and 32.8 months for the patients that underwent a flow study versus patients who did not, respectively (p

Background The revised fourth edition of the World Health Organization Classification of Tumors of the Central Nervous System-published in 2016-established 1p19q codeletion as the molecular hallmark for the diagnosis of oligodendrogliomas. Fluorescence in situ hybridization (FISH) is currently the most commonly used modality for 1p19q testing. However, as with most laboratory testing, 1p19q FISH testing has a false-positive rate, potentially resulting in an erroneous diagnosis of oligodendroglioma with significant implications for the choice of therapy and prognosis. Methods The authors describe a case series of 5 patients treated at the Ohio State University James Cancer Center to illustrate the problem of false-positive 1p19q FISH results. Results In our case series, the authors present a spectrum of possibilities for conflicting 1p19q testing results and the clinical consequences. The authors present 4 cases that, in retrospect, are believed to have had a false 1p19q FISH results. One other case may represent a true transformation of oligodendroglioma to glioblastoma or a second malignancy. Neuro-oncologists should pay attention to additional molecular markers, namely ATRX, TP53, and MGMT methylation status, before discussing the pathology with the patient and formulating a treatment plan. Conclusions Pathologists and neuro-oncologists should be aware of false-positive 1p19q FISH results as they can significantly change treatment and prognosis for glioma patients. Moreover, this issue should be taken into account when designing clinical trials specific to this disease cohort.

Background Leptomeningeal carcinomatosis (LMC) is a complication of advanced malignancies wherein metastatic disease invades the meninges of the central nervous system via contiguous spread from bone or brain metastases or hematogenous spread from systemic disease. Breast cancer is the most common solid tumor etiology of LMC. Approximately 5% of patients (pts) with breast cancer develop LMC. LMC has a median survival of 4 weeks when untreated and 8-16 weeks with treatment. The diagnosis of LMC remains challenging with only 60% of pts having cerebrospinal fluid (CSF) positive for malignant cells. There is no generally accepted standard of care for treatment of LMC but it may involve intrathecal or systemic chemotherapy, whole brain or spinal radiotherapy, or a combination of modalities. We aimed to assess detection and treatment strategies of LMC in pts with breast cancer treated at the Ohio State University Comprehensive Cancer Center-James (OSUCCC-James) to better characterize the disease and guide clinical care. Methods An IRB-approved single-institution retrospective protocol was developed. Medical records of 469 pts who had undergone a procedure related to LMC diagnosis or treatment were identified and reviewed to determine study eligibility. Comprehensive data was obtained through information warehouse and chart review was performed for the eligible 69 pts with breast cancer diagnosed with LMC and treated at the OSUCCC-James between January 1, 2005 and December 31, 2015. Descriptive statistics were used to summarize demographic and clinical characteristics. Overall survival (OS) was defined as time from LMC diagnosis to death or last known follow-up, and was generated using Kaplan Meier methods. Comparisons in OS between groups were analyzed using Log-rank tests. Results Sixty-nine female pts were included in the analysis with the following characteristics: median age 55.7 years (range: 48-60.6 years), Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (86%; N=59), and Caucasian (78%; N=54). They had the following subtypes hormone receptor positive (HR +), and human epidermal growth factor receptor (HER2) negative (61%, N=42), triple negative (25%, N=17) and HER2 positive (10%, N=7). The most common sites of metastases included bone (42%), brain (28%), and lung (12%). The median time between the diagnosis of first metastasis and LMC was 0.9 years (range: 0-3.2 years). Of the 40 (58%) pts who underwent lumbar puncture, 21 (52%) pts had positive CSF cytology. Sixty-eight pts (99%) had MRI findings suggestive of LMC. The most common treatment modalities were systemic chemotherapy (N=14, 41%), radiotherapy (N=12, 35%), and intrathecal chemotherapy (N=14, 35%). Fifty-six pts (81%) had a change in systemic chemotherapy agent after diagnosis. The median OS of all pts was 2.4 months (95% confidence interval: 1.2-4.4). Pts with ER+/PR+/HER2- had a better OS (4.4 months, 95%CI 1.5, 6.1)) compared to those with HER2+ (1.3 months, 95%CI 0.2, 1.9) or ER-/PR-/HER2- (0.6 months, 95%CI 0.0, 15.8) subtypes (p-value=0.004). Pts with negative CSF cytology had a greater OS compared to those with positive CSF cytology (9.8 vs. 0.7 months, p=0.026) and pts who had a change in systemic treatment had a greater OS compared with patients who had no new treatment (2.5 months vs. 1.2 months, p =0.039). No significant difference was seen in OS between ECOG performance status groups. Conclusions LMC is a relatively rare yet devastating complication of breast cancer. Based on our institutional experience, LMC remains a clinical challenge and is associated with poor OS. Pts with triple negative and HER2 positive disease and those with high disease burden fare worse. Pts who had change in systemic therapy fare better. Dedicated clinical trials are urgently needed to improve outcomes. Citation Format: Hannah Rinehardt, Nicole Williams, Evan Morgan, Mahmooud Kassem, Marilly Palettas, Abdul Miah, Iyad Alnahhas, Pilar Guillermo Prieto Eibl, Anupama Suresh, Vinay Puduvalli, Pierre Giglio, Maryam Lustberg, Robert Wesolowski, Sagar Sardesai, Daniel Stover, Jeffrey VanDeusen, Jose Bazan, Bhuvaneswari Ramswamy, Anne Noonan. Assessment of leptomeningeal carcinomatosis management and outcomes in patients with advanced breast cancer from 2005 to 2015: A single institution experience [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-20-07.

Despite recent advances in cancer therapeutics, glioblastoma (GBM) remains one of the most difficult cancers to treat in both the primary and recurrent settings. GBM presents a unique therapeutic challenge given the immune-privileged environment of the brain and the aggressive nature of the disease. Furthermore, it can change phenotypes throughout the course of disease—switching between mesenchymal, neural, and classic gene signatures, each with specific markers and mechanisms of resistance. Recent advancements in the field of immunotherapy—which utilizes strategies to reenergize or alter the immune system to target cancer—have shown striking results in patients with many types of malignancy. Immune checkpoint inhibitors, adoptive cellular therapy, cellular and peptide vaccines, and other technologies provide clinicians with a vast array of tools to design highly individualized treatment and potential for combination strategies. There are currently over 80 active clinical trials evaluating immunotherapies for GBM, often in combination with standard secondary treatment options including re-resection and anti-angiogenic agents, such as bevacizumab. This review will provide a clinically focused overview of the immune environment present in GBM, which is frequently immunosuppressive and characterized by M2 macrophages, T cell exhaustion, enhanced transforming growth factor-β signaling, and others. We will also outline existing immunotherapeutic strategies, with a special focus on immune checkpoint inhibitors, chimeric antigen receptor therapy, and dendritic cell vaccines. Finally, we will summarize key discoveries in the field and discuss currently active clinical trials, including combination strategies, burgeoning technology like nucleic acid and nanoparticle therapy, and novel anticancer vaccines. This review aims to provide the most updated summary of the field of immunotherapy for GBM and offer both historical perspective and future directions to help inform clinical practice.

Trametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 + 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT.Patients with brain metastases (BM) received daily trametinib for 28 days, starting 7 days prior to and continuing through WBRT (37.5 Gy/15 fractions). Dose levels (DL)1-3 were 1.0, 1.5, and 2.0 mg. The MTD of trametinib plus WBRT, the max dose where ≤1 of 6 patients experienced a dose limiting toxicity (DLT), was the primary endpoint.10 patients were enrolled (median age-59 [47-64], BM-5 [1-10], 50% melanoma). Three and 7 patients were assigned to DL1 and 2. One DL2 patient withdrew. 89% of remaining patients completed therapy per protocol, but 1 DL2 patient with systemic progression discontinued therapy at 30 Gy. Thirteen grade (G)3-4 toxicities were observed, of which 12 occurred at DL2 (4/6 of patients). DLT was reached at DL2 (G4 thrombocytopenia and G3 diarrhea, 1 each). There were no G5 toxicities. Median overall survival was 2.2 months. During the study period, changing practice patterns favored utilization of stereotactic radiosurgery (SRS). Thus, the trial closed early prior to completion.In a patient population representative of modern candidates for WBRT, trametinib plus WBRT is highly toxic with a MTD1.5 mg. The safety of trametinib with SRS remains an important question for future study.

Background Glioblastoma remains a deadly brain cancer with dismal prognosis. Genetic alterations, including IDH mutations, 1p19q co-deletion status and MGMT promoter methylation have been proven to be prognostic and predictive to response to treatment in gliomas. In this manuscript, we aimed to correlate other mutations and genetic alterations with various clinical endpoints in patients with IDH-wild-type (IDHwt) glioblastoma. Methods We compiled a comprehensive clinically annotated database of IDHwt GBM patients treated at the Ohio State University Wexner Medical Center for whom we had mutational data through a CLIA-certified genomic laboratory. We then added data that is publicly available from Memorial Sloan Kettering Cancer Center through cBioPortal. Each of the genetic alterations (mutations, deletions, and amplifications) served as a variable in univariate and multivariate Cox proportional hazard models. Results A total of 175 IDHwt GBM patients with available MGMT promoter methylation data from both cohorts were included in the analysis. As expected, MGMT promoter methylation was significantly associated with improved overall survival (OS). Median OS for MGMT promoter methylated and unmethylated GBM was 26.5 and 18 months, respectively (HR 0.45; P = .003). Moreover, EGFR/ERBB alterations were associated with favorable outcome (HR of 0.37 (P = .003), but only in MGMT promoter unmethylated GBM. We further found that patients with EGFR/ERBB alterations who also harbored PDGFRA amplification had a significantly worse outcome (HR 7.89; P = .025). Conclusions Our data provide further insight into the impact of genetic alterations on various clinical outcomes in IDHwt GBM in 2 cohorts of patients with detailed clinical information and inspire new therapeutic strategies for IDHwt GBM.

BACKGROUND Standard of care (SOC) and patient survival in glioblastoma have changed little in the past 17 years. We evaluated in a phase 3 trial whether adding an autologous tumor lysate-loaded dendritic cell vaccine (murcidencel) to SOC extends survival. Patients and METHODS Newly diagnosed glioblastoma patients were randomized 2:1 to either murcidencel or placebo. Under a crossover design, all patients could receive murcidencel following tumor recurrence. All parties remained blinded regarding treatments before recurrence. Patients thus received murcidencel at new diagnosis (nGBM) or at recurrence (rGBM) following crossover from placebo. The primary and secondary endpoints compare overall survival (OS) with contemporaneous, matched external controls. Four sets of analyses were conducted to ensure rigorous matching of the controls, reduce biases, and confirm the robustness of the results. RESULTS 331 patients were enrolled. With the crossover, 89% received murcidencel. Median OS (mOS) for nGBM patients (n = 232) was 19.3 months from randomization (22.4 months from surgery) with murcidencel vs. 16.5 months from randomization in the controls (HR = 0.80, p = 0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For rGBM (n = 64), mOS was 13.2 months from relapse vs. 7.8 months in the controls (HR = 0.58, p < 0.001). Survival at 24 months post-recurrence was 20.7% vs. 9.6%, and at 30 months post-recurrence was 11.1% vs 5.1%. In nGBM patients with methylated MGMT (n = 90), mOS was 30.2 months from randomization (33 months from surgery) with murcidencel vs. 21.3 months from randomization in the controls (HR = 0.74, p = 0.027). The treatment was well tolerated, with only 5 serious adverse events deemed at least possibly related to the vaccine. CONCLUSION Clinically meaningful and statistically significant survival extension was seen in both nGBM and rGBM patients treated with murcidencel and SOC compared with contemporaneous, matched external controls who received SOC alone.

Atypical and anaplastic meningiomas (WHO Grade 2 and WHO Grade 3 respectively) represent a subgroup of meningiomas that tend to have higher rates of recurrence with associated’s higher morbidity and mortality than the more common WHO Grade 1 meningiomas. Our laboratory data demonstrated that galectin-3 (Gal-3), a multifunctional β-galactoside-binding protein, is highly expressed in these meningioma subtypes as compared to normal brain tissue. However, the root of the profoundly immunosuppressive tumor microenvironment in meningioma cells is not fully understood. To address this, we used a Gal-3 inhibitor TD 139 paired with low-intensity non-invasive transcranial direct current stimulation (tDCS) to suppress tumor growth and enhance the immune response in the preclinical model. Treatment of tDCS (50 mV/mm for 30 min) followed by 1 mM of TD139 induced cell death in anaplastic meningioma in vitro human triple co-culture model but has no effect on mouse cortical neurons. Furthermore, we demonstrated that inhibiting of Gal-3 expression significantly decreased the protein levels of urokinase-type plasminogen activator receptor as well as phosphorylation of Akt and upregulates Bax expression. Treatment with TD139 (1mg/kg per day for 14 days) with tDCS [350 μA (1 x 30 min/day) for 7 times (within 14 Days) showed a significantly (∼60%) decrease in MGS2 atypical meningioma tumor growth in orthotopic allograft model (at Day 41). The percent survival of tumor-bearing mice treated with TD139 and tDCS was significantly higher than an untreated tumor or single treatment. Following TD139 plus tDCS treatment, our results demonstrated significant meningioma cell death via a decrease in NDRG4 (Meningioma marker) and were associated with downregulation of Ki-67 in treated tumors. Based on our substantial preliminary data, we believe that this proposed translational work has the potential to be an effective combinational modality form of treatment for atypical and malignant meningiomas.

PURPOSE Hypoxia from inhibition of angiogenesis reduces DNA repair capacity. Targeting homologous recombination pathway also has anti-angiogenic effects. To examine the synergistic effects of disrupting DNA repair pathways and angiogenesis in glioblastoma, we combine cediranib (ced), a pan vascular endothelial growth factor (VEGF) receptor inhibitor with olaparib (ola), a poly-ADP ribose polymerase (PARP) inhibitor compared with bevacizumab (bev), a VEGF-A inhibitor alone. To identify potential biomarkers predicting response to treatments, we also perform whole exome sequencing on archival tissues. METHODS Bevacizumab-naïve adult patients with first or second recurrence of glioblastoma after radiation and temozolomide were randomly assigned to cediranib (30mg PO daily)/olaparib (200mg PO twice daily) or bevacizumab (10mg/kg IV every 2 weeks). The primary end point was progression-free survival (PFS) at 6 months. The secondary end points included safety and overall survival (OS). Whole exome sequencing of formalin-fixed paraffin embedded archival tissue from 23 patients was performed. RESULTS We are presenting the final data from this trial. Between December 2017 and November 2018, a total 70 adult patients with recurrent glioblastoma were randomly assigned to receive ced/ola (n = 35) or bev (n = 35). With a data cut off on 5/30/2022, median PFS was 118 days and 92 days in ced/ola and bev groups, respectively (hazard ratio, 1.099, 95% CI 0.6-2, p = 0.76). Median overall survival was 269.5 days and 192 days in ced/ola and bev groups, respectively (hazard ratio, 0.6892, 95% CI 0.39-1.2, p = 0.2). Whole exome sequencing was performed in total 23 patients (24 samples), 14 patients in the ced/ola group and 9 patients in the bev group. CONCLUSION No significant survival benefit was observed in patients with recurrent glioblastoma treated with ced/ola compared to patients treated with bev monotherapy. Potential biomarkers predicting response to treatment identified from the whole exome sequencing on archival tissues will be presented.

Glioblastoma (GB) is an aggressive tumor showing extensive intertumoral and intratumoral heterogeneity. While preserving as much surrounding normal brain tissue as possible, neurosurgeons must aim to harvest maximal tumor tissue from a variety of tumor locations in an effort to capture heterogenic samples in high volume for molecular and pathologic diagnosis and translational research. A key challenge is the ability to consistently procure high-quality biologically active specimens. In this investigation, we implemented an automated intraoperative system to eliminate inconsistencies in the methodology of tissue collection, handling, and biological preservation immediately in the OR suite to establish a repeatable, standardized practice for obtaining high-quality tissue samples without the need for additional staff. Through this process, we were able to characterize matched specimens from GB patients or GB tumors from corresponding GB-allograft mice and compare the quality of traditional handling and collection processes of intraoperative tissue used in most neurosurgical operating rooms versus an automated resection, collection, and biological preservation system (APS) that captures, preserves, and biologically maintains tissue in a prescribed and controlled microenvironment. Matched specimens/or tissues were then processed in parallel at various time points and temperatures, evaluating viability, RNA and protein concentrations, and isolation of GB cell lines. We found that APS-derived GB slices stored in an APS modified medium remained viable and maintained high-quality RNA and protein concentration for up to 24 hours. Our results showed that primary GB cell cultures derived in this manner had improved growth over the widely used collection and preservation methods. Currently, we are continuing the investigation of collected samples in brain tumor animal models to further understand potential differences within the tumor region harvested and the cellular changes that occur over time. Our hope is this research will lead to new discoveries in the diagnosis and treatment of brain tumors.

Glioblastoma (GB) patients often present with either radiation-induced necrosis (RN) or develop tumor recurrence (TR). Radiologically, differentiating between these two disease states is particularly difficult, especially utilizing traditional MRI techniques. Accurately distinguishing these separate states is important, as failure to do so can ultimately lead to unnecessary surgical intervention or early cessation of appropriate radiation therapy. Currently, distinction between these pathologies is made using best clinical judgement by the neuro-oncology team. Therefore, there is a need for developing novel non-invasive techniques that can reliably distinguish between radiation necrosis and tumor recurrence. Primary data was collected utilizing orthotopically transplanted GL261 mouse GB cells in a C57BL/6 mouse. Tumor induction was verified by MRI after two weeks. RN and TR were initiated using an aggressive radiation dose fractionation (12 Gy or 60 Gy). This was completed using a 4 mm radiation cone such that one portion of the tumor received 100% dose of 12 Gy or 60 Gy fraction which is sufficient to cause RN, whereas the tumor edge received only 50% of the dose, allowing for tumor recurrence. Our data demonstrated mice tumor recurrence and radiation necrosis on MRI imaging. Axial T2-weighted MRI and DKI sequence at 2 weeks following implantation demonstrated edema compatible with tumor recurrence. One week later, the T2-weighted MRI and DKI sequences demonstrated continued tumor progression. In a separate mouse with orthotopic glioblastoma implantation with high dose (60 Gy) radiation treatment, T2 imaging and DKI demonstrated areas of tumor and suspected central radiation necrosis. DKI imaging biomarkers was compared by liquid biopsy, H&E staining, and Immunohistochemistry (IHC) analysis of sacrificed mice. Our H&E staining results showed typical pathological features of GB and RN, and TR in each case. This result demonstrated that our proposed model for radiation induction was effective at achieving its goal.

Molecular heterogeneity has confounded attempts to target individual pathways in brain tumors. However, gliomas with BRAF mutations have been identified as being uniquely vulnerable to targeted therapies. Such mutations are predominantly seen in brain tumors of the adolescent and young adult population. Given that accurate and timely identification of such mutations is essential for offering appropriate treatment, treatment centers should offer both immunohistochemical and sequencing methods for detection of these mutations to guide treatment. Additional studies of these tumors at recurrence would also allow identification of breakthrough resistance mechanisms that may also be targetable for treatment. Due to the relative rarity of these tumors, multicenter collaborative studies will be essential in achieving long term control of these tumors.

2035 Background: Isocitrate dehydrogenase ( IDH) 1 and IDH2 mutations ( IDH1/2mt) are the most common mutations in gliomas, occurring in over 70% of low grade and 20% of higher grade gliomas. IDH1/2mts are associated with improved prognosis, although tumors typically recur and progress to a higher grade despite first lines of treatment. Recent preclinical studies have suggested IDHmt and accumulation of 2-HG confer a “BRCAness” phenotype, a vulnerability that can be targeted through PARPi. To test this hypothesis, we conducted a multicenter study of olaparib monotherapy in patients (pts) with IDH1/2mt gliomas that had progressed despite standard therapy. Methods: Eligible pts had contrast enhancing and biopsy confirmed IDH1/2mt glioma that progressed despite standard therapy. Pts with prior treatment with PARPi or IDHmt inhibitors were excluded. The primary endpoint was overall response rate (ORR). Secondary objectives were progression free survival (PFS), overall survival (OS) and duration of response (DR). Olaparib 300 mg orally twice daily was given. A standard Simon 2 stage design was used. Stage 1 included 15 pts. If 2/15 pts responded stage 2 would expand by 30 pts. Responses were assessed with RANO criteria and reviewed centrally. Results: 15 evaluable pts were enrolled. Most recent histology as per 2021 WHO classification was 12 astrocytoma (4 grade 2, 3 grade 3, 5 grade 4) and 3 oligodendroglioma (2 grade 2, 1 grade 3). A total of 13 pts’ tumors had IDH1 R132H mutations; 2 pts had IDH2mt (R172G, R172K). All pts had >1 and 10 pts had >2 prior lines of systemic therapy (median 2, range 1-4). Most toxicities were grade 1 or 2. Nausea (67%) and fatigue (47%) were most frequent. Grade 3 lymphopenia, thrombocytopenia, and hypertension were seen in 1 patient each. Best response was stable disease (SD) in 9 pts and 6 pts had disease progression (PD). The median PFS was 3.6 months, 6-month PFS rate 26.7%, median OS 13.2 months. For pts with SD, median PFS was 5.5 months; 4 pts had SD for > 6 months. 2/6 pts with PD had confirmed WHO grade 4 by histology; 4 had CDKN2A deletion. CDKN2A deletion was unknown for 2 pts. Conclusions: Olaparib was well tolerated in this pt population. The study did not meet the pre-specified response-based threshold for moving to step 2, but prolonged SD was observed in pts with grades 2 and 3 histologies, suggesting olaparib monotherapy could be of clinical benefit in select pts. Grade 4 tumors per the 2021 WHO classification defined by histology or CDKN2A mutation derived minimal to no benefit from this drug highlighting the usefulness of this new classification for future patient stratification and trial design and suggesting investigation of this treatment earlier in the disease course might be of interest. Further studies are needed to identify other molecular or clinical predictive markers of benefit from PARPi as well as novel drug combinations for improved efficacy in this population. Clinical trial information: NCT03212274.

Diffuse midline glioma with histone H3 lysine27-to-methionine mutation (H3 K27M mutation) is a rare, aggressive tumor that is designated as World Health Organization (WHO) grade IV regardless of histologic features. Preoperative diagnosis remains challenging due to limited evidence regarding distinctive clinical and imaging characteristics. We describe the case of a young woman who presented with progressively worsening headaches due to communicating hydrocephalus. MR imaging with contrast of the cervical and thoracic spine revealed diffuse leptomeningeal enhancement with focal areas of intramedullary and subarachnoid T2 hyperintensity and enhancement, suggestive of a potential infectious process. Intraoperatively, no epidural pathology was identified, and with the differential diagnosis remaining broad, a second procedure was conducted involving intradural exploration and biopsy of a lesion. This was then identified as a diffuse midline glioma with H3 K27M mutation. The nonfocal clinical presentation in the setting of communicating hydrocephalus as well as the significant exophytic tumor growth and imaging findings made the initial diagnosis unique and challenging. This case, therefore, emphasizes the rare presentation of this tumor, and the need for further understanding of the clinical and imaging characteristics of this disease as well as the need for effective therapeutics.

Background Radiation necrosis (RN) is a potential complication after radiation therapy for brain tumors. It is hypothesized that VEGF plays an important role in the pathophysiology of RN. Bevacizumab, a monoclonal antibody against VEGF-A, is often successful in the management of RN. The objective of this study is to assess whether VEGF receptor (VEGFR) inhibitors, a group of oral tyrosine kinase inhibitors (TKIs), can prevent or reverse RN. Methods We retrospectively studied a cohort of 102 patients with renal cell carcinoma and brain metastases seen at The Ohio State University James Cancer Center between January 1, 2011 and April 30, 2019. We identified those who developed RN and analyzed the temporal relationship between the use of VEGFR TKIs and the development of RN. Results The cumulative incidence of RN is 13.7% after radiation treatments that included LINAC-based stereotactic radiosurgery, fractionated stereotactic radiotherapy, or Gamma Knife radiosurgery. There was no statistically significant difference in the cumulative incidence of RN between patients taking TKIs and patients who were off TKIs (9.9% and 11.5% respectively, P = .741). The median time to development of RN was only numerically shorter in patients taking TKIs (151 vs 315 days, P = .315). One patient developed RN after stopping cabozantinib. Eight patients developed RN while on cabozantinib, pazopanib, or sunitinib. One patient was started on axitinib during active RN without significant improvement subsequently. Conclusions VEGFR TKIs do not consistently prevent RN. The therapeutic effects of VEGFR TKIs against RN warrant further research.

PURPOSE/OBJECTIVE(S) The standard of care for elderly glioblastoma patients (GBM) is 40 Gy in 15 fractions with temozolomide (TMZ). However, this regimen has a lower biologic equivalent dose (BED) compared to the Stupp regimen of 60 Gy in 30 fractions. We hypothesize that dose escalated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) will have superior survival compared to 40 Gy in 15 fractions. MATERIALS/METHODS Elderly patients (> 60 yo) who received hypofractionated radiation with TMZ were included in this analysis. Overall survival (OS) and progression free survival (PFS) were defined as the time elapsed between surgery/biopsy and death from any cause or progression. Baseline characteristics were compared with pairwise tests. Univariate and multivariate analyses were performed. RESULTS 66 newly-diagnosed patients were eligible for this analysis. 39 patients were treated with 40 Gy in 15 fractions, and 27 patients were treated with 52.5 Gy in 15 fractions. The median follow up for this cohort was 8.8 months. Patients were well balanced with no significant differences in age, sex, MGMT, extent of resection, or KPS. The median OS was 7.9 months in the 40 Gy arm and 13.1 months in the 52.5 Gy arm (P = 0.035). For unmethylated patients, the median OS was 6.7 months in the 40 Gy arm and 11.3 months in the 52.5 Gy arm (P = 0.012). Increasing planning treatment volume (P = 0.007) was associated with decreased OS. On multivariate analysis, MGMT methylation (HR 0.45 [0.23-0.87] P = 0.018) and dose escalation (HR 0.45 [0.21-0.96] 0.04) remained independent prognostic factors for OS. In a multivariate model for PFS, only dose-escalation was significant (HR 0.49 [0.25-0.98] P = 0.045). No significant differences in toxicity were observed between treatment groups. CONCLUSION Dose-escalation to 52.5 Gy in 15 fractions was associated with superior OS and PFS compared to standard of care 40 Gy in 15 fractions. This treatment regimen gives the elderly population an alternative to Stupp that is not de-escalating therapy. These hypothesis generating data support dose-escalated hypofractionation in future prospective trials. AUTHOR DISCLOSURE H.K. Perlow: None. M. Yang: None. B. Klamer: None. R. Raval: None. D.M. Blakaj: None. A.L. Arnett: None. S. Beyer: None. J.C. Grecula: None. M. Ammirati: None. J.B. Elder: None. R.R. Lonser: None. D. Hardesty: None. S.S. Ong: None. P. Giglio: None. C. Pillainayagam: None. J. Goranovich: None. A. Chakravarti: None. V. Gondi: Partner; Radiation Oncology Consultants, Ltd. Honoraria; UpToDate, RaySearch. Partnership; Radiation Oncology Consultants, Ltd. Co-Principal Investigator; NRG Oncology. P.D. Brown: None. J.D. Palmer: Research Grant; Varian Medical Systems, The Kroger Company. Consultant; Huron Consulting. Speaker's Bureau; Varian Medical Systems, Depuy Synthes. Advisory Board; Novocure. Member of panel; NCCN.

Background The current standard of care for the management of patients with newly diagnosed glioblastoma (GBM) includes maximal safe resection followed by radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ). While it is well established that TMZ has better efficacy in patients with MGMT promoter methylation, it remains an area of debate whether TMZ should be omitted when treating GBM patients with unmethylated MGMT. Methods We conducted a systematic review and meta-analysis to provide separate estimates of median overall survival (OS) and progression-free survival (PFS) for patients with methylated and unmethylated GBM treated with RT with or without TMZ. We searched multiple databases from inception to January 13, 2020. Results The median OS for patients with unmethylated GBM treated with RT/TMZ pooled from 5 phase III studies (N = 655) was 14.11 months (95% confidence interval [CI], 13.18-15.04) with a median PFS of 4.99 months (95% CI, 4.25-5.72). In contrast, the median OS for patients with methylated GBM pooled from 6 studies (N = 753) was 24.59 months (95% CI, 22.19-26.99) with a median PFS pooled from 7 studies (N = 805) of 9.51 months (95% CI, 7.41-11.61). There is a paucity of prospective data pertaining to OS/PFS in unmethylated patients treated with RT only and therefore a direct comparison was not possible. Conclusions This meta-analysis provides estimates of survival for patients with MGMT methylated or unmethylated GBM treated with RT/TMZ. Further research is needed to delineate whether TMZ should be withheld for patients with unmethylated GBM outside of the setting of clinical trials.

Glioblastoma (GB) remains incurable despite aggressive chemotherapy, radiotherapy, and surgical interventions; immunotherapies remain experimental in clinical practice. Relevant preclinical models that can accurately predict tumor response to therapy are equally challenging. This study aimed to validate the effect of the naturally occurring agent diallyl trisulfide (DATS) in human GB in relevant pre-clinical models. Ex vivo slice culture, in vivo cell line derived orthotopic xenograft and patient-derived orthotopic xenograft (PDX) animal models of GB were utilized to assess efficacy of treatment with DATS. Our results showed 72-h treatments of 25 µM DATS induced cell death in ex vivo human GB slice culture. We treated U87MG orthotopic xenograft models (U87MGOX) and patient-derived orthotopic xenograft models (PDX) with daily intraperitoneal injections of DATS for 14 days. Magnetic resonance (MR) imaging of mice treated with DATS (10 mg/kg) demonstrated reduced tumor size at 5 weeks when compared with saline-treated U87MGOX and PDX controls. Hematoxylin (H&E) staining demonstrated dose-dependent reduction in gross tumor volume with decreased proliferation and decreased angiogenesis. Western blotting showed that DATS was associated with increases in histone acetylation (Ac-Histone H3/H4) and activated caspase-3 in this novel preclinical model. Histological assessment and enzyme assays showed that even the highest dose of DATS did not negatively impact hepatic function. DATS may be an effective and well-tolerated therapeutic agent in preventing tumor progression and inducing apoptosis in human GB.

Background: PRMT5 catalyzes symmetric arginine dimethylation of protein substrates with important roles in cancer cell growth/survival, including glioblastoma (GBM) cells. PRT811 is a brain penetrant, potent, selective, oral PRMT5 inhibitor with preclinical efficacy in a GBM orthotopic model (Zhang AACR 2020). An open-label Phase I study of PRT811 in patients (pts) with advanced solid tumors and recurrent high-grade glioma (NCT04089449) is ongoing. Dose escalation results are presented herein. Materials and Methods: This study assesses the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity (RECIST v1.1, Lugano, & RANO) of PRT811 administered at varying doses/schedules (15-600 mg daily [QD]; 300 mg twice daily [BID]). Serum symmetric dimethylarginine (sDMA) and intron retention, a marker of PRMT5-mediated mRNA splicing fidelity, were assessed as measures of PRMT5 target engagement and function, respectively. Results: As of 18 June 2021, 38 unselected pts with recurrent or refractory disease had enrolled (22 solid tumor, 16 GBM). Median number of prior lines of systemic therapies was 2. No dose-limiting toxicities have been identified. Most frequent treatment-related adverse events (TRAEs), any grade, were nausea (n=10, 26%), vomiting (n=7, 18%), diarrhea (n=4, 11%), fatigue (n=4, 11%), constipation (n=3, 8%), and pruritis (n=3, 8%). Decreased lymphocyte count (n=1, 3%) and vomiting (n=1, 3%) were the only Grade ≥3 TRAEs. 28 pts discontinued treatment, mainly due to disease progression. No pts discontinued due to treatment-emergent AEs (TEAEs). PRT811 exhibited linear PK characteristics. At the highest evaluated dose (600 mg QD), Cmax,of 3777 nM, AUC of 12,487 nM.hr, and T½ of 5.8 hrs were observed. Comparison of PK parameters of 300 mg administered either QD or BID demonstrated similar PK with no accumulation with the BID schedule. Serum sDMA levels decreased by 80% with 600 mg QD. PRMT5-mediated mRNA splicing fidelity in peripheral blood mononuclear cells showed increased intron retention in specific transcripts at the higher PRT811 doses, indicating PRMT5 functional activity was decreased. A partial response was observed in 1 pt with GBM (>9 months duration) who remains on study. In addition, a pt with uveal melanoma (spliceosome SF3B1 mutation) achieved a 25% decrease in tumor burden per RECIST v1.1. An additional 3 pts with solid tumors had stable disease ≥6 mo. Conclusions: PRT811 was well tolerated with a favorable safety profile when administered at either QD or BID schedules. Target engagement and inhibition of PRMT5 functional activity were observed across multiple dose levels. Preliminary evidence of antitumor activity was observed in GBM and uveal melanoma. The expansion phase of the study will be initiated in select tumor types upon establishing the recommended expansion dose. Citation Format: Gerald S. Falchook, Jon Glass, Varun Monga, Pierre Giglio, David Mauro, John Viscusi, Peggy Scherle, Neha Bhagwat, William Sun, Rachel Chiaverelli, Eric Mintah, Lydia Clements, Tanner M. Johanns, Meredith McKean. A phase 1 dose escalation study of protein arginine methyltransferase 5 (PRMT5) brain penetrant inhibitor PRT811 in patients with advanced solid tumors, including recurrent high-grade gliomas [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P044.

Purpose/Objective(s) Lower grade gliomas (LGG, World Health Organization Grade II and III) are characterized by variable clinical behavior and variable outcomes. While previously identified clinically molecular stratification factors add prognostic insight over histologic classification alone, significant heterogeneity exists with respect to overall outcome among patients. The purpose of this study was to evaluate nine machine learning algorithms on a combined clinical, mutational and methylation data of 293 adult LGGs. Materials/Methods 293 clinically annotated LGG samples with genome-wide methylation data available in the TCGA atlas were included in the study. Clinically relevant information included age at diagnosis, sex, IDH, TP53, ATRX mutations, 1p/19q status, tumor grade, histology, disease status and overall survival status. Methylation data of 450 genes with the highest variance across all samples were included. We used a total of nine machine learning algorithms in RapidMiner to evaluate the accuracy of each in predicting the overall survival status (deceased/living.) Those included tree-based and neural networks-based algorithms, support vector machine, and linear regression. Results Gradient boosted trees achieved the greatest predictive accuracy (86.76%, living and deceased class recall of 84.75% and 91.67%, respectively), followed by Decision Tree (84.52%, class recall of 85.25 and 82.61%, respectively). The largest weight in each model was disease-free status. Combined clinical and methylation data achieved greater sensitivity and specificity compared to either methylation or clinical data only: methylation data-based analysis without inclusion of clinical data achieved maximum accuracy of 79.56% with Deep Learning (living and deceased class recall of 95% and 39.13%, respectively), while clinical data-only based analysis showed highest accuracy of 89.16% with Random Forests, with a class recall for living and deceased of 98.36% and 63.64%, respectively. Conclusion The combination of clinical and methylation data achieves a remarkable accuracy in predicting overall survival outcome in LGG patients, with highest overall class recall. The class recall (true positive rate or sensitivity) for deceased patients of combined data is superior to both clinical data-only and methylation data-only based analysis.

BACKGROUND We report the responses, toxicities and long-term outcomes of gemcitabine, paclitaxel and oxaliplatin (GemPOx) regimen administered, in responsive patients, prior to single cycle marrow-ablative chemotherapy (thiotepa, etoposide and carboplatin) with autologous hematopoietic progenitor cell rescue (HDCx+AuHPCR). METHODS Since December 2009, 11 recurrent/refractory patients (10 MMGCT, 1 germinoma; 10 males; mean age 16.5 years, range 7–46 years) have been treated with up to four cycles of gemcitabine (800mg/M2), paclitaxel (170mg/M2) and oxaliplatin (100mg/M2) administered on one day at 14 days intervals. RESULTS All 11 patients were enrolled on a prospective multi-center trial, which was closed in October 2019. Three patients achieved complete remissions (tumor marker and/or imaging studies), five achieved partial remissions, two developed disease progression (PD), and one was withdrawn after one cycle for severe paclitaxel neurotoxicity followed by rapid tumor progression and death. One patient with PD after one cycle had pathologically-confirmed metastatic transformation to pure embryonal rhabdomyosarcoma, and rapidly expired. A second patient, with pure pineal choriocarcinoma, progressed after the second GemPOx cycle, ultimately died of tumor progression. Eight of the 11 responsive patients subsequently underwent HDCx+AuHPCR; five of these received some form of radiotherapy. Seven patients (six MMGCT, one germinoma) are alive and disease-free without recurrence for a mean of 94 months (range 74–118 months) since completion of therapy. CONCLUSION GemPOx is an effective re-induction regimen for patient with recurrent CNS germ cell tumors, with acceptable toxicities; when followed by marrow-ablative chemotherapy and subsequent irradiation/re-irradiation, the regimen produces encouraging long-term disease-free survival.

BACKGROUND Despite our deeper understanding of the genomic alterations associated with glioblastoma (GBM), only a few genetic and epigenetic modifications have been proven to be meaningful in clinical practice. We have identified molecular parameters of prognostic relevance in IDHwt GBM using patient data from the Ohio State University (OSU) and the publicly available MSK-IMPACT database. METHODS A clinically annotated database of glioma patients at OSU- whose tumors were analyzed through Foundation One genomic testing- was utilized to examine mutation and copy number variation (CNV) data. 73 patients with IDHwt GBM were included in this study cohort along with 200 similar patients from the MSK-IMPACT cohort. Data from the MSKCC group was extracted from the cBioPortal database. Altered genes were correlated with clinical outcomes using Cox proportional hazards models. Univariate and multivariate analyses were applied, and variables included: MDM/P53, CDKN2A/B, CDK/CCND, RB1, EGFR/ ERBB, FGFR, PDGFR/KIT, NF1, PI3K, PI3K class 2, MYC and TERT promoter mutations. RESULTS Using univariate and multivariate analyses, EGFR activating alterations (amplification, mutations) and RB1 alterations (deletion, mutations) showed significant correlation with favorable outcome in IDHwt GBM: HR 0.496 for EGFR (p< 0.0001) and 0.454 for RB1 (p=0.025). Furthermore, the presence of PDGFR alterations, in EGFR altered tumors only, carried a significantly worse survival in univariate and multivariate analyses: HR 5.094 (p=0.004). This suggests an interaction between EGFR and PDGFR that could be of therapeutic relevance. CONCLUSIONS We found that GBM tumors harboring EGFR and/or RB1 alterations have better survival compared to tumors that are EGFR/RB1 wild-type. Moreover, PDGFR alterations worsens survival in EGFR altered GBM. This data provides further insights that might guide targeted therapies in IDHwt GBM.

BACKGROUND Like most proliferating tumors, GBM relies heavily on accurate DNA repair for maintenance of genome stability. Dysfunction in repair of both single and double strand DNA breaks by PARP inhibition and impairment of homologous recombination, respectively, would be synthetically lethal. In this study we combined the PARP inhibitor olaparib with cediranib, a pan VEGF receptor inhibitor. Cediranib may mediate disruption in the homologous recombination pathway through its antiangiogenic properties. METHODS Through the Experimental Therapeutics Clinical Trials Network, we performed an open-label randomized phase II study of bevacizumab (BEV)- naive adult patients with first or second recurrence of glioblastoma after radiation and temozolomide. Patients were randomized 1:1 to receive either olaparib 200 mg by mouth twice daily with cediranib 30 mg by mouth daily or BEV 10 mg/kg IV every 2 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints included safety and overall survival. Exploratory objectives included blood, tissue and imaging-based biomarkers of response to treatment. RESULTS Seventy patients were enrolled. Median age was 60.5 years (range: 19–79), 39% females, median KPS was 90 (range: 60–100). Baseline characteristics were well balanced. With a data cut-off of 5/2/2019, PFS6 was 14% [95% CI 4–30%] in the cediranib/olaparib arm vs 30.9% [95% CI 12.7–51.2%] in the BEV arm. Median OS was 247 days in the cediranib/olaparib arm vs 201 days in the BEV arm, HR 0.816, 95% CI (0.431, 1.546). Related grade 3, 4 or 5 toxicity was experienced in 29% vs 12% of patients for the cediranib/olaparib vs BEV arm. CONCLUSION Treatment with cediranib/olaparib failed to increase PFS and OS in patients with recurrent GBM. Blood, tissue and imaging correlates will be presented to help understand why this treatment combination was unsuccessful.

INTRODUCTION: Gliomas are highly heterogeneous primary brain tumors which result in a disproportionately high degree of morbidity and mortality despite their locoregional occurrence. Advances in the understanding of the biological makeup of these malignancies have yielded a number of potential tumor-driving pathways which have been identified as rational targets for therapy. However, early trials of agents that target these pathways have uniformly failed to yield improvement in outcomes in patients with malignant gliomas. AREAS COVERED: This review provides an overview of the most common biological features of gliomas and the strategies to target the same; in addition, the current status of immunotherapy and biological therapies are outlined and the future directions to tackle the challenges of therapy for gliomas are examined. EXPERT OPINION: The limitations of current treatments are attributed to the inability of most of these agents to cross the blood brain barrier and to the intrinsic heterogeneity of the tumors that result in treatment resistance. The recent emergence of immune-mediated and biological therapies and of agents that target metabolic pathways in gliomas have provided strategies that may overcome tumor heterogeneity and ongoing trials of such agents are anticipated to yield improved outcomes.

TPS2069 Background: High-grade gliomas (WHO grade III-IV) patients experience marked morbidity and mortality. While the standard of care for newly diagnosed high-grade glioma patients is surgery followed by concurrent chemotherapy and radiation therapy (RT), the outcomes remain poor. BMX-001 (MnTnBuOE-2-PyP5+) is a metalloporphyrin with differential action in response to radiation therapy and chemotherapy-induced oxidative stress. As shown in preclinical evaluations, BMX-001, when used with radiation, can protect normal, healthy tissues and augment cell kill in malignant cancer cells, notably, human glioblastoma xenografts. We evaluated the safety of BMX-001 in combination with concurrent RT and temozolomide (TMZ) in a phase 1 study of newly diagnosed high-grade glioma patients and we found that BMX-001 is safe and well-tolerated in this population. The maximum tolerated dose of BMX-001 during concurrent RT and TMZ was determined to be 28 mg delivered subcutaneously (SC) followed by 16 biweekly SC doses at 14 mg (Peters et al., Neuro-Oncology 2018). Methods: For this multi-site, open-label, phase 2 study (NCT02655601), we will randomize approximately 160 patients 1:1 to concurrent RT and TMZ with BMX-001 versus concurrent RT and TMZ alone. Key eligibility criteria include newly diagnosed histologically confirmed high-grade glioma (WHO III-IV), 18 ≥ years, and Karnofsky performance status ≥ 70%. The primary endpoint is overall survival. Secondary endpoints are objective cognitive performance, bone marrow protection, safety and tolerability, progression-free survival, overall tumor response rate, and plasma pharmacokinetics. Exploratory endpoints are patient-reported outcomes of health-related quality of life (as assessed by Functional Assessment of Cancer Therapy–Brain, Functional Assessment of Cancer Therapy-Cognition, and Functional Assessment of Chronic Illness Therapy-Fatigue), qualitative hair loss, and white matter integrity (as measured by MRI diffusion tensor/susceptibility imaging). Since November 2018, this phase 2 study has enrolled 147 of 160 high-grade glioma patients at nine sites in US. Clinical trial information: NCT02655601.

TPS1099 Background: HER2+ breast cancer patients with leptomeningeal disease (LMD) represent a poor prognosis population with a high unmet clinical need. Although a multitude of treatment options are available for the management of systemic disease, once metastases travel to the leptomeninges, patients have a lack of treatment options aside from traditional local approaches. Data from a phase I/II study reveals intrathecal (IT) trastuzumab to be well tolerated with improved overall survival (OS) compared to historical controls in HER2+ breast LMD. Radiotherapy can improve the flow of IT therapy through the cerebrospinal fluid (CSF) and provide symptomatic relief. The monoclonal antibody pertuzumab is used in conjunction with trastuzumab in the management of metastatic and localized HER2+ breast cancer. Given the role of radiotherapy in the management of LMD along with the role of pertuzumab in the management of HER2+ breast cancer, there is a strong clinical rationale to combine radiotherapy with IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. Methods: The study is designed as a prospective, single-arm, nonrandomized, open-label, phase I/II trial of radiation therapy followed by IT trastuzumab/pertuzumab in the management of HER2+ breast LMD. HER2+ LMD patients identified by magnetic resonance imaging (MRI) and/or CSF cytology, ≥ 18, with a life expectancy > 8 weeks are eligible. Treatment is initiated with radiotherapy, whole brain radiotherapy and/or focal brain/spine radiation followed by IT trastuzumab/pertuzumab. Safety and feasibility will be monitored by a modified toxicity probability interval-2 (mTPI-2) design. Dose reductions of IT trastuzumab will not be allowed. Once the maximum tolerated dose of IT pertuzumab is determined, the phase II portion of the study will commence to determine OS. Secondary objectives involve defining the CSF pharmacokinetics of IT trastuzumab/pertuzumab, evaluating the response rate (leptomeningeal and parenchymal), and progression free survival (leptomeningeal and parenchymal) following IT trastuzumab/pertuzumab. In the phase 2 portion, a single-arm two-stage trial is designed using the Restricted-Kwak-and-Jung’s Method. The primary endpoint is one-year OS. An interim analysis will be performed after 20 patients are enrolled. This study is open with 1 patient enrolled at the time of submission. Clinical trial information: NCT04588545 .

Background Carboplatin is a potent cytoreductive agent for a variety of solid tumors. However, when delivered systemically, clinical efficacy for the treatment of high grade gliomas is poor due to limited penetration across the blood-brain barrier (BBB). Direct intracerebral (IC) convection-enhanced delivery (CED) of carboplatin has been used to bypass the BBB and successfully treat the F98 rat glioma. Based on these studies, we initiated a Phase I clinical trial. Objective This Phase I clinical trial was conducted to establish the maximum tolerated dose and define the toxicity profile of carboplatin delivered intracerebrally via convection enhanced delivery (CED) for patients with high grade glial neoplasms. Methods Cohorts of 3 patients with recurrent WHO grade III or IV gliomas were treated with escalating doses of CED carboplatin (1–4 μg in 54mL over 72 hours) delivered via catheters placed at the time of recurrent tumor resection. The primary outcome measure was determination of the maximum tolerated dose (MTD). Secondary outcome measures included overall survival (OS), progression-free survival (PFS), and radiographic correlation. Results A total of 10 patients have completed treatment with infusion doses of carboplatin of 1μg, 2μg, and 4μg. The total planned volume of infusion was 54mL for each patient. All patients had previously received surgery and chemoradiation. Histology at treatment include GBM (n = 9) and anaplastic oligodendroglioma (n = 1). Median KPS was 90 (range, 70 to 100) at time of treatment. Median PFS and OS were 2.1 and 9.6 months after completion of CED, respectively. A single adverse event possibly related to treatment was noted (generalized seizure). Conclusions IC CED of carboplatin as a potential therapy for recurrent malignant glioma is feasible and safe at doses up to 4μg in 54mL over 72 hours. Further studies are needed to determine the maximum tolerated dose and potential efficacy.

Ewing sarcoma family of tumors predominantly affect the pediatric population in the long bones of the extremities or the pelvis, and only 8% of cases arise within the spine. Primary Ewing’s sarcoma of the cervical spine is extremely rare and less than 30 cases have been reported in the literature thus far. Here we present a case of primary Ewing’s sarcoma of the cervical spine in a 28-year-old female who presented with a three-month history of neck pain and right arm radiculopathy. MRI revealed a homogeneously contrast enhancing, eccentric mass with dural tail at C2-C7. After undergoing a hemilaminectomy, histopathology confirmed extraosseous Ewing’s sarcoma with CD99 positivity. A comprehensive systemic and neuraxis work-up ruled out overt metastasis. We extrapolated data from children’s cooperative group studies and IESS-II clinical trial to formulate a three phase treatment protocol as described below. To date, patient is in remission with no evidence of any residual disease in the cervical spine. In conclusion, although Primary Ewing’s sarcoma of the cervical spine is extremely rare it should be considered a differential diagnosis in patients with neck pain and a spinal mass under the age of thirty. Less than 25% of EFT’s present with overt metastasis and almost all have subclinical metastatic disease at the time of diagnosis, therefore, a comprehensive evaluation and systemic chemotherapy is recommended. We recommend a multidisciplinary approach of surgical decompression to preserve neurological functions, followed by compressed chemotherapy regimens, reevaluation for local treatment, and adjuvant chemotherapy.

INTRODUCTION Treatment-induced cerebral necrosis (TN) is a challenging complication encountered in neuro-oncology. Diagnosis and treatment of TN remains poorly defined. METHODS In this single institution, retrospective study, consecutive patients with gliomas and TN between 01/01/2012 and 04/20/2020 at the OSUCCC were identified. Details of the tumor treatment, molecular markers, radiological and pathological findings of TN, as well as treatment, recurrence rate and management upon recurrence were collected. RESULTS Of the 53 patients analyzed, 37 had glioblastoma, 7 had anaplastic oligodendroglioma and 9 had grade II or III astrocytoma. MGMT promoter hypermethylation was present in 31/50 (59%) and IDH mutation in 17/53 (32%). Diagnosis of TN was based on histology in 43/53 (81%) or clinical/radiographic features in 10/53 (19%). Worsening of focal weakness (36%), seizures (9%) or being (30%) were common presentations at TN diagnosis. Patient with right compared to left hemisphere involvement were more symptomatic at TN diagnosis. (p=0.049). Bevacizumab (BEV) (51%), resection (28%), steroids only (9%) or Laser Interstitial Thermal Therapy (6%) were used to treat TN. Steroids were weaned off in 20/27 (74%) after receiving BEV. Among all treatments, BEV was significantly associated with a better outcome (resolution or partial improvement of enhancement in 84.6%) (p=0.0006, Bonferroni corrected p< 0.005). TN Recurrence occurred in 36%, 70% and 100% of the patients treated with BEV, resection and LITT respectively. The median duration to TN recurrence was 10 weeks (range: 3–70 weeks). Initial treatment used for TN, MGMT methylation and IDH mutation status did not predict TN recurrence. (p=0.074; p=0.819; p=0.607 respectively). CONCLUSIONS BEV appears to be a superior treatment to control TN overall. Recurrence of TN in patients previously treated with BEV was 36%. There was no difference in the risk of developing recurrent TN based on MGMT or IDH status.

INTRODUCTION While advocacy for inmates with cancer has recently gained momentum, little is known about management of brain tumors in inmates. Delays in acknowledging or recognizing nonspecific initial symptoms can lead to delayed diagnosis and treatment. Inmates with cancer are reported to either be ignored or receive substandard care due in part to cost or logistics (American Civil Liberties Union; ASCO Post 2018). METHODS In this retrospective study, we identified inmates with gliomas seen in the Ohio State University Neuro-oncology Center between 1/1/2010-4/20/2019. RESULTS Twelve patients were identified. Median age at presentation was 39.5 years (range 28-62). Eleven patients were Caucasian and one was African American. Diagnoses included glioblastoma (GBM) (n=6), anaplastic astrocytoma (n=1), anaplastic oligodendroglioma (n=1), low-grade astrocytoma (n=3) and anaplastic pleomorphic xanthroastrocytoma (n=1). Patients were more likely to present early after seizures or focal neurologic deficits (9/12) than after headaches alone. Patients with GBM started RT 12-71 days after surgery (median 34.5). One patient’s post-RT MRI was delayed by a month and another with GBM had treatment held after 4 cycles of adjuvant temozolomide (TMZ) due to “incarceration issues”. For one patient who received adjuvant TMZ, the facility failed to communicate with the primary team throughout treatment. Two patients suffered significant nausea while on chemotherapy due to inability to obtain ondansetron in prison, or due to wrong timing. 7/12 (58%) patients were lost to follow-up for periods of 3-15 months during treatment. Three patients refused adjuvant treatment. CONCLUSIONS Although this is a small series, our results highlight the inequities and challenges faced by inmates with gliomas who are more likely to forego treatments or whose incarceration prevents them from keeping appropriate treatment and follow-up schedules. Additional studies are needed to define and address these deficiencies in the care of inmates with brain tumors and other cancers.

INTRODUCTION Radiation necrosis (RN) is a potential complication after radiation therapy to primary brain tumors and brain metastases. The pathophysiology of RN is not well understood but it is hypothesized that vascular endothelial growth factor (VEGF) plays an important role. Bevacizumab, a monoclonal antibody against VEGF-A, is often successful in the management of RN. The objective of this study is to assess whether VEGF receptor (VEGFR) inhibitors, a group of oral tyrosine kinase inhibitors (TKIs), can prevent or reverse cerebral radiation necrosis METHODS We retrospectively studied a cohort of 102 patients with renal cell carcinoma (RCC) and brain metastases seen at The Ohio State University James Cancer Center between 01/01/2011 and 04/30/2019. We identified those who developed RN and analyzed the temporal relationship between the use of VEGFR TKIs and the development of RN. RESULTS The cumulative incidence of RN in our cohort is 13.7% after radiation treatments that included LINAC-based stereotactic radiosurgery, fractionated stereotactic radiotherapy, or Gamma Knife radiosurgery. There was no statistically significant difference in the cumulative incidence of RN between patients taking TKIs and patients who were off TKIs (9.9% and 11.5% respectively, p= 0.741). The median time to development of RN was only numerically shorter in patients taking TKIs (151 versus 315 days, p=0.315). One patient developed RN after stopping cabozantinib. Three other patients developed RN while on cabozantinib. Two patients developed RN while on pazopanib, and 3 patients developed RN while on sunitinib. One patient was started on axitinib during active RN without significant improvement subsequently. CONCLUSIONS VEGFR TKIs do not consistently prevent or reverse cerebral radiation necrosis and do not seem to have the efficacy that bevacizumab has against RN.

TPS2577 Background: Patients diagnosed with malignant high-grade gliomas (WHO grade III-IV) experience significant morbidity and mortality associated with these cancers. While the mainstay of therapy for patients with newly diagnosed high-grade glioma is surgery followed by concurrent chemotherapy and radiation therapy (RT), the outcomes remain very poor. BMX-001 (MnTnBuOE-2-PyP5+) is a metalloporphyrin with differential action in response to radiation therapy and chemotherapy-induced oxidative stress. Early preclinical studies demonstrated BMX-001’s ability to act as a radioprotectant to healthy tissue such as a central nervous white matter and as a radiosensitizer to cancer cells, in particular, human glioblastoma xenografts. We evaluated the safety of BMX-001 in combination with concurrent RT and temozolomide (TMZ) in a phase I study of newly diagnosed high-grade glioma patients, and we found that BMX-001 is safe and well-tolerated in this population. The maximum tolerated dose of BMX-001 during concurrent RT and TMZ was determined to be 28 mg delivered subcutaneously (SC) followed by 16 biweekly SC doses at 14 mg (Peters et al., Neuro-Oncology 2018). Methods: For this multi-site, open-label, phase II study (NCT02655601), we will randomize approximately 160 patients 1:1 to concurrent RT and TMZ with BMX-001 versus concurrent RT and TMZ alone. Key eligibility criteria include newly diagnosed histologically confirmed high-grade glioma (WHO III-IV), 18 ≥ years, and Karnofsky performance status ≥ 70%. The primary endpoint is overall survival. Secondary endpoints include cognitive performance as assessed by standardized cognitive testing, bone marrow protection, safety and tolerability, progression-free survival, overall tumor response rate, and plasma pharmacokinetics. Exploratory endpoints are health-related quality of life (as assessed by Functional Assessment of Cancer Therapy–Brain, Functional Assessment of Cancer Therapy-Cognition, and Functional Assessment of Chronic Illness Therapy-Fatigue), qualitative hair loss, and white matter integrity (as measured by MRI diffusion tensor/susceptibility imaging). Since November 2018, this phase II study has enrolled 64 of 160 high-grade glioma patients at six sites with future sites planned to be implemented. Clinical trial information: NCT02655601 .

Meningiomas are common intracranial brain tumors. Despite surgery and/or radiation therapy, recurrence rates occur in approximately 8–10 % of tumors. This may be due to the dysregulation of the cyclin D and cyclin-dependent kinase (CDK) pathway in malignant meningioma cells and radiation-resistant meningioma cells. The cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway controls the cell cycle restriction point, and is commonly dysregulated in meningioma; making it a rational target for antimeningioma therapy. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function against Rb+ meningiomas cells in vitro, ex vivo and in vivo xenograft model. Meningioma tumors in SCID mice treated daily with intraperitoneal injections of palbociclib for 14 days dose dependly with X ray irradiation. Treatment effects were examined by immunoblot, cell viability, apoptosis, and cell cycle progression. Radiation resistance BENMEN1 cells were developed after exposure to repeated 320 kV X ray irradiation. Since CDK4 and CDK6 are proteins that are major part of a cell cycle regulatory pathway in meningioma that also includes p16, cyclin D, and the retinoblastoma (Rb) protein, we analyzed those parameters. Our both in vitro and in vivo data clearly demonstrate that pallbociclib (CDK 4/6 inhibitor) treatment reduced proliferation and has additional effects on cell cycling, including induction of an RB-associated G(1) arrest against Rb+ malignant meningioma cells and radiation-resistant meningioma cells. We did not see any significant effect of palbociclib on Rb – meningima cells. Our results also demonstrated that palbociclib treatment inhibits CDK4 and CDK6 expression and also decreases E2F target gene expression (CCNA2 and CCNE2). All together, our results provide strong evidence that palbociclib can be applied to Rb+ meningiomas as a therapeutic agent.

BACKGROUND: Saposin C-dioleylphosphatidylserine (SapC-DOPS) is a novel blood-brain barrier penetrant nanoliposomal agent that targets externalized phosphatidylserine overexpressed on tumor cell membranes. A recent Phase 1a BXQ-350 trial (NCT02859857) reported SapC-DOPS was well tolerated in both solid tumor and high-grade glioma (HGG) patients with potential for treating clinically challenging gliomas, including their diffuse infiltrative components. METHODS: We evaluated the HGG subset of the ongoing Phase 1 study of IV BXQ-350 administered on Days 1–5, 8, 10, 12, 15, 22 (cycle 1) and each 28 day cycles thereafter. MRI neuroimaging (e.g. Axial T1-post-contrast Ax SE T1 POST-FC and medically necessary views) at Days 29, 57, 113, and 171 (or withdrawal) were completed. RANO assessment, functional neurological deficits, ECOG Performance Status, and safety were assessed. RESULTS: The HGG patients (9/17) were dosed at 0.7 (N = 1), 1.1 (N = 1), 1.4 (N = 2), 1.8 (N = 2), or 2.4 (N = 3) mg/kg, with 8/9 completing a full cycle before withdrawal (7 due to progression, 1 voluntary withdrawal). BXQ-350 was not linked to dose limiting toxicities or severe adverse reactions. Functional neurological deficits and ECOG decline were proportional to radiological progression, with ECOG scores declining from a baseline 0–1 in 2/9 (22%) to 3. One patient completing 6 cycles (>12 months) of BXQ-350 therapy (0.7 mg/kg) exhibited stable disease, -7% lesion size, and no significant progressive functional neurological deficits. Three patients underwent surgery for progression while on treatment. CONCLUSIONS: BXQ-350 was well tolerated by GBM patients with promising best response apparent in neuroimaging, suggesting therapeutic benefit warranting further trials. Updates from the ongoing trial will be presented.

Triple-negative breast cancers (TNBC) often exhibit an aggressive phenotype and their progression from the primary tumor setting to the metastatic setting is the critical event defining Stage IV disease, no longer considered curable. The microenvironment at brain sites is known to play a key role in influencing the ultimate fate of metastatic cells. Specifically, defects in MHC class I/II antigen processing molecules may negatively impact the clinical course and the response to T cell-based immunotherapy. In the present investigation, we analyzed the expression level of leukocyte antigen class I/II antigen processing molecules on TNBC cells (mouse: EO771, human: MDA MB231) in primary cell-line specific media and organ (brain) conditioned media to better understand their in vivo metastatic potential. TAP1 encodes a protein necessary for transport of cytosolic peptides into membrane bound organelles for MHC 1 presentation. Our western blot data showed lower level expression of MHC class I/II antigen processing molecules including Transporter associated with Antigen Processing protein 1 (TAP1) on human TNBC cells in both cell-line specific normal media and brain conditioned media. Furthermore, TNBC cells stably transfected with silencing hairpin (sh)RNA for TAP1 demonstrated a decreased susceptibility to cytotoxic T lymphocytes in in both cell-line specific media conditioned media and organ (brain) conditioned media. This data supports the functional significance of TAP expression in TNBC cells. Taken together, our data suggest that patients with low or defective TAP in TNBC cells may be at higher risk for developing brain metastases. The examination of expression of MHC class I/II and related antigen processing molecules, as critical components of the antitumor immune system, may be useful for the prediction of tumor progression and metastasis risk of triple negative breast cancer.

Glioblastoma (GB) is the most common and highly aggressive adult brain cancer. Dysfunction of receptor tyrosine kinases, such as ALK, c-Met and VEGF have all been implicated in the progression of this malignancy and resistance to therapy. Traditional therapeutic strategies targeting ALK/c-Met or VEGF have not yet given satisfactory outcomes. Myxoma virus (MYXV) is a novel oncolytic virus that has been shown to replicate in GB models. Here, we investigated the efficacy of MYXV as monotherapy, or in combination with 1 Gy radiation plus c-Met/ALK inhibitor crizotinib and VEGF inhibitor bevacizumab in different cell lines (GL261, T9, and U118) surgically obtained from GB patients. We investigated the molecular mechanisms of apoptotic death by Western blots. Colorimetric assay demonstrated that treatment with MYXV plus radiation with crizotinib or bevacizumab caused apoptosis due to an increase in activation of caspase-3 and decrease in expression of Bcl-2 proteins in GB cells and tissues. Most importantly, MYXV plus radiation significantly enhanced the anti-cancer effect of crizotinib, bevacizumab and temozolomide, in GB cell lines as well as in fresh tumor biopsies from GB patients. Our studies also suggest that induction of apoptosis by MYXV does not depend on the functional status of the GB cell lines or in the GB tissues. Further studies in different animal models of GB are warranted in the future to determine whether MYXV in combination with radiation, crizotinib or bevacizumab may be useful as anti-cancer agent for the management of human GBs in vivo.

Summary Background Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma. Methods In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150–200 mg/m 2 for 5 of 28 days) for 6–12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour 2 post-chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479. Findings Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease [SRD], and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20·1 months (95% CI 18·5–22·1) in the rindopepimut group versus 20·0 months (18·1–21·9) in the control group (HR 1·01, 95% CI 0·79–1·30; p=0·93). The most common grade 3–4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache (six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] in the control group), of which one—a pulmonary embolism in a 64-year-old male patient after 11 months of treatment—was assessed as potentially related to rindopepimut. Interpretation Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma. Funding Celldex Therapeutics, Inc.

OBJECTIVES 1) Determine the response rate (RR) after chemotherapy with high-dose methotrexate with or without vincristine in patients with primary CNS lymphoma. 2) Determine the difference in adverse effects with the use of vincristine. 3) Determine the difference in progression-free survival (PFS) and overall survival (OS) between the 2 groups. METHODS Retrospective study in patients 18–89 years with primary CNS lymphoma that received chemotherapy with rituximab (R), methotrexate (M), procarbazine (P), and vincristine (V) R-MPV, R-MV, R-MP, or R-M between 2010 and 2018 at The Ohio State University. Response rate by cycle 7 was compared with odds ratio. Kaplan-Meier curves were used to compare OS and PFS. RESULTS 29 patients were included: 16 (55%) received vincristine. 14/16 patients treated with vincristine and 4/13 in the other group also had procarbazine. 12/29 patients had a complete response after a maximum of 7 cycles. The odds of complete response were 24% higher in patients treated with vincristine but the difference did not reach statistical significance. Side effects were higher in the vincristine arm. The most common was peripheral neuropathy (75% vs 8% - all grades). Median PFS was 60.7 months for the vincristine group and 23.7 months for the non-vincristine group. Median OS was 85.3 months for the vincristine group and 67.1 months for the non-vincristine group. OS and PFS curves did not differ significantly. CONCLUSIONS The use of vincristine in high-dose methotrexate chemotherapy regimens for CNS lymphoma was not associated with a statistically significant difference in RR. Patients who received vincristine had more side effects and there were no significant differences in OS and PFS. The sample size and rate of procarbazine use may be confounding factors. Further studies are necessary to determine the effect of vincristine in RR and OS in these patients.

OBJECTIVE Reporting and citation bias based on positive versus negative outcome among completed phase III interventional brain tumor trials (IBTTs) have not been previously reported. Thus, we aimed to assess the evidence. METHODS Clinicaltrials.gov was used to obtain all phase III IBTTs completed prior to December 31st 2016. Trials closed due to poor accrual or non-phase III were excluded. Data about the funding source, type of intervention, conducted at U.S or Non-U.S locations, patients enrolled, primary completion date, time to dissemination of results in months (either reported on clinicaltrials.gov or published in a journal), citations per year (from web of science) and outcome (positive or neutral/negative) were abstracted. Median time to dissemination was estimated using Kaplan-Meier estimates and a log rank test for statistical significance. The number of citations per year for positive and negative/neutral studies was compared using a t-test. RESULTS 65 studies were analyzed. The median time from primary completion to dissemination of results for trials with a positive outcome was 20 months (n = 20; 95% CI: 12–31) compared to 30 months for trials with a negative outcome (n=35; 95 % CI: 22 – 37) (p = 0.095). The average number of citations per year for trials with a positive outcome is 62.4 (n = 21; range 1.1 – 614.8) compared to 25.0 for trials with a negative outcome (n=35; range 0.14 - 158.8) (p = 0.213). There was no significant difference in time to dissemination based on the funding source, type of intervention or the location where the trial was conducted. CONCLUSION Positive phase III IBTTs results are disseminated earlier and are cited more frequently compared to negative trials. However, there is no statistically significant evidence of reporting or citation bias.

e13537 Background: Leptomeningeal disease (LMD) is an uncommon event in patients with gliomas which is estimated to occur in 4% of cases and is associated with poor outcome. Genomic alterations in gliomas that precipitate LMD have not been characterized. Methods: We performed a retrospective chart review of patients with gliomas (grade II-IV)- for whom we have genomic testing data at The Ohio State University. We identified patients who developed LMD. LMD was defined as leptomeningeal enhancement as seen on brain or spine imaging. Patients with negative cerebrospinal fluid (CSF) cytology were not excluded if imaging was convincing of LMD. Genomic testing was performed through Foundation One. Results: 129 charts of glioma patients were reviewed. We identified 6 patients with LMD. One is still alive. All patients were diagnosed histologically as glioblastoma. One patient had Lynch syndrome. All patients were men with a median age at diagnosis of 44 (range 20-65). All tumors appeared to have extended into the ventricles on brain imaging. 4 tumors had evidence of subependymal spread prior (range 45-93 days) or at the time of LMD enhancement. 4 patients had available CSF studies: 2 of whom had evidence of atypical or malignant cells. CSF protein was elevated in all four samples (range 113-492 mg/dL). CSF glucose was low in all four samples (range < 10-46 mg/dL). 5 tumor samples were IDH wild type whereas 1 had IDH1 R132H mutation. MGMT promoter was methylated in 3 tumors and unmethylated in 3. The genomic alterations varied among samples and included EGFR V765M mutation (N = 1), PDGFR amplification (N = 1), PDGFRA Y849C subclonal mutation (N = 1), CDKN2A/B loss (N = 3), TP53 mutations (N = 4) and TERT promoter mutations (N = 3). No case had EGFR amplification or EGFRvIII mutation. Other alterations observed included DNMT3A mutation, KIT, MYC and MDM2 amplifications and RB1 losses. PD-L1 expression ranged from 5-40%. One intracranial sample had a 20% PD-L1 expression with LMD from this tumor exhibiting 40% PD-L1 expression. Of the five deceased patients (all IDH WT), median overall survival (OS) was 355 days (range 184-557). Median OS after LMD diagnosis was 84 days (range 58-225). Conclusions: In this series, 4.5% of glioma patients developed LMD. Samples were associated with a variety of genomic alterations but without a specific predictor of leptomeningeal involvement. This is possibly due to the small number of cases. Physical proximity of the tumor to the ventricles appears to be a potential risk factor. Larger studies of LMD in gliomas are warranted to identify potential genetic drivers, if any exist.

e13554 Background: Leptomeningeal carcinomatosis (LMC) is a complication of advanced malignancies wherein primary tumors metastasize to the leptomeninges surrounding brain and spinal cord. LMC complicates 4-15% of malignant solid tumors with incidence increasing as survival of patients with advanced cancer improves. Diagnostic methods include magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) cytology. MRI findings may be nonspecific, and the gold standard of diagnosis is malignant cytology on CSF analysis. We assessed detection methods, incidence, and outcomes of LMC at The Ohio State University Comprehensive Cancer Center from 2005-2015. Methods: This was an IRB-approved single-institution retrospective study of 160 patients with confirmed diagnosis of LMC who were treated at the OSUCCC-James between Jan 1, 2005 and Dec 31, 2015. Patients with hematologic and central nervous system malignancies were excluded. Descriptive statistics were used to summarize demographic and clinical characteristics. Overall survival (OS) was defined as time from LMC diagnosis to death or last known follow-up, and was generated using Kaplan-Meier methods. Results: Median age of LMC diagnosis was 55.8 years (range: 48, 62.5). 69 (43%) patients had primary breast cancer, 41 (26%) had lung cancer, and 17 (11%) had melanoma. 73 patients (46%) presented with stage IV disease at initial diagnosis of the primary cancer, 41 (26%) with stage III disease, and 26 (16%) with stage II disease. Median time from diagnosis of primary cancer to diagnosis of LMC was 2 years (range: 0, 31.2). 158 (99%) patients had metastases at the time of LMC diagnosis, predominantly in bone (36%) or brain (36%). Median OS was 1.9 months (CI: 1.3, 2.5). 160 (100%) patients had an MRI of the brain or spine and 155 (97%) had MRI findings consistent with LMC. 75 (47%) patients underwent lumbar puncture, and 39 (52%) had CSF cytology positive for malignancy. Conclusions: Patients with LMC commonly presented with stage IV breast cancer, lung cancer, or melanoma with metastases to the brain or bone. Despite treatment, prognosis remains poor and confirmation of diagnosis can be challenging. Clinicians should have a low threshold for investigating LMC in high risk patients presenting with neurologic signs or symptoms.

Glioblastoma (GBM) is the most common primary brain tumor. Despite aggressive treatment, GBM almost always recurs. The current standard-of-care for treatment of newly diagnosed GBM has remained relatively unchanged since 2005: maximal safe resection followed by concomitant chemoradiation (CRT) with temozolomide (TMZ), and subsequent adjuvant TMZ. In 2011, the first-generation tumor treating fields (TTF) device, known at the time as the NovoTTF-100A System (renamed Optune), was approved by the Food and Drug Administration (FDA) for treatment of recurrent GBM. The TTF device was subsequently approved as an adjuvant therapy for newly-diagnosed GBM in 2015. The following is a review of the TTF device, including evidence supporting its use and limitations.

Glioblastoma, the most lethal brain tumor, remains incurable despite aggressive chemotherapy and surgical interventions. New chemotherapeutics for glioblastoma have been explored in preclinical models and some agents have reached the clinical setting. However, success rates are not significant. Previous investigations involving diallyl trisulfide (DATS), a garlic compound, indicated significant anti-cancer effects in glioblastoma in vitro. DATS has also been shown to inhibit histone deacetylase activity and impede glioblastoma tumor progression. We hypothesized that DATS would block ectopic U87MG tumor by multiple pro-apoptotic pathways via inhibiting histone deacetylase (HDAC). To prove this, we developed ectopic U87MG tumors in SCID mice and treated them daily with intraperitoneal injections of DATS for 7 days. Results indicated that DATS (10 μg/kg-10 mg/kg) dose-dependently reduced tumor mass and number of mitotic cells within tumors. Histological and biochemical assays demonstrated that DATS reduced mitosis in tumors, decreased HDAC activity, increased acetylation of H3 and H4, inhibited cell cycle progression, decreased pro-tumor markers (e.g., survivin, Bcl-2, c-Myc, mTOR, EGFR, VEGF), promoted apoptotic factors (e.g., bax, mcalpian, active caspase-3), and induced DNA fragmentation. Our data also demonstrated an increase in p21Waf1 expression, which correlated with increased p53 expression and MDM2 degradation following DATS treatment. Finally, histological assessment and enzyme assays showed that even the highest dose of DATS did not negatively impact hepatic function. Collectively, our results clearly demonstrated that DATS could be an effective therapeutic agent in preventing tumor progression and inducing apoptosis in human glioblastoma in vivo, without impairing hepatic function.

Glioblastoma multiforme (GBM) is recognized as the most common and lethal form of central nervous system cancer. Currently used surgical techniques, chemotherapeutic agents, and radiotherapy strategies have done very little in extending the life expectancies of patients diagnosed with GBM. The difficulty in treating this malignant disease lies both in its inherent complexity and numerous mechanisms of drug resistance. In this review, we summarize several of the primary mechanisms of drug resistance. We reviewed available published literature in the English language regarding drug resistance in glioblastoma. The reasons for drug resistance in glioblastoma include drug efflux, hypoxic areas of tumor cells, cancer stem cells, DNA damage repair, and miRNAs. Many potential therapies target these mechanisms, including a series of investigated alternative and plant-derived agents. Future research and clinical trials in glioblastoma patients should pursue combination of therapies to help combat drug resistance. The emerging new data on the potential of plant-derived therapeutics should also be closely considered and further investigated.

Meningiomas are the most common primary brain tumor reported in the United States each year and account for approximately 30% of primary neoplasms. Though in most cases the etiology of meningiomas is unclear, prior exposure to radiation is responsible for a subset of meningiomas. Some have speculated that there may be a relationship between pretreatment characteristics and radiotherapy parameters in the development of radiation-induced meningiomas (RIM). Compared with their sporadic counterparts, currently, the clinical treatment involves is similar with radiation used as a first line therapy. Novel therapeutic agents being investigated in the treatment of these tumors, rely on the direct or cell cycle-mediated induction of DNA damage to promote cellular apoptosis. Our pre-clinical data showed that disruption of p16INK4a-Cdk4-Rb (retinoblastoma) pathways plays a significant role in the development of RIM in Rb+ low-gradelow-grade meningioma cells. These observations highlight the critical role of the p16INK4a-Cdk4-Rb pathway in RIM and suggest that targeting this pathway might be a promising strategy to improve the therapeutic efficacy among RIM patients. Pretreatment characteristics and radiotherapy parameters which may influence the time interval for development of radiation-induced Rb+ meningiomas (RIM) were identified. Our results also demonstrated that CDK 4/6 Inhibitor, significantly suppresses radiation induced malignant transformation and prolonged survival in a cell-free, slice culture model and xenograft model of meningioma. Success of the proposed therapeutic strategies in both in vitro and in vivo models may form the basis for future research.