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Purpose: Isocitrate dehydrogenase (IDH) 1 and IDH2 mutations (IDH1/2mt) are frequent in glioma. Preclinical studies suggest IDH1/2mts confer “BRCAness” phenotype, a vulnerability that can be targeted through PARP inhibition. To test this hypothesis, we conducted a multicenter study of olaparib monotherapy in patients with IDH1/2mt gliomas. Methods: Patients with recurrent, contrast-enhancing IDH1/2mt gliomas were enrolled in a two-step phase II trial; the primary endpoint was overall response rate per Response Assessment in Neuro-Oncology (RANO) criteria. Olaparib 300 mg orally twice daily was given. Results: A total of 15 evaluable patients were enrolled. Histology was astrocytoma (N = 12) and oligodendroglioma (N = 3). Most toxicities were grade 1 or 2. Best response was stable disease (SD) in 9 (60%) patients. Median progression-free survival (PFS) was 3.63 months and median overall survival was 20.7 months. For patients with SD, median PFS was 5.53 months; 4 patients had SD for >6 months. Among patients with best response progressive disease (N = 6), 5 had grade 4 tumor and 4 had known CDKN2A alteration. PFS was 5.23 months for grades 2 or 3 tumors (N = 10) versus 1.8 months for grade 4 (N = 5; P = 0.0013). Conclusion: The study did not meet the prespecified response-based activity threshold for moving to step 2. However, prolonged SD was observed in patients with grades 2 and 3 histologies, suggesting olaparib monotherapy could be of clinical benefit in select populations. Grade 4 tumors per 2021 World Health Organization classification defined by histology or CDKN2A alteration derived no benefit from this drug, highlighting the usefulness of this classification for future patient stratification and trial design. Significance: A single-arm phase II trial of olaparib in IDH-mutant glioma demonstrated clinically significant prolonged SD for select patients with grade 2/3 disease, suggesting potential benefit of olaparib in IDH-mutant gliomas.

Purpose: Glioblastoma is a malignant brain tumor requiring careful clinical monitoring even after primary management. Personalized medicine has suggested use of various molecular biomarkers as predictors of patient prognosis or factors utilized for clinical decision making. However, the accessibility of such molecular testing poses a constraint for various institutes requiring identification of low-cost predictive biomarkers to ensure equitable care. Methods: We collected retrospective data from patients seen at Ohio State University, University of Mississippi, Barretos Cancer Hospital (Brazil), and FLENI (Argentina) who were managed for glioblastoma—amounting to nearly 600 patient records documented using REDCap. Patients were evaluated using an unsupervised machine learning approach comprised of dimensionality reduction and eigenvector analysis to visualize the inter-relationship of collected clinical features. Results: We discovered that white blood cell count of a patient during baseline planning for treatment was predictive of overall survival with an over 6-month median survival difference between the upper and lower quartiles of white blood cell count. By utilizing an objective PDL-1 immunohistochemistry quantification algorithm, we were further able to identify an increase in PDL-1 expression in glioblastoma patients with high white blood cell counts. Conclusion: These findings suggest that in a subset of glioblastoma patients the incorporation of white blood cell count and PDL-1 expression in the brain tumor biopsy as simple biomarkers predicting glioblastoma patient survival. Moreover, use of machine learning models allows us to visualize complex clinical datasets to uncover novel clinical relationships.

Representativeness of Study Participants

Definition of Progression, Tumor Classification, and Eligibility Criteria, retreatment criteria

Purpose:Isocitrate dehydrogenase (IDH) 1 and IDH2 mutations (IDH1/2mt) are frequent in glioma. Preclinical studies suggest IDH1/2mts confer “BRCAness” phenotype, a vulnerability that can be targeted through PARP inhibition. To test this hypothesis, we conducted a multicenter study of olaparib monotherapy in patients with IDH1/2mt gliomas.Methods:Patients with recurrent, contrast-enhancing IDH1/2mt gliomas were enrolled in a two-step phase II trial; the primary endpoint was overall response rate per Response Assessment in Neuro-Oncology (RANO) criteria. Olaparib 300 mg orally twice daily was given.Results:A total of 15 evaluable patients were enrolled. Histology was astrocytoma (N = 12) and oligodendroglioma (N = 3). Most toxicities were grade 1 or 2. Best response was stable disease (SD) in 9 (60%) patients. Median progression-free survival (PFS) was 3.63 months and median overall survival was 20.7 months. For patients with SD, median PFS was 5.53 months; 4 patients had SD for >6 months. Among patients with best response progressive disease (N = 6), 5 had grade 4 tumor and 4 had known CDKN2A alteration. PFS was 5.23 months for grades 2 or 3 tumors (N = 10) versus 1.8 months for grade 4 (N = 5; P = 0.0013).Conclusion:The study did not meet the prespecified response-based activity threshold for moving to step 2. However, prolonged SD was observed in patients with grades 2 and 3 histologies, suggesting olaparib monotherapy could be of clinical benefit in select populations. Grade 4 tumors per 2021 World Health Organization classification defined by histology or CDKN2A alteration derived no benefit from this drug, highlighting the usefulness of this classification for future patient stratification and trial design.Significance:A single-arm phase II trial of olaparib in IDH-mutant glioma demonstrated clinically significant prolonged SD for select patients with grade 2/3 disease, suggesting potential benefit of olaparib in IDH-mutant gliomas.

Supplementary Table from Infigratinib in Patients with Recurrent Gliomas and FGFR Alterations: A Multicenter Phase II Study

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.

Supplementary Figure from Infigratinib in Patients with Recurrent Gliomas and FGFR Alterations: A Multicenter Phase II Study

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.

Background and purpose: Primary central nervous system lymphoma (PCNSL) lesions often show avid contrast enhancement on T1-weighted contrast-enhanced MRI sequences. However, several case reports and a clinical study have described PCNSL in patients with no contrast enhancement on MRI. We assessed whether overall survival (OS) time was related to any tumor characteristics (lesion location, volume, and number; contrast enhancement; necrosis; proximity to the subarachnoid space; and edema) on MRI in patients with PCNSL. Materials and Methods We retrospectively reviewed records (MRI features, pathology, and survival data) of all patients at our institution with PCNSL who had been seen from, 2007 through 2017, and had undergone pretreatment MRI. Results We identified 79 patients (42 men, 37 women) with a mean age at diagnosis of 61.7 ± 10.4 years. The mean OS duration was 44.6 ± 41.7 months. The most common pathological diagnosis (74 patients) was diffuse large B-cell lymphoma. No associations were found between OS time and lesion location, volume, and number; contrast enhancement; necrosis; proximity to the subarachnoid space; or edema. However, a sole patient with non-enhancing PCNSL on MRI was found to have low-grade disease, with prolonged survival (>83 months). Several other patients with leptomeningeal disease had a mean OS time of 80 months. Patients with hemorrhagic lesions had a mean OS of 25.5 months. Conclusions The survival time for patients with PCNSL may be longer than previously thought, especially for patients with leptomeningeal seeding and lesions with hemorrhagic components Also, non-enhancing tumors may be less aggressive than enhancing tumors.

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:The standard of care for elderly glioblastoma (GBM) 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.Methods:Elderly patients (≥ 65 years old) who received hypofractionated radiation with TMZ from 2010-2020 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 between patients who received 40 Gy and 52.5 Gy. Univariable and multivariable analyses were performed.Results: 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. Overall survival (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. Conclusions: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.

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.

Extent of resection of low grade glioma (LGG) is an important prognostic variable, and may influence decisions regarding adjuvant therapy in certain patient populations. Immediate postoperative magnetic resonance image (MRI) is the mainstay for assessing residual tumor. However, previous studies have suggested that early postoperative MRI fluid-attenuated inversion recovery (FLAIR) (within 48 h) may overestimate residual tumor volume in LGG. Intraoperative magnetic resonance imaging (iMRI) without subsequent resection may more accurately assess residual tumor. Consistency in MRI techniques and utilization of higher magnet strengths may further improve both comparisons between MRI studies performed at different time points as well as the specificity of MRI findings to identify residual tumor. To evaluate the utility of 3 T iMRI in the imaging of LGG, we volumetrically analyzed intraoperative, early, and late (~ 3 months after surgery) postoperative MRIs after resection of LGG.A total of 32 patients with LGG were assessed retrospectively. Residual tumor was defined as hyperintense T2 signal on FLAIR. Volumetric assessment was performed with intraoperative, early, and late postoperative FLAIR via TeraRecon iNtuition.Perilesional FLAIR parenchymal abnormality volumes were significantly different comparing intraoperative and early postoperative MRI (2.17 ± 0.45 cmIntraoperative 3 T MRI without further resection appears to better reflect the volume of residual tumor in LGG compared with early postoperative 3 T MRI. Early postoperative MRI may overestimate residual tumor. As such, intraoperative MRI performed after completion of tumor resection may be more useful for making decisions regarding adjuvant therapy.

Background Myelopathy of the dorsal columns is a rare complication of intrathecal (IT) chemotherapy that occurs most frequently with IT methotrexate and cytarabine. This diagnosis is made with a combination of magnetic resonance imaging, somatosensory evoked potentials, and elevated cerebrospinal fluid (CSF) protein levels, particularly myelin basic protein. Case Description A 73-year-old man with blastic plasmacytoid dendritic cell neoplasm and known central nervous system involvement underwent standard treatment, including 5 doses of IT cytosine arabinoside. Following this, he had documented CSF clearance of disease. One year later, he developed progressive lower extremity weakness, numbness, and bowel/bladder dysfunction. Magnetic resonance imaging and repeat CSF analysis demonstrated recurrence, and he underwent further IT administration of methotrexate and cytarabine. CSF clearance of malignant cells was again established. However, weakness progressed to quadriplegia; loss of bowel/bladder control; and severe sensory loss, particularly vibration and proprioception. Repeat magnetic resonance imaging demonstrated high signal intensity in bilateral posterior columns. A lower thoracic spine dorsal column biopsy revealed cord destruction and diffuse macrophage infiltration with profound destruction of the neuropil. Conclusions Although dorsal column myelopathy has previously been described in association with IT chemotherapy, this has solely been diagnosed on the basis of clinical examination, electrodiagnostic criteria, radiographic findings, and CSF analysis. This case provides a pathologic evaluation of an antemortem obtained specimen revealing diffuse macrophage infiltration and profound destruction of the neuropil. Whereas the mechanism underlying spinal cord toxicity following IT chemotherapy remains largely unknown, this case demonstrates a potentially macrophage-mediated process.

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.

PurposeLeptomeningeal carcinomatosis (LMC), a common complication of advanced malignancies, is associated with high morbidity and mortality, yet diagnosis and treatment decisions remain challenging. This study describes the diagnostic and treatment modalities for LMC and identifies factors associated with overall survival (OS). MethodsWe performed a single-institution retrospective study of 153 patients diagnosed with LMC treated at The Ohio State University between January 1, 2010 and December 31, 2015. ResultsMedian age at diagnosis was 55.7 years, and 61% had Eastern Cooperative Oncology Group baseline performance status ≤1. Most common primary tumors were breast (43%), lung (26%), and cutaneous melanoma (10%). At presentation, most patients were stage III-IV (71%) with higher grade tumors (grade III: 46%). Metastases to bone (36%), brain (33%), and lung (12%) were the most common sites with a median of 0.5 years (range, 0-14.9 years) between the diagnosis of first metastasis and of LMC. 153 (100%) patients had MRI evidence of LMC. Of the 67 (44%) who underwent lumbar puncture (LP), 33 (22%) had positive cerebrospinal fluid (CSF) cytology. Most patients received radiotherapy for LMC (60%) and chemotherapy (93%) for either the primary disease or LMC. 28 patients received intrathecal chemotherapy, 22 of whom had a primary diagnosis of breast cancer. 98% died with median OS of all patients was 1.9 months (95% CI: 1.3-2.5 months). ConclusionDespite improved treatments and targeted therapies, outcomes of LMC remain extremely poor. Positive CSF cytology was associated with lower OS in patients who had cytology assessed and specifically in patients with breast cancer. CSF cytology serves as an important indicator for prognosis and helps aid in developing individualized therapeutic strategies for patients with LMC.

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.

AimsReporting 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.MethodsClinicaltrials.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.Results67 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.ConclusionThere was no evidence of reporting or citation bias among completed phase III IBTTs. Nevertheless, positive phase III IBTTs were reported more promptly and cited more often compared to negative or neutral trials. These findings might need consideration for risk of bias assessment while conducting systematic reviews.

Background Primary central nervous system lymphoma (PCNSL) is a rare malignancy with few treatment options. One regimen used for induction is rituximab, high-dose methotrexate (HD-MTX), procarbazine, and vincristine (R-MPV). A common institutional practice is removing vincristine (VCR) from this regimen due to its poor CNS penetration and associated toxicities. The aim of this study was to evaluate how the omission of VCR from HD-MTX-based induction impacted clinical outcomes. Methods In a retrospective review, patients with PCNSL who received HD-MTX-based induction therapy between January 1, 2010 and May 31, 2018 were evaluated. Patients were stratified according to treatment into 2 groups, VCR-containing therapy versus no VCR. The primary endpoint was complete response (CR) rate following the completion of induction chemotherapy. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse event rate. Results Twenty-nine patients were included: 16 patients in the VCR group and 13 in the non-VCR group. A CR was achieved in 7 (44%) and 5 (38%) (odds ratio [OR] = 1.24; 95% confidence interval [CI]: 0.28–5.53) patients, respectively. Median OS was 85.3 (95% CI: 20.2–85.3) versus 67.1 months (95% CI: 10.5–NR) and median PFS was 60.7 (95% CI: 9.4–NR) versus 23.7 months (95% CI: 4.7–NR) in the VCR group versus non-VCR group, respectively. The incidence of any grade peripheral neuropathy was higher in the VCR group. Conclusions CR rate, OS, and PFS were similar between groups regardless of VCR inclusion. Adverse events were higher in the VCR group. Larger studies are required to further evaluate the efficacy of VCR in PCNSL induction regimens.

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.