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Background Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody–drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs. Methods In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. Results There were 639 randomized patients (median age 60, range 22–84; 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82–1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% confidence interval [CI] 0.70–1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56–0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61–0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3–4), causing 12% to discontinue. Conclusions Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM. No new important safety risks were identified.

BackgroundLimitations in trial design, accrual, and data reporting impact efficient and reliable drug evaluation in cancer clinical trials. These concerns have been recognized in neuro-oncology but have not been comprehensively evaluated. We conducted a semi-automated survey of adult interventional neuro-oncology trials, examining design, interventions, outcomes, and data availability trends.MethodsTrials were selected programmatically from ClinicalTrials.gov using primary malignant central nervous system tumor classification terms. Regression analyses assessed design and accrual trends; effect size analysis utilized survival rates among trials investigating survival.ResultsOf 3038 reviewed trials, most trials reporting relevant information were nonblinded (92%), single group (65%), nonrandomized (51%), and studied glioblastomas (47%) or other gliomas. Basic design elements were reported by most trials, with reporting increasing over time (OR = 1.24, P < .00001). Trials assessing survival outcomes were estimated to assume large effect sizes of interventions when powering their designs. Forty-two percent of trials were completed; of these, 38% failed to meet their enrollment target, with worse accrual over time (R = −0.94, P < .00001) and for US versus non-US based trials (OR = 0.5, P < .00001). Twenty-eight percent of completed trials reported partial results, with greater reporting for US (34.6%) versus non-US based trials (9.3%, P < .00001). Efficacy signals were detected by 15%–23% of completed trials reporting survival outcomes.ConclusionLow randomization rates, underutilization of controls, and overestimation of effect size, particularly pronounced in early-phase trials, impede generalizability of results. Suboptimal designs may be driven by accrual challenges, underscoring the need for cooperative efforts and novel designs. The limited results reporting highlights the need to incentivize data reporting and harmonization.

Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single-arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1% [95% CI 4.23; 8.76%] for cytotoxic chemothera + pies (ORR = 7.59% for lomustine, 7.57% for temozolomide, 0.64% for irinotecan, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2 = 0.4078, P < .0001), biologics (R2 = 0.4003, P = .0003), and immunotherapy trials (R2 = 0.8994, P < .0001), but not anti-angiogenic agents (R2 = 0, P = .8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2 = 0.3900, P < .0001; mOS [weeks] = 1.4xORR + 24.8). Assuming an ineffective cytotoxic (control) therapy has ORR = 7.6%, the average ORR for lomustine and temozolomide trials, a sample size of ≥40 patients with target ORR>25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P < .01) and adequate power (>80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR >25% (which translates to a median OS of approximately 15 months) and a sample size of ≥40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study.

Background Accurate CNS tumor diagnosis can be challenging, and methylation profiling can serve as an adjunct to classify diagnostically difficult cases. Methods An integrated diagnostic approach was employed for a consecutive series of 1258 surgical neuropathology samples obtained primarily in a consultation practice over 2-year period. DNA methylation profiling and classification using the DKFZ/Heidelberg CNS tumor classifier was performed, as well as unsupervised analyses of methylation data. Ancillary testing, where relevant, was performed. Results Among the received cases in consultation, a high-confidence methylation classifier score (>0.84) was reached in 66.4% of cases. The classifier impacted the diagnosis in 46.7% of these high-confidence classifier score cases, including a substantially new diagnosis in 26.9% cases. Among the 289 cases received with only a descriptive diagnosis, methylation was able to resolve approximately half (144, 49.8%) with high-confidence scores. Additional methods were able to resolve diagnostic uncertainty in 41.6% of the low-score cases. Tumor purity was significantly associated with classifier score (P = 1.15e−11). Deconvolution demonstrated that suspected glioblastomas (GBMs) matching as control/inflammatory brain tissue could be resolved into GBM methylation profiles, which provided a proof-of-concept approach to resolve tumor classification in the setting of low tumor purity. Conclusions This work assesses the impact of a methylation classifier and additional methods in a consultative practice by defining the proportions with concordant vs change in diagnosis in a set of diagnostically challenging CNS tumors. We address approaches to low-confidence scores and confounding issues of low tumor purity.

Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4,793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1%[95% CI 4.23; 8.76%] for cytotoxic chemotherapies (ORR=7.59% for CCNU, 7.57% for TMZ, 0.64% for CPT-11, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2=0.4078,P0.0001), biologics (R2=0.4003,P=0.0003), and immunotherapy trials (R2=0.8994,P0.0001), but not anti-angiogenic agents (R2=0, P=0.8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2=0.3900, P0.0001; mOS[weeks]=1.4xORR+24.8). Assuming an ineffective cytotoxic (control) therapy has ORR=7.6%, the average ORR for lomustine and temozolomide trials, a sample size of ≥40 patients with target ORR25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P0.01) and adequate power (80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR25% (which translates to a median OS of approximately 15 months) and a sample size of ≥40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study.

Background To determine if proton radiotherapy (PT), compared to intensity-modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma (GBM). Methods Eligible patients were randomized unblinded to PT vs IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes (PROs). Results A total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45-1.75; P = .74). PT was associated with a lower rate of fatigue (24% vs 58%, P = .05), but otherwise, there were no significant differences in PROs at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44-1.23; P = .24) or OS (HR, 0.86; 95% CI, 0.49-1.50; P = .60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P = .02). Conclusions In this signal-seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient-reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for GBM and cognitive preservation in patients with lower-grade gliomas with a longer survival time.

Background No standard medical treatment exists for adult patients with recurrent ependymoma, and prospective clinical trials in this population have not succeeded because of its rarity and challenges in accruing patients. The Collaborative Ependymoma Research Network conducted a prospective phase II clinical trial of dose-dense temozolomide (TMZ) and lapatinib, targeting the unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status and increased expression of ErbB2 (human epidermal growth factor receptor 2) and ErbB1 (epidermal growth factor receptor) in ependymomas. Methods Patients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma were eligible and received dose-dense TMZ and daily lapatinib. The primary outcome measure was median progression-free survival (PFS). Landmark 6- and 12-month PFS and objective response were measured. Serial assessments of symptom burden using the MD Anderson Symptom Inventory Brain Tumor (MDASI-BT)/MDASI–Spine Tumor modules were collected. Results The 50 patients enrolled had a median age of 43.5 years, median Karnofsky performance status of 90, and a median of 2 prior relapses. Twenty patients had grade III, 16 grade II, and 8 grade I ependymoma. Half had spinal cord tumors; 15 had a supratentorial tumor, 8 infratentorial, and 2 had disseminated disease. Treatment was well tolerated. The median PFS was 7.8 months (95% CI: 5.5,12.2); the 6- and 12-month PFS rates were 55% and 38%, with 2 complete and 6 partial responses. Measures of symptom burden showed reduction in moderate-severe pain and other disease-related symptoms in most patients. Conclusions This treatment, with demonstrated clinical activity with objective responses and prolonged disease control associated with disease-related symptom improvements, is an option as a salvage regimen for adult patients with recurrent ependymoma.

Background Glioblastoma survival remains unchanged despite continuing therapeutic innovation. Herein, we aim to (i) develop chimeric antigen receptor (CAR) T cells with a specificity to a unique antigen, carbonic anhydrase IX (CAIX), which is expressed in the hypoxic microenvironment characteristic of glioblastoma, and (ii) demonstrate its efficacy with limited off-target effects. Methods First we demonstrated expression of CAIX in patient-derived glioblastoma samples and available databases. CAR T cells were generated against CAIX and efficacy was assessed in 4 glioblastoma cell lines and 2 glioblastoma stem cell lines. Cytotoxicity of anti-CAIX CAR T cells was assessed via interferon gamma, tumor necrosis factor alpha, and interleukin-2 levels when co-cultured with tumor cells. Finally, we assessed efficacy of direct intratumoral injection of the anti-CAIX CAR T cells on an in vivo xenograft mouse model using the U251 luciferase cell line. Tumor infiltrating lymphocyte analyses were performed. Results We confirm that CAIX is highly expressed in glioblastoma from patients. We demonstrate that CAIX is a suitable target for CAR T-cell therapy using anti-CAIX CAR T cells against glioblastoma in vitro and in vivo. In our mouse model, a 20% cure rate was observed without detectable systemic effects. Conclusions By establishing the specificity of CAIX under hypoxic conditions in glioblastoma and highlighting its efficacy as a target for CAR T-cell therapy, our data suggest that anti-CAIX CAR T may be a promising strategy to treat glioblastoma. Direct intratumoral injection increases anti-CAIX CAR T-cell potency while limiting its off-target effects.

BACKGROUND Glioblastoma is an aggressive brain tumor with high mortality. The development of new therapies is critical for improving patient outcomes. LMP400, a novel topoisomerase I (TOP1) inhibitor, traps TOP1 cleavage complexes, thereby generating DNA damage. Poly(ADP-ribose) polymerase (PARP) is involved in DNA repair responses triggered by TOP1 inhibition. Niraparib is a potent PARP inhibitor that can cross the blood-brain barrier. Loss of phosphatase and tensin homolog (PTEN) occurs in 40% of GBM patients and is known to promote DNA damage repair deficiency. Here, we hypothesize that PTEN loss presents a vulnerability to a combined induction of DNA damage and inhibition of repair mechanisms. METHODS Human glioblastoma cells (U251, SNB-75, SF-295, LN18) and patient-derived glioblastoma stem cells (GSC923 and GSC827) were treated with LMP400 and/or Niraparib. Cell viability and apoptosis were examined using Celigo image cytometer and Annexin V/PI assay at 72h after treatment. Single clones after PTEN knockdown using shRNA were isolated after puromycin selection. For planned studies of PTEN knockout, sgRNA plasmids targeting PTEN will be transiently transfected and GFP-positive single KO clones will be isolated. PTEN will be restored in PTEN-null cells using lentiviral transduction. RESULTS CRISPR-Cas9 KO screening in GSC923 cells suggests that LMP400 is unlikely a substrate for ABC transporters. LMP400 and Niraparib synergistically induced cytotoxic effects in U251, SF-295, GSC923, GSC827 cells lacking PTEN expression. Combined LMP400/Niraparib led to increased expression of gamma-H2AX, cleaved caspase 3 and PARP, indicative of enhanced DNA damage and cell death. CONCLUSION LMP400 and Niraparib act synergistically to target PTEN-deficient glioblastoma by inducing DNA damage and cell death. These results will be further verified in isogenic cells in vitro as well as in vivo in a mouse model driven by PTEN deletion which would strongly support a novel therapeutic strategy in a subset of glioblastoma with PTEN loss.

Recognizing the importance of clinical outcomes assessments (COA), the RANO-PRO Working Group recommends inclusion of core symptoms/functions in clinical care/research for malignant glioma patients. This study evaluated the association between the recommended symptoms (pain, perceived cognition, seizures, aphasia, treatment-specific symptoms) and functions (physical: weakness, walking; and role/social: work, usual activities) and disease progression in these patients. MDASI-Brain Tumor and EQ-5D-3L scores, Karnofsky Performance Status (KPS), and Neurologic Function Score (NFS) were evaluated in relation to disease progression by chi-square tests, independent- and paired-samples t-tests, adjusted for multiple comparisons. Our sample included 336 patients with malignant glioma; 82% white, 64% male, median age=52 (21-79). Imaging study revealed disease progression for 46% of patients. All symptoms except seizures and difficulty concentrating were worse in the group whose imaging showed disease progression versus stable disease, as well as the functions of walking, work, activity, and self-care (0.8 < difference < 1.8). Patients with disease progression were 4 times more likely to have a poor KPS (≤ 80) and worse NFS. Among patients with disease progression (n=112), all symptoms, except seizures, worsened from first assessment to time of progression. Up to 22% of patients reported worsening mobility, self-care, and usual activity; 46% and 35% had worsened KPS and NFS, respectively. Seven symptoms and functions were each individually reported by at least 10% of patients as having worsened the most. Worsening of symptoms and functions was not observed among patients with stable disease, except in difficulty understanding. Identified core symptoms/functions worsen at the time of progression demonstrating the relationship between priority constructs and a traditional tumor response measure while highlighting the importance of longitudinal collection of COA. The pattern of worsening was observed via both patient- and clinician-reported outcomes, emphasizing the utility of COA in clinical care and clinical trials.

The National Cancer Institute Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) program focuses on improving approaches to care and treatment for 12 rare CNS tumors, each with < 2,000 diagnoses per year. To reach this rare population, the primary objective was to develop a website to share educational resources that provide patients direct access to clinical care and trials. METHODS: The NCI-CONNECT website uses the Drupal platform within NCI’s framework and the content is free to syndicate. A multidisciplinary team developed tumor-specific content in English and Spanish, clinical trial information, and survivorship resources using evidence-based sources. The Central Brain Tumor Registry of the United States provided statistics on incidence and prevalence of rare tumors. Population reach was calculated using Adobe Experience Cloud website analytics. NCI-CONNECT referrals and study participation data were collected prospectively. RESULTS: The English website launched in September 2018 and visits have increased 2,384%. The Spanish website launched in March 2020 and visits have increased 1,137%. From April 2020 to March 2021, top website page views by English page views / Spanish page views / people living with this disease include oligodendroglioma (43,859 / 8,241 / 11,757), ependymoma (31,579 / 12,684 / 13,294), meningioma (30,261 / 19,507 / 2,692), medulloblastoma (28,487 / 9,999 / 3,840), diffuse midline gliomas (23,064 / 3,851 / 6,033), and pineal region tumors (19,939 / 9,973 / 1,297). Referral rates and participation have accelerated – 45% of patients visiting the Neuro-Oncology Clinic at NIH have a rare CNS tumor and 409 patients enrolled in an NCI-CONNECT study. CONCLUSION: Patient-focused websites can provide guidance to those affected by rare cancers outside of in-person health care visits. The NCI-CONNECT website is an educational and clinical resource for patients and families affected by rare CNS tumors and was created to raise awareness and improve patient outcomes.

Cognitive dysfunction (CD) is common among primary brain tumor (PBT) patients and adds to the overall symptom burden. Standardized assessments able to be incorporated into routine clinical in-person and telehealth care are needed. Here, we report the feasibility, utility, and satisfaction with use of the Montreal Cognitive Assessment (MoCA) in telehealth and clinical settings by trained clinical providers. Feasibility and provider satisfaction were assessed through survey responses, and patient performance on the MoCA, after a reliability check, was reported through descriptive statistics. Seventy-nine MoCAs on 71 patients were completed in clinic (n=55) or telehealth (n=24). Majority of patients were white (83%) males (54%) with high grade PBTs (66%), and half of patients had completed at least a college education. In clinic, providers (n=9) reported the MoCA took 5-20 minutes to complete, was easy to incorporate into routine practice (78%), believed it was accurate in assessing cognition (67%), and was useful in determining treatment (88%). The average in-person MoCA score was 25 (range: 6 to 30), with 31% of scores classified as abnormal (≤26). In telehealth, providers (n=11) found the administration of the MoCA prior to attending participation in the telehealth visit helpful (75%), discussed the results with their clinical team (75%) and patient (63%), and believed the MoCA was accurate in assessing cognition remotely (63%). On average, patients took 13 minutes (9-22) to complete testing, with three tests discordant on reliability scoring and one patient unable to complete testing. The average telehealth MoCA score was 26 (12-30), with 29% of scores classified as abnormal. Overall, testing was feasible in both clinical and telehealth settings, and providers reported satisfaction with its use. Future studies should evaluate validity in a larger sample and include analysis of relevant cut-off scores, impact of disease, tumor treatment, and genomic predispositions.

CNS tumor patients are highly symptomatic causing interference with activity and worse quality of life. Social distancing due to the COVID-19 pandemic increased demands on the patient, caregivers, clinicians, and the health care system. The NCI’s Neuro-Oncology Branch Natural History Study (NHS) systematically collected patient-reported outcomes (PROs) provide insight into how these challenges influenced symptom burden and interference during the COVID year. METHODS: Patient and disease characteristic as well as patient-reported symptoms and interference (MDASI-BT/-SP) and general health status (EQ-5D-3L) from 3/2020-2/2021) were compared to NHS normative sample collected prior to 3/2020. RESULTS: The sample (n = 178) was primarily White (82%), male (55%), median age of 45 (range 18 – 79) and KPS ³ 90 (51%). The majority had high-grade (70%) brain (83%) tumors (BT) with ≥ 1 prior recurrence (60%) and 25% were on active treatment. Clinical visits were primarily conducted via telehealth (64%) and 20% of all patients were diagnosed with progression at the time of assessment. Most commonly reported moderate-severe symptoms among BT patients were fatigue (30%), difficulty remembering (28%), feeling drowsy (22%). Among spinal cord tumor patients, fatigue (39%), pain (35%) and numbness/tingling in arms/legs/trunk (35%) were most frequently reported. These symptoms were reported in similar frequencies by the normative sample. Nearly half of the COVID year sample (48%) reported moderate-severe activity-related interference. Reported problems with mobility (38%), self-care (19%), pain/discomfort (40%), and usual activities (50%) were similar in both groups except for increased mood disturbance (53%) was reported during the COVID year. CONCLUSION: These findings support CNS tumor patients remained highly symptomatic with significant impact on health-related quality of life during the COVID year. Clinicians should develop timely individual care plans to help BT patients navigate their disease course. Evaluation of risk associated with more severe symptoms and functional limitations are ongoing.

Glioblastoma (GBM) is a highly malignant CNS tumor with very poor survival despite intervention with conventional therapeutic strategies. Although the CNS is separated from the immune system by the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier, emerging evidence of immune surveillance and the selective infiltration of GBMs by immune suppressive cells indicates that there is breakdown or compromise of these physical barriers. This in turn offers hope that immunotherapy can be applied to specifically target and reduce tumor burden. One of the major setbacks in translating immunotherapy strategies is the hostile microenvironment of the tumor that inhibits trafficking of effector immune cells such as cytotoxic T lymphocytes into the CNS. Incorporating important findings from autoimmune disorders such as multiple sclerosis to understand and thereby enhance cytotoxic lymphocyte infiltration into GBM could augment immunotherapy strategies to treat this disease. However, although these therapies are designed to evoke a potent immune response, limited space in the brain and cranial vault reduces tolerance for immune therapy–induced inflammation and resultant brain edema. Therefore, successful immunotherapy requires that a delicate balance be maintained between activating and retaining lasting antitumor immunity.

Background We previously reported the unexpected finding of significantly improved survival for newly diagnosed glioblastoma in patients when radiation therapy (RT) was initiated later (>4 wk post-op) compared with earlier (≤2 wk post-op). In that analysis, data were analyzed from 2855 patients from 16 NRG Oncology/Radiotherapy Oncology Group (RTOG) trials conducted prior to the era of concurrent temozolomide (TMZ) with RT. We now report on 1395 newly diagnosed glioblastomas from 2 studies, treated with RT and concurrent TMZ followed by adjuvant TMZ. Our hypothesis was that concurrent TMZ has a synergistic/radiosensitizing mechanism, making RT timing less significant. Methods Data from patients treated with TMZ-based chemoradiation from NRG Oncology/RTOG 0525 and 0825 were analyzed. An analysis comparable to our prior study was performed to determine whether there was still an impact on survival by delaying RT. Overall survival (OS) was investigated using the Kaplan-Meier method and Cox proportional hazards model. Early progression (during time of diagnosis to 30 days after RT completion) was analyzed using the chi-square test. Results Given the small number of patients who started RT early following surgery, comparisons were made between >4 and ≤4 weeks delay of radiation from time of operation. There was no statistically significant difference in OS (hazard ratio = 0.93; P = 0.29; 95% CI: 0.80-1.07) after adjusting for known prognostic factors (recursive partitioning analysis and O6-methylguanine-DNA methyltransferase methylation status). Similarly, the rate of early progression did not differ significantly (P = 0.63). Conclusions We did not observe a significant prognostic influence of delaying radiation when given concurrently with TMZ for newly diagnosed glioblastoma. The effects of early (1-3 wk post-op) or late (>5 wk) initiation of radiation tested in our prior study could not be replicated.

Background Standard therapy for chordoma consists of surgical resection followed by high-dose irradiation. Protein phosphatase 2A (PP2A) is a ubiquitously expressed serine/threonine phosphatase involved in signal transduction, cell cycle progression, cell differentiation, and DNA repair. LB100 is a small-molecule inhibitor of PP2A designed to sensitize cancer cells to DNA damage from irradiation and chemotherapy. A recently completed phase I trial of LB100 in solid tumors demonstrated its safety. Here, we show the therapeutic potential of LB100 in chordoma. Methods Three patient-derived chordoma cell lines were used: U-CH1, JHC7, and UM-Chor1. Cell proliferation was determined with LB100 alone and in combination with irradiation. Cell cycle progression was assessed by flow cytometry. Quantitative γ-H2AX immunofluorescence and immunoblot evaluated the effect of LB100 on radiation-induced DNA damage. Ultrastructural evidence for nuclear damage was investigated using Raman imaging and transmission electron microscopy. A xenograft model was established to determine potential clinical utility of adding LB100 to irradiation. Results PP2A inhibition in concert with irradiation demonstrated in vitro growth inhibition. The combination of LB100 and radiation also induced accumulation at the G2/M phase of the cell cycle, the stage most sensitive to radiation-induced damage. LB100 enhanced radiation-induced DNA double-strand breaks. Animals implanted with chordoma cells and treated with the combination of LB100 and radiation demonstrated tumor growth delay. Conclusions Combining LB100 and radiation enhanced DNA damage-induced cell death and delayed tumor growth in an animal model of chordoma. PP2A inhibition by LB100 treatment may improve the effectiveness of radiation therapy for chordoma.

BACKGROUND Disrupted sleep, including daytime hypersomnolence, is a core symptom reported by primary brain tumor patients and often manifests after radiotherapy. The biological mechanisms driving cranial radiation-induced hypersomnolence (C-RIH) remain unclear but we hypothesize this may result from damage to neural circuits controlling sleep behavior. We developed a mouse model of C-RIH to explore the impact of radiation on the brain: examining region-specific differences in acute DNA damage response and neuroanatomic structure. METHODS Mice received whole brain radiation then behaviors were monitored using PhenoTyper® cages to determine optimal dose and long-term effects. To test short-term neurologic effects, brains were collected 1hr post-radiation then stained for γH2AX, a signal for DNA damage. Long-term effects were quantified 1-month post-treatment using neuroimaging to determine brain volume and T1 mapping changes in regions associated with sleep, circadian rhythms, and cognition. RESULTS Mice displayed decreased general activity and increased daytime sleep in a dose-dependent and sustained manner. Histologic staining demonstrated that DNA damage following radiation varies across the brain, with homeostatic sleep regions and cognitive regions expressing higher levels of γH2AX than the circadian suprachiasmatic nucleus. These findings were supported by in vitro studies comparing radiation effects in SCN and cortical astrocytes using both trypan blue (F(1,18)=235.937, p< 0.001) and clonogenic assays (F(1,24)=40.796, < 0.001). Brain volumes were significantly smaller in irradiated than sham animals in the hippocampus (t(4)=3.833, p=0.019) and the pontine central grey (t(4)=3.504, p=0.025). T1 maps also showed significant changes in relaxation times in many cognitive regions but not sleep or circadian areas. CONCLUSIONS These findings suggest that the homeostatic sleep region and cognitive circuits are vulnerable to radiation and may be relevant to the development of treatment plans in patients. We plan to introduce intracranial tumor to the model to evaluate the impact of timing of treatment and C-RIH on survival.

Gliomatosis cerebri (GC) is a controversial entity no longer recognized as a histopathologic-defined diagnosis, characterized by diffuse, commonly bilateral infiltration of cerebral hemispheres. The purpose of this report is to describe clinical, imaging, patient-reported outcomes (PRO’s) and pathologic characteristics of clinically-defined cases from a large natural history study cohort (N=769). Of 19 patients, 10 male, 16 white, mean age at diagnosis 43 (19-70), seventeen presented as primary GC, while 2 developed GC after treatment. Ten patients were IDH-WT, 7 IDH-M, and 2 IDH undetermined. The majority (7/10) IDH-WT patients presented acutely (5 with seizures), whereas, 3 had a protracted presentation of 2 weeks-3months with 6/10 having enhancing tumors and 8/10 undergoing biopsy only. On histopathologic review, 4 were anaplastic astrocytoma (AA), 3 GBMs, 2 grade II astrocytoma, and 1 histone-mutated glioma. Nearly all (9/10) IDH-WT patients received radiation with concurrent and adjuvant temozolomide. 7/10 IDH-WT patients had a survival of only 1.5yrs or less from diagnosis. Of the 7 IDH-M patients, 4 had protracted presentations of 1 month-5 years. 6/7 had non-enhancing tumors at presentation. 4 had biopsy only and 3 underwent partial resection. 3 were AA, 2 grade II astrocytoma, 1 grade II oligodendroglioma, and 1 grade IV astrocytoma. 3/7 received radiation with concurrent and adjuvant temozolomide, 3/7 chemotherapy alone, and 1 RT alone. All 7 IDH-M patients survived 3+ years from diagnosis (range 3-10+ yrs). Both patients who developed GC later, were IDH-M, with prolonged survival (3.5yrs and the other still alive 10+yrs). PRO's at time of last clinical assessment revealed GC patients to be highly symptomatic with mean overall symptom burden, depression, and anxiety higher than our overall glioma population. GC patients have a varied clinical course mandating further investigation to enable better prognostic definition to refine treatments based on the varying clinical and molecular characteristics.

BACKGROUND Little is known about the mechanisms that render cancer cells dependent on certain nutrients from the microenvironment. Cysteine is a non-essential amino acid, since it can be synthetized from methionine through the transsulfuration pathway; moreover, cysteine is also uptake from the diet as cystine. We have investigated the metabolism of cysteine in glioma cell lines, and how cysteine/cystine-deprivation alters their antioxidant response in addition to the effect of this nutrient restriction to viability and proliferation in vitro and in vivo. METHODS Cysteine metabolism was investigated through LCMS-based 13C-tracing experiments and the expression levels of key enzymes in the transsulfuration pathway were also explored. Finally, a mouse model of IDH1 mutant glioma was subjected to a cysteine/cystine-free diet and tumor metabolism was analyzed by LCMS. RESULTS Herein, we report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. Using several 13C-tracers and analysis of cystathionine synthase and cystathioninase levels, we revealed that glioma cells were not able to upregulate the transulfuration pathway cysteine, which allows methionine to be converted to cysteine in cysteine/cystine deprived conditions. We demonstrated that exogenous cysteine/cystine are crucial for glutathione synthesis, and impact growth and viability. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine-free diet survived longer, with concomitant reductions in glutathione and cysteine plasma levels. At the endpoint higher levels of oxidative stress were detected despite the systemic recovery of cysteine-related metabolites in the plasma. CONCLUSION The results presented herein reveal an alternative therapeutic approach combining cysteine/cysteine-deprivation diets and treatments involving ROS production by limiting the ability of glioma cells to quench oxidative stress through dietary interventions. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.

BACKGROUND Despite the growing number of neuro-oncology clinical trials, there have been limited advances in the treatment of malignant primary central nervous system tumors. We surveyed the landscape of past, ongoing, and planned trials to assess trends in their interventions, outcomes, and design considerations to guide future studies. METHODS Data on interventional trials on ClinicalTrials.gov were accessed programmatically using AACT and R. Neuro-oncology trials were isolated using primary malignant brain tumor classification terms. Instrument names from PROQOLID were used to identify clinical outcome assessment (COA) use. Linear regression was used to assess chronological trends; power analyses utilized CBTRUS survival rates among trials investigating overall survival. RESULTS We identified 3039 interventional brain tumor trials that started between 1966 and 2025. Trials were most frequently phase II (43%), completed (40%), non-blinded (92%), single-group assignment (65%), non-randomized (51%) studies targeting glioblastoma (45%). Planned outcomes were reported by 93% of trials; this included adverse event or toxicity (54%), overall/x-year survival (44%), progression free survival (43%), maximum tolerated dose (16%), and objective response rate (14%). Evaluating the anticipated and actual trial enrollment, we estimate that only 10% and 8% of trial arms, respectively, were sufficiently powered to assess overall survival endpoints. 21% of trials mentioned the use of a COA (first trial initiated in 1992), majority of which were patient-reported outcomes. Among these, 25% and 58% reported COA as a primary or secondary outcome, respectively. The rate of COA use increased linearly over time at 1.1%/year but remained less than 5 trials per year until 2003. Ongoing work is investigating treatment mechanisms of actions and evidence of preclinical efficacy among brain tumor studies. CONCLUSIONS Low randomization rates and underpowered trial design may impede interpretability of efficacy. Increasing trends in COA use suggests cumulative influence of advocacy efforts to holistically evaluate net clinical benefit of interventions.

BACKGROUND Primary CNS tumors are associated with uncertainty likely contributing to mood disturbance that is common throughout the disease trajectory. The intersection of the COVID-19 pandemic with a CNS tumor diagnosis may further impact the anxiety/depression experienced in this population. This study assessed key anxiety/depression symptoms in patients with CNS tumors prior to and during the COVID year. METHODS Patient reported outcomes (PROs), including the PROMIS Anxiety and Depression Short Forms and EQ-5D-3L, were collected at the time of clinical or telehealth evaluation from the COVID year (March 2020-February 2021) and were compared to assessments through February 2020 (a NOB-normative sample), reflecting what we would typically see in our regular clinic evaluations. RESULTS The COVID sample (N = 178) was primarily White (82%), male (55%), median age of 45 (range 18–79), and KPS ³ 90 (50%). The majority had high grade (70%) brain (83%) tumors with ³ 1 prior recurrence (60%) and 25% were on active treatment. Visits were primarily conducted via telehealth (64%) and 20% had progression at assessment. Compared to the NOB-normative sample, patients reported significantly higher depression scores (moderate-severe, 17% vs. 12%, p < 0.05), but not anxiety (18% vs. 16%). Eleven percent reported both moderate-severe anxiety and depressive symptoms (8% pre-COVID). Overall health assessed by the EQ-5D-3L was similar to the normative sample in all dimensions, apart from impact of moderate/extreme mood disturbance, which was more prevalent in the COVID year (53% vs. 43%, p < 0.05%). CONCLUSION Patients with CNS tumors are at risk for significant symptoms of depression and anxiety; this risk was heightened during the COVID year. Further evaluation of clinical factors associated with risk are underway. These findings highlight the need for assessments and interventions that can be administered via telehealth to address the mental health needs of this vulnerable population. Radiobiology

SIGNIFICANCE AND AIMS Past research in PBT patients has demonstrated that minorities may have a survival advantage compared to Whites for high-grade tumors, though little is known about their illness experience given their underrepresentation in clinical trials. This study explored differences in PROs across race-ethnicity within a large PBT cohort describing associated burden and risk for minority populations where data is scarce. METHODS Demographic, clinical characteristics, MDASI-Brain Tumor, PROMIS Depression and Anxiety Short-Forms, and Neuro-QoL Cognitive Function were collected from the most recent timepoint for PBT patients enrolled on the Natural History Study. Descriptive statistics, one-way ANOVA, and linear regression were used to report results. RESULTS The sample included 562 PBT patients (58% male, median age = 50 [18-85]) comprised of 79% White, 6% African American (AA), 10% Hispanic, and 5% Asian patients per self-report. Most patients had a high-grade glioma (60%), with 28% on active treatment and 44% with good KPS (90-100). Among the most commonly reported moderate-severe symptoms were fatigue ( > 40% in all groups), difficulty remembering (30-40% of Asians, AAs, and Whites), and disturbed sleep (44% in Asians, 29% in Hispanics), while hemiparesis was common only for AA patients (37%). There were no differences between groups with respect to symptom burden and interference, mood disturbance, or cognitive function. Race/ethnicity group was not predictive of overall symptom burden or interference, but for all groups, higher KPS predicted lower symptom and interference scores (p < .001 and p = .004, respectively). CONCLUSION While some symptoms were common across ethnoracial groups, there were differences in symptom patterns, suggesting there may be other factors driving their illness experience. Future exploration of socioeconomic and cultural factors that might contribute to the symptom burden of minorities is warranted, which may allow development of targeted interventions to improve clinical outcomes in these groups.

Primary brain tumor (PBT) patients experience high symptom burden and functional limitations, which may be impacted by the economic strain and mood disturbance during the COVID-19 pandemic. We assessed financial toxicity and associated patient reported outcomes (PROs) after one year of lockdown in a cohort of PBT patients. Patient and disease characteristics and PROs including FACIT-COST, MDASI-Brain Tumor, PROMIS-Anxiety/Depression short forms, and EQ-5D-3L were collected from 7/2020 to 5/2021 from participants in our Natural History Study. Descriptive statistics, Pearson correlations, and independent samples t-tests evaluated PRO relationships. The cohort included 112 PBT patients: 57% male, 87% white, mean age = 47 (range 25 – 80). Majority were married (65%), completed ≥ 4-year college degree (73%), earned annual family income ≥ $50,000 (68%) and living with a high-grade glioma (72%) complicated by recurrence (51%). Using FACIT-COST, 56% reported some financial hardship due to illness with a mean FACIT-COST of 28.3 (SD = 11.3, range: 0 - 44). Half of patients reported feeling moderately to extremely anxious or depressed. Non-Whites and Hispanics as well as those not currently working reported worse financial toxicity compared to White non-Hispanics and individuals currently working (21.4 vs 29.8 and 25.7 vs 30.4, respectively). Worse financial toxicity scores strongly correlated with worse overall symptom burden (r = -0.55) and interference (r = -0.42), worse anxiety (r = -0.39) and depression scores (r = -0.44), and worse overall HRQOL scores (r = –0.33)[all p< .01]. This is the first report of FACIT-COST in PBT patients to our knowledge and demonstrates that non-White individuals living with high grade glioma who are not currently working due to their tumor reported worse financial toxicity which was strongly correlated with higher symptom burden and interference with lower HRQOL. Future studies to assess financial toxicity longitudinally and post-pandemic using the FACIT-COST are needed.

Cross-sectional studies indicate that patients with gliomas report significant depressive/anxiety symptoms and symptom-related interference with daily activities at diagnosis and throughout the illness trajectory. Our study aimed to explore relationships between these mood disturbances and symptom interference with respect to progressive disease (PD) in glioma patients. Demographic, clinical characteristics, MDASI-Brain Tumor (interference items), and PROMIS Anxiety and Depression Short-Forms were collected at the time of imaging surveillance, before discussing imaging results. Comparisons between patients with/without PD and respective change scores were calculated at study entry and at subsequent assessments. Independent t-tests, Chi-square tests, and paired sample t-tests were used to report results. The sample included 438 glioma patients (62% male, 84% Caucasian, 82% high-grade) with median age of 51 years (range 18-82); 42% had PD with 60% reporting past recurrence(s); 45% had poor Karnofsky Performance Status (KPS); and median time from diagnosis was 2 years (range: 0-30). On average, patients with PD on imaging at time of assessment reported significantly greater anxiety (p = 0.008), depression (p < 0.001), and symptom interference (p < 0.001) than those with stable disease. Additionally, more patients with PD reported moderate-severe anxiety (25%) and depression (22%) than patients with stable disease (15% and 12%, respectively). When evaluating change scores, patients with PD reported worse symptom interference (p < 0.001) but stable mood disturbance, while patients with stable disease reported improved depression (p = 0.018) and unchanged anxiety symptoms compared to baseline. Although mood disturbance is higher for patients with PD, some of these patients do not experience worsening, but rather a continuation of ongoing psychological symptoms, which may portend a worse illness trajectory. Identifying these patients early in this trajectory to evaluate potential biologic correlates between mood and prognosis is warranted to validate these findings.

Prior reports suggest the low prevalence of primary central nervous system (PCNS) tumors and the healthcare setting where patients seek care can contribute to diagnostic delays, potentially affecting prognosis. This descriptive report highlights findings from patient-reported data at presentation collected from a sample of 623 PCNS tumor patients. Participants were White (88%), males (56%), median age at diagnosis 41 (2-79) with high grade (HG) (66%) brain tumors (BT) (89%). Among BT patients, 30% reported ≥ 3 concurrent symptoms at presentation including headaches (40%), seizures (30%), and memory problems or difficulty with balance/walking (20% each). Over half (57%) had symptoms for < 6 months before diagnosis and 60% presented to the Emergency Room. Sixty-five percent of HG BT patients had symptoms for < 6 months prior to diagnosis compared to low grade (LG) tumors (40%) and had surgery in < 1 month from presentation (68% vs 51%, p < 0.01). More HG BT patients presented with weakness in the arms/legs than LG BT (14% vs 8%). Among spine tumor (ST) patients, 45% reported ≥ 3 concurrent symptoms at presentation including back pain (65%), sensory changes (45%), and weakness (40%). Almost half (46%) were symptomatic for > 1 year before diagnosis, presented in an outpatient clinic (64%) with 41% having surgery < 1 month from presentation. Younger (40% vs 16%) and HG ST patients (56% vs 21%) more often reported symptoms for < 6 months before diagnosis. HG ST patients more often presented to Emergency Rooms (67% vs 25%) and had surgery < 1 month from presentation (60% vs 36%). Further analysis of symptom presentation and clinical course is ongoing. Tumor location, grade, patient age and healthcare setting were associated with the time from clinical presentation to diagnosis. Development of aids providing guidance on diagnostic evaluation/treatment to front-line healthcare providers is warranted.

Karnofsky performance status (KPS) scale, a clinician-reported measure, is used to assess patients’ functional ability and as a metric for trial eligibility. Glioma patients often have a degree of neurologic deficit which can invariably affect performance status. There is little research comparing KPS, patient-reported cognitive outcomes, and objective cognitive outcomes. 273 primary brain tumor patients enrolled in the NOB Natural History Study were included in this report. We evaluated Pearson correlations between KPS (range 40-100), dichotomized as Good KPS (KPS ≥ 90) and Poor KPS (KPS ≤ 80), and MDASI-BT cognitive symptom factor, NeuroQoL Cognitive Function t-score, EQ-5D-3L index score, and objective MoCA test. The majority of patients were white (81%), male (58%) with a median 50 years of age (range 24-79). Most had high grade gliomas (74%), 22% were on active treatment, and 55% had prior tumor recurrences. Providers reported a poor KPS in 37% of patients. KPS correlated with the MDASI-BT cognitive symptoms (r = -0.32), NeuroQoL (r = 0.39), and EQ-5D-3L index score (r = 0.55) (all p < 0.01). Patients with poor KPS reported moderate-severe cognitive symptoms on the Neuro-QoL Cognitive Function (40%), moderate-severe difficulty remembering on the MDASI-BT (37%), and difficulty with usual activities on the EQ-5D-3L (83%). In a subset of 27 patients, MoCA scores were assessed but no significant correlation was found with KPS (r = 0.19, p = 0.352). Patient-reported and objective cognitive dysfunction was seen in up to 36% of those with good KPS. These data demonstrate that perceived cognitive testing is associated with poor KPS but may also occur in those with good performance status. The results underscore the need for alternative measures of cognitive functioning to further explore the impact in those with good KPS and the use of the MoCA in a larger sample.

BACKGROUND The utility of geriatric assessment (GA) has been evaluated in older adults diagnosed with solid tumors other than primary brain tumors (PBT). We assessed several key GA domains in adults with PBT receiving tumor-directed treatment. METHODS Patient and disease characteristics and key GA domains within patient-reported outcomes (PROs) including symptom burden (MDASI-BT), Anxiety/ Depression (PROMIS-short forms) and general health status (EQ-5D-3L) were systematically and prospectively collected between 9/2016–8/2019 from adults diagnosed with PBT. Descriptive statistics and regression analyses were used to assess PROs. RESULTS Of 581 participants, 92 were 65 – 85 years old (median age = 70 years; “older”) and 489 were ≤ 64 years (median age = 46 years; “younger”). Tumor grade distribution in the older group was 74% WHO grade III/IV, 26% WHO grade I/II; tumor types included gliomas and meningiomas with no tissue diagnosis in 3 patients. Older patients were 49% less likely to receive chemotherapy and twice as likely to have KPS ≤ 80 (p=0.003, OR=0.51, OR=1.98). More older patients reported problems with mobility (57% vs 44%), self-care (38% vs 26%), and usual activities (64% vs 51%) than younger patients. Charlson Comorbidity Index mean scores were significantly higher in older patients (3.5 vs 0.6, p< 0.001). The top 3 most frequently reported moderate-to-severe symptoms were similar in older vs younger groups: fatigue (44% vs 41%), feeling drowsy (29% vs 30%) and difficulty remembering (28% vs 29%). Feeling distressed was the only symptom whose frequency differed between the age groups (11% older vs 27% younger, p=0.001). CONCLUSION Older PBT patients had lower performance status, more co-morbidities and increased functional impairments, affirming that GA is relevant. Symptom burden was similarly high in both age groups. These findings support conducting GA concurrently in future symptom intervention and therapeutic clinical trials for adults with PBT receiving tumor-directed treatment.

BACKGROUND Our study aimed to identify vulnerabilities within sphingolipid metabolism with potential to translate to therapeutics. While the vital role of sphingolipids in maintaining rheostat balance and as secondary messengers for signaling pathways (involving proliferation, invasion, migration, and angiogenesis) has been well-documented, their role has not been widely investigated in gliomas. Therefore, metabolic analysis of sphingolipid pathway for IDH1-R132H (IDH1 mut ) glioma cell lines was conducted in order to elucidate susceptible targets. METHODS Global sphingolipid quantification utilized high-throughput LCMS analysis. Pathway protein expression was measured via Western blots in vitro and derived from patients using The Cancer Genome Atlas analysis. RESULTS We probed the impact of decreasing D-2HG on the sphingolipid metabolism after treating a panel of IDH1 mut glioma cells with IDH1-R132H mut inhibitor, AGI5198. This revealed significant downregulation of N,N-dimethylsphingosine (NDMS), C17-sphingosine, and C18-sphinganine. Coincidentally, sphingosine-1-phosphate (S1P) was significantly upregulated in these gliomas. We conducted rational drug screen which revealed that inhibition of SPHK1 with N,N-dimethylsphingosine in combination with C17-sphingosine triggered biostatic dose-response across IDH1 mut gliomas and low impact on IDH WT glioblastoma (GBM) cells. Western analysis revealed that the IDH1 mut gliomas and IDH WT GBM expressed sphingosine kinase-1 (SPHK1). Data also unveiled a discovery that SPHK2 was highly expressed in the GBM cells while remarkably absent in the glioma cells. CONCLUSION Herein, we provide evidence that certain IDH1 mut gliomas present epigenetic silencing of SPHK2 which creates dependency on SPHK1 for S1P; thus, increasing sensitivity to targeting sphingolipid metabolism, and creating susceptibility to proliferation arrest and subsequent cellular death. S1P production has been reported to be elevated particularly for malignant glioblastomas in prior studies; whereas our research revealed that it is relatively low in IDH mut by comparison with IDH WT tumor cells. These findings suggest targeting the sphingolipid metabolism may present a promising strategy to improve survival for patients diagnosed with IDH1 mut gliomas.

BACKGROUND Increased de novo lipogenesis is a hallmark of cancer metabolism. In this study, we interrogated the role of de novo lipogenesis in IDH1 mutated glioma’s growth and identified the key enzyme, Stearoyl-CoA desaturase 1 (SCD1) that provides this growth advantage. MATERIALS ANDMETHODS We prepared genetically engineered glioma cell lines (U251 wild-type: U251WT and U251 IDHR132H mutant: U251RH) and normal human astrocytes (empty vector induced-NHA: NHAEV and IDHR132H mutant: NHARH). Lipid metabolic analysis was conducted by using LC-MS and Raman imaging microscopy. SCD1 expression was investigated by The Cancer Genome Atlas (TCGA) data analysis and Western-blotting method. Knock-out of SCD1 was conducted by using CRISPR/Cas9 and shRNA. RESULTS Previously, we showed that IDH1 mut glioma cells have increased monounsaturated fatty acids (MUFAs). TCGA data revealed IDH mut glioma shows significantly higher SCD1 mRNA expression than wild-type glioma. Our model systems of IDH1 mut (U251RH, NHARH) showed increased expression of this enzyme compared with their wild-type counterpart. Moreover, addition of D-2HG to U251WT increased SCD1 expression. Herein, we showed that inhibition of SCD1 with CAY10566 decreased relative cell number and sphere forming capacity in a dose-dependent manner. Furthermore, addition of MUFAs were able to rescue the SCD1 inhibitor induced-cell death and sphere forming capacity. Knock out of SCD1 revealed decreased cell proliferation and sphere forming ability. Decreasing lipid content from the media did not alter the growth of these cells, suggesting that glioma cells rely on de novo lipid synthesis rather than scavenging them from the microenvironment. CONCLUSION Overexpression of IDH mutant gene altered lipid composition in U251 cells to enrich MUFA levels and we confirmed that D-2HG caused SCD1 upregulation in U251WT. We demonstrated the glioma cell growth requires SCD1 expression and the results of the present study may provide novel insights into the role of SCD1 in IDH mut gliomas growth.

Circadian clock genes have been linked to differences in clinical outcomes in cancer, including gliomas. However, these studies have not accounted for established prognostic markers, including mutations in Isocitrate Dehydrogenase (IDH). To study the connection between circadian clock genes and glioma outcomes while accounting for IDH mutational status, we analyzed multiple publicly available gene expression datasets. Unsupervised clustering of 13 clock gene transcriptomic signatures from The Cancer Genome Atlas resulted in four distinct transcriptomic clusters, two clusters were enriched for IDH mutant (Circadian 1-2) and the others for IDH wild-type gliomas (Circadian 3-4). Within these clusters we observed differential prognosis of the patients by Kaplan–Meier analysis (Circadian 1-2, p=0.0001; Circadian 3-4, p=0.0002) suggesting that these transcriptomic circadian subtypes might reflect different disease states. Further analyses using Cox Proportional Hazards Regression showed that lower Period (PER) gene expression was associated with worse prognosis (increasing PER expression HR=0.655, p=0.007) independent of IDH wild-type status (HR=5.312, p< 0.001) and increasing age (HR = 1.04, p< 0.001). Lower PER expression was associated with enrichment of a number of immune signaling pathways. These findings prompted the exploration of the relationship between microenvironment and clock genes using the Ivy GAP dataset to explore tumor location-specific differences and single cell RNA sequencing data from Darmanis (accession: GSE84465) to explore cell-specific differences. Circadian clock genes were found to be differentially expressed across anatomical tumor locations and cell types, including microglia. In ongoing studies we are examining the role of the microenvironment and PER2 expression on tumor growth by disrupting PER2 expression in tumor cells and microglia using IDH mutant and wild-type in vitro models. Clock gene expression is a potential prognostic biomarker in glioma and further studies to elucidate the importance of circadian rhythms in other cell types beyond the tumor are warranted.

BACKGROUND The American Academy of Neurology Institute and Society for Neuro-Oncology recommend multidisciplinary tumor board (MTB) meetings as a quality metric in neuro-oncology. With the COVID-19 pandemic resulting in travel restrictions, we expanded our existing MTB by transitioning to a virtual format that maintained our commitment to providing consultation for primary CNS tumor cases. This transition permitted participation by neuro-oncology teams from over 30 Brain Tumor Trials Collaborative (BTTC)/National Cancer Institute-Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) centers across the United States. Here, we describe results from opening our MTB remotely to these teams. METHODS We retrospectively reviewed records from remote MTB meetings held between April 2020 and March 2021. To gauge the impact of our MTB on clinical management, we administered a brief survey querying BTTC members. RESULTS Twenty-eight providers presented 41 cases during 24 virtual MTB meetings (range: 1-4 cases per meeting). Two cases (5%) were presented only for educational value. Approximately half (54%) of the cases discussed dealt with diagnosis/management of an NCI-CONNECT rare CNS tumor. During MTB discussions of the 39 cases seeking diagnosis/management recommendations, 32% received clinical trial recommendations, 10% were suggested to enroll in the NCI Neuro-Oncology Branch (NOB) Natural History Study (NCT02851706), 17% received a recommendation to obtain central neuropathology review, and 100% received recommendations for further disease management. Most BTTC survey respondents (83%) found these recommendations impactful in the management/treatment of their presented case or generally useful/informative for their clinical practice. CONCLUSION We describe the feasibility and utility of an innovative virtual multi-institutional MTB. These novel remote meetings allowed for discussion of complex neuro-oncology cases and recommendations from experts, particularly important for those with rare CNS tumors. Our study’s findings during the COVID-19 pandemic of the value of providing remote access to MTBs should apply post-pandemic.

Background Glioma-associated macrophages and microglia (GAMs) are components of the glioblastoma (GBM) microenvironment that express MerTK, a receptor tyrosine kinase that triggers efferocytosis and can suppress innate immune responses. The aim of the study was to define MerTK as a therapeutic target using an orally bioavailable inhibitor, UNC2025. Methods We examined MerTK expression in tumor cells and macrophages in matched patient GBM samples by double-label immunohistochemistry. UNC2025-induced MerTK inhibition was studied in vitro and in vivo. Results MerTK/CD68+ macrophages increased in recurrent tumors while MerTK/glial fibrillary acidic protein-positive tumor cells did not. Pharmacokinetic studies showed high tumor exposures of UNC2025 in a syngeneic orthotopic allograft mouse GBM model. The same model mice were randomized to receive vehicle, daily UNC2025, fractionated external beam radiotherapy (XRT), or UNC2025/XRT. Although median survival (21, 22, 35, and 35 days, respectively) was equivalent with or without UNC2025, bioluminescence imaging (BLI) showed significant growth delay with XRT/UNC2025 treatment and complete responses in 19%. The responders remained alive for 60 days and showed regression to 1%-10% of pretreatment BLI tumor burden; 5 of 6 were tumor free by histology. In contrast, only 2% of 98 GBM mice of the same model treated with XRT survived 50 days and none survived 60 days. UNC2025 also reduced CD206+ macrophages in mouse tumor samples. Conclusions These results suggest that MerTK inhibition combined with XRT has a therapeutic effect in a subset of GBM. Further mechanistic studies are warranted.

NRG BN001 is an ongoing randomized phase II trial of dose-intense (DI-RT) versus standard dose photon-based radiation therapy (SD-RT) with temozolomide (TMZ) for newly diagnosed glioblastoma. We report preliminary results of Group 1, DI-RT delivered with IMRT while SD-RT could be 3DCRT or IMRT. Group 2, DI-RT delivered with proton therapy, continues to accrue. From 10/2014 to 7/2018, 229 patients were eligible and randomized. Differences in overall survival following DI-RT versus SD-RT were not significant. Patients were scheduled to complete NCF testing at baseline, cycle 3 (within 7 days of cycle 4), and cycle 12 (day 22–28 of cycle 12, or 60 weeks from completion of chemoradiation). At baseline, 93–94% of eligible patients completed NCF testing. Compliance for evaluable patients at cycle 3 and cycle 12 was 66–68% and 51–54%, respectively, across the battery of NCF tests. The most common reasons for missing data were patient refusal (cycle 3: 14%, cycle 12: 22–23%) and institutional error (cycle 3: 9–10%, cycle 12: 14–15%). A prespecified secondary endpoint analysis was conducted to evaluate differences in NCF between SD-RT and DI-RT based on the Clinical Trial Battery Composite (CTB COMP), which is the mean of the standardized scores from the NCF test battery (HVLT-R, TMT, COWA). There was no statistically significant between arm difference in change from baseline on the CTB COMP at cycle 3 (DI-RT vs SD-RT mean/SD, 0.0 +/- 1.3 vs -0.3 +/- 1.5, p=0.370, Cohen’s d=0.22) or cycle 12 (DI-RT vs SD-RT mean/SD, 0.2 +/- 1.7 vs 0.2 +/- 1.1, p=0.977, Cohen’s d=0.01). A mixed effects longitudinal model of the CTB COMP yielded a non-significant time by treatment effect interaction (p=0.216). There were no significant differences in change scores between arms on any NCF test at cycles 3 or 12. NCF outcomes were similar for photon-based SD-RT and DI-RT.

Ependymomas are rare primary tumors of the central nervous system in children and adults that comprise histologically similar but genetically distinct subgroups. The tumor biology is typically more associated with the site of origin rather than being age-specific. Genetically distinct subgroups have been identified by genomic studies based on locations in classic grade II and III ependymomas. They are supratentorial ependymomas with C11orf95-RELA fusion or YAP1 fusion, infratentorial ependymomas with or without a hypermethylated phenotype (CIMP), and spinal cord ependymomas. Myxopapillary ependymomas and subependymomas have different biology than ependymomas with typical WHO grade II or III histology. Surgery and radiotherapy are the mainstays of treatment, while the role of chemotherapy has not yet been established. An in-depth understanding of tumor biology, developing reliable animal models that accurately reflect tumor molecule features, and high throughput drug screening are essential for developing new therapies. Collaborative efforts between scientists, physicians, and advocacy groups will enhance the translation of laboratory findings into clinical trials. Improvements in disease control underscore the need to incorporate assessment and management of patients' symptoms to ensure that treatment advances translate into improvement in quality of life.

Clinical outcome assessments (COAs) are increasingly being used in determining the efficacy of new treatment regimens. This was typified in the recent use of a symptom-based instrument combined with an organ-based measure of response for the approval of ruxolitinib in myelofibrosis. There are challenges in incorporating these COAs into clinical trials, including designating the level of priority, incorporating these measures into a combined or composite endpoint, and dealing with issues related to compliance and interpretation of results accounting for missing data. This article describes the results of a recent panel discussion that attempted to address these issues and provide guidance to the incorporation of COAs into clinical trials, including novel statistical designs, so that the testing of new treatments in patients with cancers of the central nervous system can incorporate these important clinical endpoints.

BACKGROUND Antibody therapeutic targeting of the immune checkpoints cytotoxic T-lymphocyte-associated molecule 4 (CTLA-4) and programmed cell death 1 (PD-1) has demonstrated marked tumor regression in clinical trials. MicroRNAs (miRNAs) can modulate multiple gene transcripts including possibly more than one immune checkpoint and could be exploited as immune therapeutics. METHODS Using online miRNA targeting prediction algorithms, we searched for miRNAs that were predicted to target both PD-1 and CTLA-4. MiR-138 emerged as a leading candidate. The effects of miR-138 on CTLA-4 and PD-1 expression and function in T cells were determined and the therapeutic effect of intravenous administration of miR-138 was investigated in both immune-competent and -incompetent murine models of GL261 glioma. RESULTS Target binding algorithms predicted that miR-138 could bind the 3' untranslated regions of CTLA-4 and PD-1, which was confirmed with luciferase expression assays. Transfection of human CD4+ T cells with miR-138 suppressed expression of CTLA-4, PD-1, and Forkhead box protein 3 (FoxP3) in transfected human CD4+ T cells. In vivo miR-138 treatment of GL261 gliomas in immune-competent mice demonstrated marked tumor regression, a 43% increase in median survival time (P = .011), and an associated decrease in intratumoral FoxP3+ regulatory T cells, CTLA-4, and PD-1 expression. This treatment effect was lost in nude immune-incompetent mice and with depletion of CD4+ or CD8+ T cells, and miR-138 had no suppressive effect on glioma cells when treated directly at physiological in vivo doses. CONCLUSIONS MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints which may have rapid translational potential as a novel immunotherapeutic agent.

ONC201 is the first bitopic antagonist of dopamine receptor D2 (DRD2) and allosteric mitochondrial protease ClpP agonist, that is well tolerated and induces durable tumor regressions in H3 K27M-mutant glioma patients. ONC206, a derivative of ONC201, is also a bitopic DRD2 antagonist that exhibits enhanced non-competitive effects, nanomolar potency, and disruption of DRD2 homodimers. In these studies, a FITC-casein degradation assay revealed that ONC206 also acts as an agonist of human ClpP and has a 3-fold improved potency. GEPIA database analysis showed ClpP mRNA was overexpressed in glioblastoma cells relative to normal cells. Broad nanomolar efficacy of ONC206 (GI50 < 78-889nM, 72h) was observed in >1,000 GDSC cancer cell lines with the highest sensitivity in cell lines exhibiting high ClpP and/or DRD2+/DRD5- RNA expression signatures. Among solid tumors, nervous system related cell lines were particularly sensitive. ONC206 reduced the viability of normal human fibroblasts at higher doses (GI50 > 5µM), suggesting a wide therapeutic window. Antitumor efficacy without body weight loss was observed with 50 mg/kg weekly oral ONC206 in a subcutaneous xenograft model of DRD2-overexpressing, dopamine-secreting tumor cells. Oral ONC206 at 50mg/kg exhibited a ~12 µM plasma Cmax and ~6 hours terminal half-life in Sprague-Dawley rats. Additionally, 5–10 fold higher ONC206 concentrations were observed in adrenal gland, bile duct, brain and bone marrow relative to plasma. GLP toxicology studies with weekly oral ONC206 in Sprague-Dawley rats and beagle dogs revealed no dose-limiting toxicities. Mild and reversible body weight changes were observed at the highest evaluated dose in both species. The no-observed-adverse-effect level was ≥ 16.7 mg/kg in dogs and ≥ 50 mg/kg in rats that exceed efficacious doses. A 50 mg starting dose of ONC206 was selected for the first-in-human open label, dose escalation, and food effect Phase I study in biomarker-enriched adult recurrent primary CNS tumors.

ONC201 is the first bitopic antagonist of dopamine receptor D2 (DRD2) and agonist of ClpP in oncology. In clinical trials, the small molecule has induced durable tumor regressions and clinical benefit in H3 K27M-mutant glioma patients while being well tolerated. ONC206 is a chemical derivative of ONC201 with nanomolar anti-cancer potency. In this study, we describe receptor pharmacology, gene expression profiling, acquired resistance and biodistribution studies that suggest ONC206 exhibits distinct therapeutic properties relative to ONC201. ONC206 exhibited a nanomolar Ki for DRD2 with complete specificity across human GPCRs and complete DRD2 antagonism. Schild analyses of ONC206 in cAMP and β-Arrestin recruitment assays revealed hallmarks of non-competitive DRD2 antagonism, unlike antipsychotics but similar to ONC201. Shotgun mutagenesis across DRD2 identified 7 residues critical for ONC206-mediated antagonism at orthosteric and allosteric sites. Six residues were critical for ONC201 and ONC206, however the impact varied between the two compounds and one allosteric residue was exclusive to ONC206. Structural mapping revealed that some ONC206-critical allosteric residue interactions are located at the interface of TM-IV and –V that mediates the DRD2 homodimer interface. Gene expression profiling revealed ONC206 and ONC201 induce distinct signatures in U87 glioblastoma cells, further supporting distinct functional effects. Similarly, T98G glioblastoma cells with acquired resistance to ONC201 or ONC206 reveal partial cross resistance. Finally, rat biodistribution studies revealed nanomolar CSF concentrations that exceed therapeutic thresholds, unlike ONC201. In summary, ONC206 exhibits increased non-competitive DRD2 antagonism, nanomolar potency, distinct biodistribution, differentiated gene expression and disruption of DRD2 dimers relative to ONC201. Thus, ONC206 may be uniquely poised to address tumors that are not addressed by ONC201 or have developed acquired resistance.

Sleep disturbance (SD) is a common symptom reported by PBT patients and research has demonstrated a link between sleep and stress circadian pathways. SD can impact perceived severity of other symptoms and development of psychopathology. This study explored the prevalence of moderate-severe SD in PBT patients, identifying associated clinical characteristics and co-occurrence with other tumor-related and psychological symptoms. Demographic, clinical characteristics, MDASI-Brain Tumor, and PROMIS Depression and Anxiety Short-Forms were collected at study entry. Descriptive statistics, Chi-square tests, and independent t-tests were used to report results. The sample included 424 patients (58% male, 81% Caucasian) with a median age of 49 years (range 18–81) and 58% with high-grade gliomas. Most had received treatment with surgery, radiation or chemotherapy prior to study entry, with 44% reporting a past recurrence. Moderate-severe SD (³ 5 on a 0–10 scale) was reported in 19% of patients and was associated with younger age (mean difference = 5 years), poor KPS (OR 2.2), current steroid use (OR 2.4), and tumor progression on MRI (OR 2). Those with moderate-severe SD had a higher overall symptom burden (mean difference = 2.3) and reported more moderate-severe symptoms (8 vs. 2). Patients reporting moderate-severe SD also reported higher severity in affective and cognitive symptom domains and mood-interference, with fatigue (72%), drowsiness (59%), and distress (56%) the most frequently co-occurring symptoms. Patients with moderate-severe SD also had increased prevalence of moderate-severe anxiety (32%) and depression (23%), compared to 10% in those without SD. PBT patients with moderate-severe SD are more symptomatic and have higher incidence of mood disturbance, suggesting a key role for sleep in the development of tumor-related and psychological symptoms. Future work delineating specific pathways involving sleep disturbance and co-occurring symptoms will be foundational for designing targeted sleep interventions to improve symptom burden and quality of life.

BACKGROUND Therapies targeting multiple survival pathways are desirable for high-grade gliomas. TG02 (Zotiraciclib), a CDK9 inhibitor, regulates transcription and metabolism of tumor cells and synergizes with temozolomide. A phase I/II trial was launched to test the TG02/temozolomide combined treatment in recurrent high-grade astrocytomas. Phase I results are reported here. METHODS Adults with recurrent high-grade astrocytoma, KPS≥60, adequate organ function, < 2 prior relapses were enrolled. Primary endpoint was dose limiting toxicity (DLT) in cycle1 in each arm. Bayesian optimal interval design was employed to determine the maximum tolerated dose (MTD) with the target DLT rate of 35% and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days1,12,15, and 26) and temozolomide, either as a dose-dense (DD; 125mg/m2/d, 7on/7off, Arm1) or metronomic (MN; 50mg/m2/d, Arm2) dosing schedule on a 28-day cycle. RESULTS Thirty-eight patients were evaluable; median age 50.7, KPS 90. Of 18 evaluable patients in Arm1, at TG02 dose-level 200mg, 1/6 had a DLT: Gr3 diarrhea; at dose-level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm2, at TG02 dose-level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia; at dose-level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia; at dose-level 300mg,1 of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST. TG02 dose-level of 250mg was declared as the MTD in both Arms. Using the MDASI-BT, patients with high symptom burden had increased symptoms during cycle1 but became stable as they continued treatment. CONCLUSION The combination of TG02 at the MTD of 250mg with DD or MN temozolomide was tolerated. Cohort expansion continues at the MTD in both arms. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation.

Patients with primary central nervous system (CNS) tumors are highly symptomatic due to the functional sequelae of their disease and an unfavorable prognosis. Virtual reality (VR) immersive technology has demonstrated benefit in improving patients’ symptom burden, such as distress, pain, anxiety, and fatigue. However, this has not been explored in a CNS tumor population. This project explored the potential use of VR for symptom management in CNS tumor patients. A descriptive analysis of MDASI-BT/MDASI-SP/PROMIS-Anxiety patient-reported outcomes (PROs) for 535 CNS tumor patients was performed to identify the common moderate-severe (> 4 on a 0–10 scale) symptoms. Additionally, a systematic review of literature was performed addressing the question “For adult patients with solid tumors, what effect does VR have on their self-reported symptoms, such as distress, anxiety and pain?” The systematic literature review resulted in 17 studies using VR in other solid tumor populations, which demonstrated improvement in pain, anxiety, and distress. However, study designs often lacked rigor and none incorporated any biomarkers to correlate with PROs. CNS tumor symptom review of our patient cohort revealed that the majority of the patients were Caucasian (83%) males (58%) with a median age of 50 years (range, 18–83). At the time of diagnosis, 35% had a gross total resection. Glioblastoma was the most common diagnosis (32%) and 50% had a high-grade glioma. The most prevalent moderate-severe symptoms in this sample was fatigue (34%), with (14%) anxiety, (18%) pain, and (19%) distress. Given the high symptom rate in our patients, the promising but limited data that VR technology could improve distress and other symptoms provides strong support for this intervention in the CNS tumor population. Further research is needed to assess feasibility and efficacy of VR, as well as incorporation of correlative biomarkers, to better determine potential improvement in patient symptom burden.

INTRODUCTION Alopecia manifests in many cancer patients receiving therapy. These patients may experience similar physical symptoms and impairment as patients with autoimmune alopecia areata. The Alopecia Areata Symptom Impact Scale (AASIS) was originally validated for patients with autoimmune disorder. However, the validity and reliability of the AASIS among primary brain tumor (PBT) patients has not been evaluated. METHODS A cross sectional survey of 100 PBT patients was conducted as part of an IRB approved prospective protocol using structured questionnaires and open-ended responses. Participants completed the AASIS to measure symptoms of alopecia areata and their impact on daily functioning along with the Body Image Scale (BIS) to assess the prevalence of body image disturbance. Analyses included factor analysis to determine the number and nature of underlying constructs, Cronbach’s alphas to assess reliability, and correlational analysis to establish concurrent validity. RESULTS Patients’ median age was 48(range 23– 74), and 56% were male. Glioblastoma was most common (32%); low grade tumors (I and II) were 30% of diagnoses. The median time from initial diagnosis was 5 years (range 0–22), and 64% of patients had a KPS of 90–100. An item from the AASIS, ‘body hair or eyelashes loss’, was deemed to be irrelevant, rated low by PBT patients and was removed. Factor analysis revealed 3 underlying constructs: physical (e.g. itchy skin, scalp hair loss), affective (e.g. feeling anxious, feeling sad) symptoms, and impact of alopecia (e.g. work, quality of life) with Cronbach’s alphas of 0.78, 0.89 and 0.96, respectively. The BIS had the highest correlation with the affective symptom subscale (0.58, p< .001). CONCLUSION Our results demonstrate the desired reliability and validity for use in studies examining alopecia and its impact in PBT patients. Dropping the term ‘areata’, the modified tool is now ASIS, and can be implemented in future studies.

PURPOSE To compare tumor progression based on clinical radiological assessment and on Response Assessment in Neuro-Oncology (RANO) criteria between GBM patients treated with proton radiotherapy (PT) vs. photon intensity modulated radiotherapy (IMRT). METHODS Eligible patients were enrolled on the described prospective phase II trial and had MR imaging at baseline and follow-up beyond 12 weeks from treatment completion. ‘Clinical’ progression was based on a radiology report of progression in combination with changes in treatment due to suspected disease progression. A single blinded observer applied RANO criteria to determine the RANO-based tumor progression. RESULTS Of 90 enrolled patients, 66 were evaluable, with median follow-up of 19.8 (Range: 3.2–65.1) months; median of 22.6 months for PT (n=25) vs. 18.9 months for IMRT (n=41). Median time to progression (TTP) was 7.9 months based on clinical progression criteria (8.1 months IMRT, 6.3 months PT) and 7.2 months (7.3 months IMRT, 5.7 months PT) by RANO criteria (p=ns for all). Median ‘clinical’ progression-free survival (PFS) was 8.7 (Range: 6.4–11.1) months; 8.9 months IMRT vs. 8.7 months PT (p=0.065). Median RANO PFS was 8.3 (range, 5.8–11.6) months: 8.3 months IMRT vs. 6.9 months PT (p=0.226). There were 14 discrepant cases: 3 had progression based on ‘clinical’ but not RANO criteria, and 11 had progression based on RANO but not ‘clinical’ criteria. CONCLUSION Based on this secondary analysis of a randomized trial of PT vs. IMRT for GBM, there was no difference in tumor progression relative to treatment technique used. There was no statistical difference in PFS noted between clinical and RANO-based assessments, but RANO criteria identified progression more often than clinical assessment, and TTP was shortened with the use of RANO criteria alone. Further development of tumor assessment tools that improve consistency and accuracy of determining tumor progression are needed to guide therapeutic trials in GBM.

The ambiguity of defining hope impacts the level of readiness faced by healthcare professionals in treating patients with glioma, a disease with an unpredictable outcome. While the initial focus of care is on the physiological effects of the disease, a sense of hope has been demonstrated to positively impact coping during illness in other cancer patients. This study describes the report of hope and the relationship between hope and mood in adult brain tumor patients at various points in the illness trajectory. This was a cross-sectional study with data collection including the use of the Herth Hope Index (HHI) within 3 subscales (temporality, readiness, interconnectedness), the Profile of Mood States-Short Form (POMS-SF) and clinical information. Descriptive statistics were used to report sample characteristics. Spearman's rho compared POMS-SF and HHI scores. 82 patients participated in the study ranging in age from 22 to 78 years (mean 44.78). Patients were primarily male (57.3%), married (76.8%) and employed (51.2%). The majority of patients had a high grade glioma (77%), with nearly half having a recurrence and over 20% on active treatment at the time of this study. The overall HHI total score for the sample was 41.32(range 13-48). Patients with recurrence had a low HHI interconnectedness (median = 14.00) score and higher total mood disturbance (median = 14.00) compared with patients without recurrence (HHI median = 15.00, Mood median = .00, p < .05). All negative mood states on the POMS-SF were negatively correlated with HHI subscales. Overall, patients reporting more hope also reported less overall mood disturbance (tension, anger, fatigue, depression, confusion). Patients with tumor recurrence reported lower hope and higher mood disturbance then those who were newly diagnosed or without recurrence. Targeting interventions specifically tailored to individual needs in improvement of quality of life throughout the disease course may include measures to address hope to facilitate positive coping strategies.

Corticosteroids are routinely used for the control of peritumoral edema in patients with brain tumors.1 They are generally used as adjuncts to tumor-directed therapies, including surgery, radiation, and chemo. The mechanisms of action of corticosteroids leading to the control of vasogenic edema and, conversely, their lack of efficacy with intracellular or toxic edema are not fully understood.1,2 Dexamethasone is the most commonly prescribed corticosteroid for this patient population, primarily because of its low mineralocorticoid activity.3 However, there has been limited study of the efficacy of other types of synthetic corticosteroids in this population. Corticosteroid dosing is often determined based on clinical evaluation and imaging findings. A common dose prescribed at the time of diagnosis of a brain tumor is in the range of 8 to 16 mg/day in divided doses, which is thought to be derived from the dose–response curves generated in the first case series of preoperative dexamethasone use in patients with primary brain tumors3,4 Corticosteroids are also commonly used at the time of tumor recurrence or to manage treatment-related reactions such as radionecrosis, but there has been little investigation about the optimal dose and duration of corticosteroids in these settings.1,5,6 Despite the well-established morbidity associated with corticosteroid use, the reporting of actual dose and duration and associated side effects is often not routine and they are not usually assessed in patients with brain tumors.1 As a result, we have limited data regarding the severity and frequency of signs and symptoms associated with the use of corticosteroids in patients with both primary and metastatic brain tumors. One retrospective study of neuro-oncology patients found that 51% (30/59) had at least one steroid toxicity and 19% (11/59) required hospital admission due to steroid-related complications.7 Another study, of 88 patients with brain metastases, reported more toxicity in those who received more than 16 mg of dexamethasone per day at the time of commencement of radiotherapy, with 91% reporting at least one dexamethasone-related side effect at some point in the treatment course.8 The use of prolonged corticosteroids has been shown to impact functional status in select patients.9 Vecht and colleagues reported that mean improvement in KPS during radiation in patients with metastatic brain tumors was less in those who experienced a corticosteroid-related side effect such as ankle edema, proximal myopathy, or Cushingoid facies. The Dexamethasone Symptom Questionnaire (DSQ) is a self-report intended as a descriptive measure to determine the incidence and severity of side effects over the last week and to examine changes in side effects associated with dexamethasone when used longitudinally. Items were generated by literature review and expert opinion and were then reviewed for content validity by the use of focus groups of cancer patients receiving dexamethasone.10 Responses are formatted using a 4-point Likert scale (1 = not at all, 2 = a little bit, 3 = quite a bit, 4 = very much). The burden of completing the DSQ is low, taking 2–3 minutes to complete. The DSQ has demonstrated face and content validity and has been used to evaluate corticosteroid-related symptoms in breast cancer patients receiving dexamethasone as an anti-emetic10,11 and to evaluate the impact in brain metastases patients undergoing radiation therapy.12 The “Chronic” revision of the questionnaire (DSQ-C) contains the original 13 items with additional sign/symptom items (for roundness of face, anger/irritability, difficulty standing from a seated position or walking, problems with fragile skin, stretch marks or easy bruising, and headaches) added by the original developers after focus-group input to better measure long-term complications associated with dexamethasone use. Given the prolonged course of corticosteroid use to control cerebral edema in brain tumor patients and the few studies on the associated signs and symptoms, we undertook this study to redress the paucity of data and evaluate the utility of the DSQ-C in brain tumor patients.

Background We conducted a phase II trial to evaluate the efficacy of dasatinib, a multitargeted tyrosine kinase inhibitor, for adults with recurrent glioblastoma (GBM). Methods Eligibility requirements were Karnofsky performance status ≥ 60%; no concurrent hepatic enzyme-inducing anticonvulsants; prior treatment with surgery, radiotherapy, and temozolomide exclusively; and activation or overexpression of ≥ 2 putative dasatinib targets in GBM (ie, SRC, c-KIT, EPHA2, and PDGFR). Using a 2-stage design, 77 eligible participants (27 in stage 1, if favorable, and then 50 in stage 2) were needed to detect an absolute improvement in the proportion of patients either alive and progression-free patients at 6 months (6mPFS) or responding (any duration) from a historical 11% to 25%. Results A high rate of ineligibility (27%) to stage 1 precluded a powered assessment of efficacy, but there was also infrequent treatment-related toxicity at 100 mg twice daily. Therefore, the study was redesigned to allow intrapatient escalation by 50 mg daily every cycle as tolerated (stage 1B) before determining whether to proceed to stage 2. Escalation was tolerable in 10 of 17 (59%) participants evaluable for that endpoint; however, among all eligible patients (stages 1 and 1B, n = 50), there were no radiographic responses, median overall survival was 7.9 months, median PFS was 1.7 months, and the 6mPFS rate was 6%. The clinical benefit was insufficient to correlate tested biomarkers with efficacy. The trial was closed without proceeding to stage 2. Conclusions Intraparticipant dose escalation was feasible, but dasatinib was ineffective in recurrent GBM. Clinical trials.gov identified. NCT00423735 (available at http://clinicaltrials.gov/ct2/show/NCT00423735).

The study goal was to determine whether changes in relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast (DSC) MRI are predictive of overall survival (OS) in patients with recurrent glioblastoma multiforme (GBM) when measured 2, 8, and 16 weeks after treatment initiation.Patients with recurrent GBM (37/123) enrolled in ACRIN 6677/RTOG 0625, a multicenter, randomized, phase II trial of bevacizumab with irinotecan or temozolomide, consented to DSC-MRI plus conventional MRI, 21 with DSC-MRI at baseline and at least 1 postbaseline scan. Contrast-enhancing regions of interest were determined semi-automatically using pre- and postcontrast T1-weighted images. Mean tumor rCBV normalized to white matter (nRCBV) and standardized rCBV (sRCBV) were determined for these regions of interest. The OS rates for patients with positive versus negative changes from baseline in nRCBV and sRCBV were compared using Wilcoxon rank-sum and Kaplan-Meier survival estimates with log-rank tests.Patients surviving at least 1 year (OS-1) had significantly larger decreases in nRCBV at week 2 (P = .0451) and sRCBV at week 16 (P = .014). Receiver operating characteristic analysis found the percent changes of nRCBV and sRCBV at week 2 and sRCBV at week 16, but not rCBV data at week 8, to be good prognostic markers for OS-1. Patients with positive change from baseline rCBV had significantly shorter OS than those with negative change at both week 2 and week 16 (P = .0015 and P = .0067 for nRCBV and P = .0251 and P = .0004 for sRCBV, respectively).Early decreases in rCBV are predictive of improved survival in patients with recurrent GBM treated with bevacizumab.

BACKGROUND: Identification of malignant progression is a major challenge in the field of Neuro-Oncology because of inability of traditional imaging methods to distinguish pseudo-progression from true progression. IDH1-mutant gliomas represent an ideal model system to study the molecular mechanisms associated with malignant progression because they appear initially indolent and non-glycolytic, but eventually a subset progress towards secondary glioblastoma with a Warburg-like phenotype. The mechanisms and molecular features associated with this transformation are poorly understood. METHODS: TS603, NCH1681 and BT142 cell lines harboring IDH1 mutation were cultured in DMEM/F12+ N2 supplement, glutamine, FGF and EGF, then either harvested for metabolomics and methylation analyses or (250,000 cells) were injected into 6-week-old SCID mice brains. MRI was used to monitor tumor size; when tumors reached 100 mm(3), mice were injected in the tail vain with 96 mM 1-(13)C pyruvate which was hyperpolarized using Oxford Hypersense hyperpolarizer and chemical shift images were acquired immediately. Metabolite quantification was done using the Agilent LC/MS 6545 QTOF mass spectrometer. DNA methylation analysis was performed using Ilumina Infinium MethylationEPIC. RESULTS AND CONCLUSIONS: Cell lines that demonstrate aggressive growth both in vitro and in vivo have lost methylation in the promoters of glycolytic enzymes and have increased mRNA and metabolite levels for the glycolysis pathway compared to the non-transformed model. Metabolic (13)C MRI using hyperpolarized(13)C pyruvate confirmed that these aggressive lines have a Warburg-like phenotype (aerobic glycolysis). Moreover, the glycolytic enzyme expression of the aggressive cell line correlated with the subset of patients that are IDH1 mutated and low-G-CIMP in TCGA database. We hypothesize that specific modulation of epigenetic markers is a mechanism of malignant transformation and that monitoring lactate production may be a biomarker of transformation.

BACKGROUND Glioblastoma-associated macrophages and microglia (GAMs) are the predominant immune cells in the tumor microenvironment. Activation of MerTK, a receptor tyrosine kinase, triggers efferocytosis and polarizes GAMs to an immunosuppressive phenotype, promoting glioma growth. Our previous findings showed that UNC2371, a small-molecule inhibitor of MerTK, induced a less immunosuppressive phenotype of GAMs. Here, we investigate the role of MerTK inhibition on glioblastoma cells in the tumor microenvironment in vitro and in vivo. METHODS Cytotoxicity of UNC2371 in glioblastoma cells was determined by cell viability and colony formation assays. The protein expression of MerTK, AKT, and Erk were quantified by Western blotting in UNC2371-treated glioblastoma cells. A syngeneic GL261 mouse orthotopic glioblastoma model was used to evaluate the survival benefit of UNC2371 treatment. Fluorescent multiplex immunohistochemistry (IHC) was used to evaluate the expression of CD206, an anti-inflammatory marker on GAMs in murine brain tumor tissues. RESULTS UNC2371 inhibited GBM cell growth with an EC50 < 100 nM in both human U251 and mouse GL261 glioma cells, but not in GAMs. UNC2371-induced cell death and decreased cell proliferation were demonstrated by colony formation assays. UNC2371 decreased protein expression of phosphorylated MerTK, AKT, and Erk, which are essential for cell survival signaling, in U251 and GL261 cells. Furthermore, UNC2371 treatment prolonged survival in the mouse orthotopic GL261 glioblastoma model, suggesting that UNC2371 induces glioma cell death. A decreased of CD206+ GAMs was found in mice glioma tissues by fluorescent multiplex IHC, consistent with our previous findings in the in vitro cell-based assays. These data suggest that in addition to alleviate immunosuppression in the glioma microenvironment, UNC2371 directly inhibits GBM cell growth in vitro and in vivo. CONCLUSION Our findings suggest that UNC2371 has a therapeutic benefit via promoting GAM polarization towards proinflammatory status in the glioblastoma microenvironment and unexpectedly, inducing tumor cell death.

BACKGROUND Approximately 5%-10% of patients with newly diagnosed glioblastoma (GBM) will fail to complete standard radiotherapy (SRT). We sought to determine the impact on survival and to identify risk factors for failure to complete SRT. METHODS A cohort of 17,451 adults with GBM were identified from the National Cancer Database. The cohort was restricted to patients diagnosed between 2005 to 2012 that were started on conventionally fractionated RT of 1.8 to 2.0 Gy per fraction to a dose of < 66Gy and. Patients were stratified by RT dose achieved: (a.) completed RT > 58Gy, (b.) nearly completed RT > 50Gy - < 58Gy, and (c.) did not complete RT < 50Gy. RESULTS Radiotherapy completion rates correlated with survival, 87% of patients completed RT and had a median OS of 13.5 months, 4% were near completers (median OS 5.7 months), and 9% did not complete RT (median OS 1.9 months). Risk factors for not completing SRT were: older age, biopsy alone, government insurance, high comorbidity score and lower income zip code (all OR > 1 and p-values < 0.05). Twenty-eight percent of patients > 80 yrs did not complete SRT (OR 2.99, 95% CI 2.36–3.80, relative to 40–49 yrs) and 19% of 70-79-yrs did not complete SRT (OR 1.99, 95% CI 1.63–2.42). CONCLUSIONS Failure to complete SRT was associated with decreased survival in our cohort. Risk factors for failure to complete SRT, include older age, biopsy alone and substantial comorbidities. Other studies have shown SRT is discontinued primarily due to clinical deterioration and/or disease progression. Therefore, these patients should be considered for alternative therapeutic management such as hypofractionated radiotherapy.