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Background and ObjectivesFinancial toxicity significantly affects many patients, especially cancer survivors. We evaluated the association of unemployment as a major contributor to financial toxicity with patient-reported outcomes (PROs) assessing multiple illness experience domains in a primary CNS tumor (PCNST) cohort.MethodsPatient and disease characteristics and PROs measuring symptom burden, interference, psychologic distress, functional impairment, and health-related quality of life (HRQOL) from participants enrolled in an institutional review board–approved observational study at the US NIH's Neuro-Oncology Branch were collected between September 2016 and December 2019. Descriptive statistics, tests of association, and comparison of group mean values were used to describe and evaluate PROs.ResultsOf the 277 participants diagnosed with a PCNST, 57% were male and 43% were female. Participants reported their race as White, non-Hispanic (78%); White, Hispanic/Latino (9%); Asian (7%); Black (4%); Native Hawaiian/Pacific Islander (1%); and other (2%) with 8% missing. The median age of the overall cohort was 45 years (range 18–74). Hispanic participants in the overall sample were 2.3 times more likely, and in the brain tumor group 3.2 times more likely, to report unemployment (p= 0.043, odds ratio [OR] 2.3, 95% CI 1.0–5.4 andp= 0.008, OR 3.2, 95% CI 1.3–7.9, respectively). 77 (28%) individuals unemployed due to tumor reported more functional impairment with walking, washing, dressing, and performing usual activities and reduced HRQOL (p< 0.001). More unemployed participants in the total sample reported moderate-to-severe depressive symptoms (25%) than those employed (8%) (χ2(1) = 13.9,p< 0.001, OR 3.7, 95% CI 1.8–7.8) and more moderate-to-severe anxiety symptoms (30%) than those employed (15%) (χ2(1) = 7.8,p= 0.005, OR 2.4, 95% CI 1.3–4.5). Unemployed participants with brain tumor reported on average 3 more symptoms as moderate-to-severe compared with those employed (t(83) = −4.0, 95% CIdifference−5 to −2,p< 0.001, Hedgeg= 0.70).DiscussionBeing unemployed due to a PCNST strongly correlated with high symptom burden, functional impairment, psychological distress, and reduced HRQOL, which may be impediments to returning to work that warrant intervention. Lack of employer-based health insurance and reduced earnings are financial sequelae of unemployment superimposed on the physical, social, and cognitive effects of living with a PCNST. Innovations to screen for and address financial toxicity and its contributing factors are needed.

INTRODUCTION: Despite an increasing aging population, older adults (≥ 65 years) with primary brain tumors (PBTs) are not routinely assessed for geriatric vulnerabilities. Recent reports of geriatric assessment (GA) in patients with glioblastomas demonstrated that GA may serve as a sensitive prognosticator of overall survival. Yet, current practice does not include routine evaluation of geriatric vulnerabilities and the relevance of GA has not been previously evaluated in broader cohorts of PBT patients. The objective of this descriptive study was to assess key GA constructs in adults with PBT dichotomized into older versus younger groups. MATERIALS AND METHODS: A cross-sectional analysis of data collected from 579 participants with PBT recruited between 2016 and 2020, dichotomized into older (≥ 65 years, n = 92) and younger (≤ 64 years, n = 487) from an ongoing observational trial. GA constructs were evaluated using socio-demographic characteristics, Charlson Comorbidity Index (CCI), polypharmacy (>5 daily medications), Karnofsky Performance Status (KPS), Neurologic Function Score (NFS), and patient-reported outcome assessments including general health, functional status, symptom burden and interference, and mood. Descriptive statistics, t-tests, chi-square tests, and Pearson correlations were used to evaluate differences between age groups. RESULTS: Older participants were more likely to have problems with mobility (58% vs. 44%), usual activities (64% vs 50%) and self-care (38% vs 26%) compared to the younger participants (odds ratios [ORs] = 1.3–1.4, ps

Background Sleep disturbance (SD) is common in patients with cancer and has been associated with worse clinical outcomes. This cross-sectional study explored the prevalence of SD in a primary brain tumor (PBT) population, identified associated demographic and clinical characteristics, and investigated co-occurrence of SD with other symptoms and mood disturbance. Methods Demographic, clinical characteristics, MD Anderson Symptom Inventory-Brain Tumor, and Patient Reported Outcome Measurement Information System Depression and Anxiety Short-Forms were collected from PBT patients at study entry. Descriptive statistics, Chi-square tests, and independent t-tests were used to report results. Results The sample included 424 patients (58% male, 81% Caucasian) with a mean age of 49 years (range 18–81) and 58% with high-grade gliomas. Moderate-severe SD was reported in 19% of patients and was associated with younger age, poor Karnofsky Performance Status, tumor progression on MRI, and active corticosteroid use. Those with moderate-severe SD had higher overall symptom burden and reported more moderate-severe symptoms. These individuals also reported higher severity in affective and mood disturbance domains, with 3 to 4 times higher prevalence of depressive and anxiety symptoms, respectively. The most frequently co-occurring symptoms with SD were, drowsiness, and distress, though other symptoms typically associated with tumor progression also frequently co-occurred. Conclusions PBT patients with moderate-severe SD are more symptomatic, have worse mood disturbance, and have several co-occurring symptoms. Targeting interventions for sleep could potentially alleviate other co-occurring symptoms, which may improve life quality for PBT patients. Future longitudinal work examining objective and detailed subjective sleep reports, as well as underlying genetic risk factors, will be important.

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Purpose:To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma.Patients and Methods:This two-stage phase I trial determined the MTD of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden.Results:Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12–24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value.Conclusions:Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.

Purpose Cancer patients experience distress and anxiety when undergoing imaging studies to monitor disease status, yet these symptoms are not always appropriately identified or well-managed. This interim analysis of a phase 2 clinical trial explored feasibility and acceptability of a virtual reality relaxation (VR) intervention for primary brain tumor (PBT) patients at the time of clinical evaluation. Methods English speaking, adult PBT patients with previous reports of distress and upcoming neuroimaging were recruited between March of 2021 and March 2022. A brief VR session was done within 2 weeks prior to neuroimaging with patient-reported outcomes (PROs) collected before and immediately post-intervention. Self-directed VR use over the next 1 month was encouraged with additional PROs assessments at 1 and 4 weeks. Feasibility metrics included enrollment, eligibility, attrition, and device-related adverse effects with satisfaction measured with qualitative phone interviews. Results Fifty-five patients were approached via email, 40 (73%) responded and 20 (50%) enrolled (9 declines, 11 screen fails). 65% of participants were ≤ 50 years, 50% were male, 90% were White/non-Hispanic, 85% had good KPS (≥ 90), and most were on active treatment. All patients completed the VR intervention, PROs questionnaires, weekly check-ins, and qualitative interview. Most (90%) reported frequent VR use and high satisfaction and only 7 mild AEs were recorded (headache, dizziness, nausea, neck pain). Conclusion This interim analysis supports feasibility and acceptability of a novel VR intervention to target psychological symptoms for PBT patients. Trial enrollment will continue to assess for intervention efficacy. Trial Registration NCT04301089 registered on 3/9/2020.

Background Cognitive impairments are a common burden for patients with primary CNS tumors. Neuropsychological assessment batteries can be too lengthy, which limits their use as an objective measure of cognition during routine care. The purpose of this study was to evaluate the feasibility and utility of the brief Montreal Cognitive Assessment (MoCA) in routine in-person and telehealth visits (as a result of the global COVID-19 pandemic) with neuro-oncology patients. Methods Seventy-one adults with primary CNS tumors completed MoCA testing in person (n = 47) and via telehealth (n = 24). Correlation analysis and patient-reported outcomes (PROs), including symptom burden and interference, perceived cognition, general health status, and anxiety and depression, were included in this study. Feasibility was assessed through a provider satisfaction questionnaire. Results Patients were primarily White (83%), college-educated (71%) males (54%) with high-grade tumors (66%). The average total score on the MoCA administered in person was 25 (range: 6-30), with 34% classified as abnormal, and the average total score via telehealth was 26 (range: 12-30), with 29% classified as abnormal. Providers reported satisfaction in using the MoCA during routine clinical care, both in person and via telehealth. Lower MoCA scores correlated with worse symptom severity, KPS, age, education, and previous treatment. Conclusions The MoCA was feasible in clinical and telehealth settings, and its relationship to clinical characteristics and PROs highlights the need for both objective and patient-reported measures of cognition to understand the overall cognitive profile of a patient with a CNS tumor.

Purpose: To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma. Patients and Methods: This two-stage phase I trial determined the MTD of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden. Results: Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12–24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value. Conclusions: Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.

BACKGROUND PBT patients experience high levels of distress and anxiety symptoms at the time of neuroimaging, yet few non-pharmacological interventions are available. This phase 2 clinical trial interim analysis explored feasibility of a VR relaxation intervention for a PBT population. METHODS PBT patients seen at NIH were recruited to participate in this single arm trial conducted via telehealth. English-speaking, adult patients with upcoming neuroimaging who can self-report symptoms and have reported distress on previous MD Anderson Symptom Inventory-Brain Tumor assessments were eligible. Exclusion criteria include recent surgery or seizures, anxiety disorders, nausea, or visual deficits. The primary intervention consisted of a brief VR session done within 2 weeks prior to neuroimaging with patient-reported outcomes (PROs) collected before and immediately post-intervention, as well as 1 week and 4 weeks later, with self-directed VR use over 1 month. A qualitative phone interview was also completed to assess patient satisfaction. RESULTS Fifty-five patients were screened and approached with 40 (73%) responding to initial reach-out and 20 ultimately enrolling (9 declines, 11 screen fails). Decline reasons included: no distress/anxiety (30%), treatment-related toxicities (11%), and unknown (59%). Seven (64%) failed screening due to exclusionary anxiety disorders (36% GAD, 18% PTSD, 9% claustrophobia). Of those enrolled, 65% were ≤ 50 years, 50% were male, 90% were White/non-Hispanic, 85% had good KPS ( > 80), 65% had high-grade tumors, and most were on active treatment. All enrolled patients completed the VR intervention and participation period, PROs questionnaires, weekly check-ins, and qualitative interview. Most patients (90%) reported frequent VR use with 7 mild adverse effects reported (headache, dizziness, nausea, neck pain). CONCLUSION These findings suggest that this intervention is feasible for this population with high enrollment and study completion, though incidence of anxiety disorders was higher than anticipated and a comprehensive evaluation of this cohort is planned.

Glioblastoma (GBM) has a median survival of less than 18 months with infrequent long-term survival (LTS). Reports on LTS to date have not identified distinct molecular or clinical/imaging characteristic in long ( >3 years) versus short (< 3 year) survivors. We identified IDH wildtype GBM patients living ≥ 3 years post diagnosis (LTS, Nf25) and a control cohort (STS, Nf76) from our Natural History Study. Available tissue was analyzed with targeted panel sequencing (Nf25) and methylation analysis (Nf21) for classification, MGMT promoter (MGMTp) status and copy number changes. Median survival and age for LTS and STS was 54mo and 48yrs, and 16mo and 56yrs, respectively. LTS were more likely to be female (2.8x) or have a GTR (2.9x) but 83% less likely to be white. MGMTp was 10x more likely to be methylated in LTS tumors (95% CI [2.6, 39.6]), yet was unmethylated in 17%. LTS were 63% and 90% less likely to have TERTp or EGFR amplification (95% CI [0.14, 0.97] and [0.04, 0.29]). Core pathway review showed 21% of LTS had at least one alteration in p53, RB and RTK/PI3K with RTK/PI3K the most common (46%) . Methylation classifier identified 74% as GBM (STS=96%) with most the RTK II subtype (53%; STS=41%) and despite classic histologic features, indicated a non-GBM diagnosis in three cases (14%).Although uncommon, there are LTS with molecularly confirmed GBM. Remarkably, not all had MGMTp methylation, were young or had extensive tumor resection. Clinical estimates of outcome in GBM patients should consider the possibility of long-term survival even with established poor prognostic factors. Imaging characteristics in a subset of these cases are reported in a separate abstract. Additional interrogation of tumor from LTS may uncover additional determinants of response and outcomes.

Sleep-wake disturbances are among the most common and severe symptoms in primary brain tumor (PBT) patients. Currently, no studies have quantified their physiological sleep measurements or compared these assessments to established patient reported outcome measures (PROs). Smart wearable devices, such as Fitbits, continuously monitor patient behaviors at home and provide detailed physiological measurements of sleep, activity, and heart rate. We hypothesized that smart wearable devices can accurately determine physiological sleep disturbances and circadian disruptions and will complement established PROs in a PBT patient population. This observational, cross-sectional trial monitors sleep and circadian rhythm variables using Fitbit smart wearable devices worn for 1 month. Additionally, participants will answer PROs questionnaires (PROMIS Sleep Disturbance and Sleep Related Impairment-Short Forms, Sleep Hygiene Index, Morningness-Eveningness questionnaire, and Consensus Sleep Diary) at study entry and during the last week on-study. The present study is a planned interim analysis of 54 patients to assess feasibility, including evaluation of enrollment, attrition, study parameter completion and data missingness. 73 PBT patients were screened and approached. Of these patients, 54 (74%) were enrolled on study and 19 (26%) declined participation (8 lacked interest, 3 discomfort wearing watches, 3 lacked smart phone, 2 unable to wear device at work, 2 unable to attend consent calls, 1 pregnancy and 1 cognitive complication). The accrued patients were 56% male, 56%³ 50 years of age, and 81% had a KPS³ 90. Patients represented different stages of treatment: 6% of patients were newly diagnosed, 24% on active treatment (11% 1st recurrence, 13% 2nd recurrence), and 70% were on imaging surveillance. Feasibility was confirmed as there were no deviations reported and 100% of PROs and study timepoints completed. Quantified Fitbit data including percent time worn and physiologic sleep parameters will be reported. Study enrollment for efficacy measures continues.

Glioblastoma (GBM) is the most aggressive primary brain malignancy with < 45% living a year beyond diagnosis which drops to 7% at five years. However, there have been reports of long-term survivors (LTS) living three to ten years beyond diagnosis. Few studies have reported on molecular factors in tumors from LTS cohorts. We identified GBM (IDH1/2 wildtype) patients living at least 3 years post diagnosis (N=25), including 16 with pre-treatment tumor tissue, from our Natural History Study. Available pre- or post-treatment tumors were analyzed with targeted panel sequencing and methylation analysis for classification, MGMT promoter status and copy number changes. Classical clinical prognostic features such as limited resection or older age did not preclude long-term survival as patients with tumor biopsy (n=1) or subtotal resection (n= 5) and patients > 60 were included in the LTS cohort. Furthermore, tumors with molecular features typically associated with poor prognosis were also in this GBM LTS group. MGMT promoter was unmethylated in 17% of tumors; EGFRvIII mutation in 13%, EGFR amplification in 33%, CDKN2A homozygous loss in 30% and complete chromosome 7 gain with 10 loss in 55%. Additionally, the methylation classifier found a higher-than-expected incidence of mesenchymal tumors (29%) and RTK II (57%). Tumors had a higher percent of TP53 mutations (44%) but lower pTERT (76%) compared to TCGA. These data suggest an individual patient’s prognosis cannot easily be predetermined based on classical clinical and molecular data. This underscores the need for further analyses to discover additional factors leading to their unexpected, prolonged survival and elucidate the role of factors typically associated with poor prognosis. Future work will include RNA-sequencing and germline whole genome sequencing to determine tumor specific gene expression and identify any possible genomic alterations that confer improved survival.

SIGNIFICANCE AND AIMS Financial toxicity (FT) after a cancer diagnosis is the consequence of decreased earnings and increased spending. In patients with primary central nervous system (PCNS) tumors, the correlation between FT and factors such as symptom burden, psychological distress, and health-related quality of life has not been extensively studied. We assessed employment status and several patient illness factors in a PCNS tumor cohort. METHODS Patient and disease characteristics and patient-reported outcomes (PROs) were collected from adults diagnosed with PCNS tumors between 9/2016-12/2019. Descriptive statistics and regression analyses were used to describe PROs. RESULTS Of 277 patients, 77 (28%) reported being unemployed due to tumor diagnosis. They reported difficulty walking (64%) and performing usual activities (64%). This group had lower general health status (p< 0.001) and higher tumor-related symptom severity (p=0.004) than employed patients. Unemployed patients reported high symptom burden with an average of 6 moderate-severe symptoms for those with brain tumors and 10 for those with spine tumors. Both brain and spine tumor patients who were unemployed reported increased mood-related interference (p=0.020), as well as moderate-severe anxiety (30%) and depression (25%) compared to employed patients (15% vs 8%, respectively). Unemployed brain tumor patients reported worse scores in cognitive and neurologic symptom subscales (p< 0.001). CONCLUSIONS AND IMPLICATIONS These data provide indirect evidence that financial toxicity that correlates with high symptom burden across several domains and lower health-related quality of life. Future research work will include the COST questionnaire to further evaluate the implications of FT in the PCNS tumor patient population.

BACKGROUND Seizures are a common symptom in patients with CNS tumors. The RANO-Seizure Control Composite Index (RANO-SCCI) was developed to monitor seizures over time by patients and clinicians. We describe the use of the RANO-SCCI as part of the NCI NOB-Natural History Study. METHODS Patients completed a RANO-SCCI prior to their clinic appointment with results shared with clinicians who then completed a RANO-SCCI as part of the same appointment. Seizure reports were tallied by respondent type and further by tumor type and grade. Concordance between patient and clinician report was also investigated. RESULTS One hundred fifty-seven patients underwent 250 clinical evaluations. Participants were primarily white (82%) males (57%) with median age 47 years (range: 19 – 78). Most had high grade (60%) primary brain (86%) tumors, were in surveillance (76%), with no prior recurrence (57%) and KPS ≥ 90 (76%). Half of patients and 62% of clinicians reported the patient ever having a seizure. The 12% discordance were all where the patient did not report a seizure, but clinicians did. There was good agreement on seizure reporting since last visit (74% patients, 78% clinicians), and anti-seizure medication use (51% patients, 57% clinicians). Seizures were reported more frequently in patients with high-grade tumors (WHO Grade 3 or 4) (60% patients, 76% clinicians) versus low-grade (WHO Grade 1 or 2) (51% patients, 59% clinicians), and among patients with oligodendrogliomas (71% patients, 85% clinicians) versus non-oligodendroglioma tumors (54% patients, 68% clinicians). CONCLUSIONS The RANO-SCCI was used for self-report and clinician report of seizure activity. A higher frequency was reported among oligodendroglioma and high-grade tumors. Disparities between patient and clinician responses may reveal a limitation in the patient’s ability to recognize and assess their seizure symptoms. Further work will investigate reporting congruence and associations with clinical and demographic characteristics.

BACKGROUND Mild cognitive impairment (MCI) commonly occurs in primary CNS tumor patients (PCTP). Our group and others have reported on the Montreal Cognitive Assessment (MoCA) as an MCI screening tool. Several abbreviated MoCA protocols have been developed for telehealth administration in other neurological diseases, with varied literature on scoring and clinical utility. We compared MoCA Full and 5-minute scores to assess utility in neuro-oncology. METHODS 71 PCTP completed the MoCA Full (abnormal: < 26/30) assessing: visuospatial/executive functioning, naming, memory, attention, language, abstraction, delayed recall, and orientation. Full scores were retrospectively recoded to the Pendlebury MoCA 5-minute protocol (abnormal: < 10/12) assessing: memory, delayed recall, and orientation. Correlation was assessed using Pearson’s coefficient. Disagreements between tests were examined using t-test and chi-square test. RESULTS Patients were primarily White (83%), college-educated (71%) males (54%) diagnosed with glioblastoma (20%), with average age of 43 years (range: 19-75), KPS > 80 (57%), prior radiation treatment (78%), and imaging surveillance at time of testing (79%). MoCA Full and 5-minute mean scores were 25.3 (SD: 4.8) and 9.9 (SD: 2.3), respectively. MCI was indicated in 32% (n= 23) of patients using MoCA Full and 27% (n= 19) using MoCA 5-minute. Where the protocols disagreed, MCI was detected only by MoCA Full in 6 patients (8%), and MoCA 5-minute in 2 patients (3%). Visuospatial/executive (p= 0.025) and abstraction (p< 0.001) subdomain scores, unique to MoCA Full, were significantly associated with MCI detected only by the MoCA Full; other subdomains, patient characteristics, and total score were not significant. The MoCA versions were highly correlated (r= 0.90). CONCLUSION High correlation and agreement between MoCA Full and 5-minute scores in this neuro-oncology patient population highlight potential telehealth utility of the MoCA 5-minute. Future prospective assessment of the MoCA 5-minute is warranted to describe optimal scoring threshold and utility in neuro-oncology.

BACKGROUND The median overall survival of patients with glioblastoma (GBM) is 10-12 months and the five-year survival ranges from 5-10%. Favorable clinical and molecular prognostic markers have been described in the literature, although an individual patient’s prognosis cannot easily be predetermined on these features as shown in the NOB-LTS project by Briceno et al. (SNO 2021). Until now, no radiologic characteristics have been correlated with better patient outcomes. We reviewed eighteen MRI features to determine if these could aid the identification of long-term survivors (LTS). METHODS From the NOB-LTS cohort of our Natural History Study, 16 long-term survivals (LTS; ≥ 3 years survival post-diagnosis) were matched based on sex, age, and extent of resection to 32 control (STS, < 3 years survival post-diagnosis) patients with NGS-confirmed IDH-wt glioblastoma. Pre-surgical MRIs (T1, T1 post-contrast, T2, T2/FLAIR, DWI, ADC) were reviewed by three blinded reviewers and analyzed based on pre-set criteria. RESULTS T1 hypointensity occurred commonly in the LTS (71%) vs STS (29%) while central heterogeneous signal occurred commonly in the STS (73%) vs LTS (50%) patients. Restricted diffusion was seen in 82% of STS and 70% of LTS cases. No difference was seen in irregular enhancement, peripheral and grey matter enhancement on T1 post-contrast images. Evaluation of T2/FLAIR images showed no difference in the number of lobes involved, presence of mass effect, heterogeneity of the signal or the perilesional signal abnormality or involvement of grey matter. CONCLUSION Our results suggest that pre-surgical MRI might be a useful prognostic tool as T1 hypointensity more frequently, and T1 central heterogeneity less commonly seen in the LTS group. These imaging findings may provide additional insights regarding the differences in tumor biology between LTS and STS. Further validation and correlation with histological/molecular characteristics are planned to better predict patient outcomes with newly diagnosed glioblastoma.

Background Primary central nervous system (CNS) tumors are often associated with high symptom burden and a poor prognosis from the time of diagnosis. The purpose of this study is to describe patient-reported outcomes (PRO) data from long-term survivors (LTS; ≥5-year survival post-diagnosis). Methods Clinical/treatment/molecular characteristics and PROs (symptom burden/interference (MDASI-BT/SP), perceived cognition (Neuro-QoL), anxiety/depression (PROMIS), and general health status (EQ-5D-3L)) were collected on 248 adult LTS between 9/2016 and 8/2019. Descriptive statistics and regression analysis were used to report results. Results Participants had a median age of 47 years (19-82) and were primarily White (83%) males (51%) with high-grade tumors (59%) and few mutations. Forty-two percent of the 222 brain tumor LTS reported no moderate-to-severe symptoms, whereas 45% reported three or more; most common symptoms were fatigue (40%), difficulty remembering (29%), and drowsiness (28%). Among spine tumor LTS (n = 42), nearly half reported moderate-to-severe weakness, pain, fatigue, and numbness/tingling, with 72% experiencing activity-related interference. Severe anxiety, depression, and cognitive symptoms were reported in up to 23% of the sample. Brain tumor LTS at higher risk for severe symptoms were more likely to be young, unemployed, and have poor KPS (Karnofsky Performance Status), whereas high symptom-risk spinal cord tumor LTS had poor KPS and received any tumor treatment. Conclusions Findings indicate LTS fall into distinct cohorts with no significant symptoms or very high symptom burden, regardless of tumor grade or mutational profile. These LTS data demonstrate the need for survivorship care programs and future studies to explore the symptom trajectory of all CNS tumor patients for prevention and early interventions.

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.

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.

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 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.

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.

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.

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.

The metabotropic glutamate 1 (mGlu1) receptor has emerged as a novel target for the treatment of metastatic melanoma and various other cancers. Our laboratory has demonstrated that a selective, non-competitive mGlu1 receptor antagonist slows human melanoma growth in vitro and in vivo. In this study, we sought to determine if the activation of a canonical G protein-dependent signal transduction cascade, which is often used as an output of mGlu1 receptor activity in neuronal cells, correlated with mGlu1 receptor-mediated melanoma cell viability. Glutamate, the endogenous ligand of mGlu1 receptors, significantly increased melanoma cell viability, but did not stimulate phosphoinositide (PI) hydrolysis in several human melanoma cell lines. In contrast, melanoma cell viability was not increased by quisqualate, a highly potent mGlu1 receptor agonist, or DHPG, a selective group I mGlu receptor agonist. Similarly to glutamate, quisqualate also failed to stimulate PI hydrolysis in mGlu1 receptor-expressing melanoma cells. These results suggest that the canonical G protein-dependent signal transduction cascade is not coupled to mGlu1 receptors in all human melanoma cells. On the other hand, dynamin inhibition selectively decreased viability of mGlu1 receptor-expressing melanoma cells, suggesting that a mechanism requiring internalization may control melanoma cell viability. Taken together, these data demonstrate that the approaches commonly used to study mGlu1 receptor function and signaling in other systems may be inappropriate for studying mGlu1 receptor-mediated melanoma cell viability.

The elemental anion chloride is generally considered a passive participant in neuronal excitability, and has never been shown to function as an agonist in its own right. We show that the antagonist-mediated, glutamate-independent inverse agonism of group II and III metabotropic glutamate (mGlu) receptors results from inhibition of chloride-mediated activation. In silico molecular modeling, site-directed mutagenesis, and functional assays demonstrate (1) that chloride is an agonist of mGlu3, mGlu4, mGlu6, and mGlu8 receptors with its own orthosteric site, and (2) that chloride is not an agonist of mGlu2 receptors. Molecular modeling-predicted and site-directed mutagenesis supported that this unique property of mGlu2 receptors results from a single divergent amino acid, highlighting a molecular switch for chloride insensitivity that is transduced through an arginine flip. Ultimately, these results suggest that activation of group II and III mGlu receptors is mediated not only by glutamate, but also by physiologically relevant concentrations of chloride.

The majority of existing research on the function of metabotropic glutamate (mGlu) receptor 1 focuses on G protein-mediated outcomes. However, similar to other G protein-coupled receptors (GPCR), it is becoming apparent that mGlu1 receptor signaling is multi-dimensional and does not always involve G protein activation. Previously, in transfected CHO cells, we showed that mGlu1 receptors activate a G protein-independent, β-arrestin-dependent signal transduction mechanism and that some mGlu1 receptor ligands were incapable of stimulating this response. Here we set out to investigate the physiological relevance of these findings in a native system using primary cultures of cerebellar granule cells. We tested the ability of a panel of compounds to stimulate two mGlu1 receptor-mediated outcomes: (1) protection from decreased cell viability after withdrawal of trophic support and (2) G protein-mediated phosphoinositide (PI) hydrolysis. We report that the commonly used mGlu1 receptor ligands quisqualate, DHPG, and ACPD are completely biased towards PI hydrolysis and do not induce mGlu1 receptor-stimulated neuroprotection. On the other hand, endogenous compounds including glutamate, aspartate, cysteic acid, cysteine sulfinic acid, and homocysteic acid stimulate both responses. These results show that some commonly used mGlu1 receptor ligands are biased agonists, stimulating only a fraction of mGlu1 receptor-mediated responses in neurons. This emphasizes the importance of utilizing multiple agonists and assays when studying GPCR function.

2031 Background: Therapies targeting multiple survival pathways simultaneously may be more effective for high-grade gliomas, a disease highly resistant to treatment. Our preclinical studies have shown potent anti-glioma effects of TG02 and synergy with temozolomide (TMZ) through modulation of transcription and cellular metabolism. A phase I/II trial was launched to test the combination of TG02 and TMZ in recurrent malignant gliomas and herein we report the phase I results. Methods: Adults with recurrent high-grade astrocytoma, KPS ≥ 60, normal organ function, ≤ 2 prior relapses were enrolled. The primary endpoint was dose limiting toxicity (DLT) from the start of the combined treatment to 4 weeks after in each arm. Bayesian optimal interval (BOIN) 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 days 1, 12, 15, and 26) and TMZ, either as a dose-dense (DD; 125mg/m2/d, 7on/7off, Arm 1) or metronomic (MN; 50mg/m2/d, Arm 2) dosing schedule on a 28-day cycle. Results: Forty patients were enrolled; 38 were evaluable; 70% male; overall median age 50.7; median KPS 90. Of 18 evaluable patients in Arm 1 (DD TMZ), at TG02 dose level 200mg, 1/6 had a DLT: Gr3 diarrhea. At TG02 dose level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm 2 (MN TMZ), at TG02 dose level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia. At TG02 dose level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia. At TG02 dose level 300mg,1 out of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST, which resulted in hospitalization. Therefore, the TG02 dose level of 250mg was declared as the MTD in both Arm 1 and Arm 2. Conclusions: The combination of TG02 at the MTD of 250mg with DD or MN TMZ has a tolerable toxicity profile. Cohort expansion continues at the MTD in both arms to conduct pharmacokinetics and pharmacogenetics to better elucidate the toxicity profile. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation with the phase II randomized component. Clinical trial information: NCT02942264.

The metabotropic glutamate 1a (mGlu1a) receptor is a G protein-coupled receptor linked with phosphoinositide (PI) hydrolysis and with β-arrestin-1-mediated sustained extracellular signal-regulated kinase (ERK) phosphorylation and cytoprotective signaling. Previously, we reported the existence of ligand bias at this receptor, inasmuch as glutamate induced both effects, whereas quisqualate induced only PI hydrolysis. In the current study, we showed that mGlu1 receptor agonists such as glutamate, aspartate, and l-cysteate were unbiased and activated both signaling pathways, whereas quisqualate and (S)-3,5-dihydroxyphenylglycine stimulated only PI hydrolysis. Competitive antagonists inhibited only PI hydrolysis and not the β-arrestin-dependent pathway, whereas a noncompetitive mGlu1 receptor antagonist blocked both pathways. Mutational analysis of the ligand binding domain of the mGlu1a receptor revealed that Thr188 residues were essential for PI hydrolysis but not for protective signaling, whereas Arg323 and Lys409 residues were required for β-arrestin-1-mediated sustained ERK phosphorylation and cytoprotective signaling but not for PI hydrolysis. Therefore, the mechanism of ligand bias appears to involve different modes of agonist interactions with the receptor ligand binding domain. Although some mGlu1a receptor agonists are biased toward PI hydrolysis, we identified two endogenous compounds, glutaric acid and succinic acid, as new mGlu1 receptor agonists that are fully biased toward β-arrestin-mediated protective signaling. Pharmacological studies indicated that, in producing the two effects, glutamate interacted in two distinct ways with mGlu1 receptors, inasmuch as competitive mGlu1 receptor antagonists that blocked PI hydrolysis did not inhibit cytoprotective signaling. Quisqualate, which is biased toward PI hydrolysis, failed to inhibit glutamate-induced protection, and glutaric acid, which is biased toward protection, did not interfere with glutamate-induced PI hydrolysis. Taken together, these data indicate that ligand bias at mGlu1 receptors is attributable to different modes of receptor-glutamate interactions, which are differentially coupled to PI hydrolysis and β-arrestin-mediated cytoprotective signaling, and they reveal the existence of new endogenous agonists acting at mGlu1 receptors.

Accurate and prompt data collection is vital to clinical research. Traditionally, patient reported outcomes (PROs) have been captured through paper/pencil format and clinical data by retrospective clinical document review. Limitations include issues of errors, data omissions and monetary cost. We report an innovative tool for data collection. The primary objective of the NOB-NHS is to provide longitudinal collection of data including clinical status and PROs. Data was initially recorded by data analysts from review of the medical record in nine forms housed in CCRs Labmatrix system. All data fields were reviewed by the clinical team for relevance to the research question, redundancy, and timing of data collection. Free text fields were replaced by pre-determined, standardized pick lists of possible responses. Data fields were then converted into 2 electronic data collection forms (new patient and follow-up) in Scribe, a CCR-developed system for PROs/electronic form data. Feasibility and concordance testing was completed. Lastly, the clinical team was trained to enter data using tablets/laptops in the clinical setting. To date, 400 patients have been registered onto the NOB-NHS, with 222 collected through electronic systems. Links are sent via email to clinicians (nurse practitioners/clinical fellows) and patients that open a survey-style data collection form with drop-down menus and pre-formatted fields. Upon completion, the form automatically syncs to Labmatrix for data deposition and storage. On average, the Study Entry Form is completed in 5 minutes; the Clinic Visit Form in 2 minutes. PROs completion rate is > 95%. Data collected in a systematic and timely manner permits researchers to build stronger queries, reduces time spent on data cleaning, and facilitates statistical analysis. Standardization of the data fields and training of both clinical staff and data managers allows research to be reliable, especially for longitudinal studies such as natural history studies.

Noncompetitive antagonists of the human metabotropic glutamate receptor subtype 5 (mGluR5) have been implicated as potential therapeutics for the treatment of a variety of nervous system disorders, including pain, anxiety, and drug addiction. To discover novel noncompetitive antagonists to the mGluR5, we initiated an SAR study around the known lead compounds MPEP and M-MPEP. Our results pointed out the critical role of the para position of the two aromatic rings, which leads to inactive products and permitted the discovery of potent mGluR5 antagonists (e.g., 16, 25, 28, 34 IC50 = 13.5, 11.9, 21, 15 nM, respectively).

The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) acts as an agonist at group II metabotropic glutamate receptors (mGluRs). NAAG is inactivated by extracellular peptidase activity yielding glutamate and N-acetylaspartate. We recently developed a series of potent NAAG peptidase inhibitors, including ZJ-11, ZJ-17 and ZJ-43. In the present study, we examined the effects of intrathecally administered ZJ-11 and ZJ-17 and intravenously administered ZJ-11 and ZJ-43 in the rat formalin test (an inflammatory pain model) and in the rat partial sciatic nerve ligation model (a neuropathic pain model). Intrathecal injection of ZJ-11 or ZJ-17 or intravenous injection of ZJ-11 or ZJ-43 suppressed both phases of the agitation behaviour induced by paw formalin injection. Intrathecal and intravenous injection of ZJ-11 suppressed the expression of Fos-like immunoreactivity, induced by paw formalin injection, in laminae I-II in segments L4-L5 of the spinal cord, suggesting an action on sensory spinal transmission. Partial sciatic nerve ligation induced significant mechanical allodynia 7 days after the nerve injury. Intrathecal injection of ZJ-11 or ZJ-17 or intravenous administration of ZJ-11 or ZJ-43 attenuated the level of mechanical allodynia induced by this nerve ligation. These effects of intrathecally or intravenously administered ZJ compounds in both the formalin test and the partial sciatic nerve ligation model were completely antagonized by pretreatment with LY-341495, a highly selective group II mGluR antagonist. Thus, elevation of extracellular NAAG, induced by the inhibition of NAAG peptidase, activates group II mGluRs and produces an analgesic effect in neuropathic and inflammatory and pain models. In contrast, peptidase inhibition did not affect the threshold for withdrawal from a noxious mechanical stimulus or from an acute thermal stimulus in the hotplate test.

The neuropeptidase glutamate carboxypeptidase II (GCPII) hydrolyzes N-acetyl-L-aspartyl-L-glutamate (NAAG) to liberate N-acetylaspartate and glutamate. GCPII was originally cloned as PSMA, an M(r) 100,000 type II transmembrane glycoprotein highly expressed in prostate tissues. PSMA/GCPII is located on the short arm of chromosome 11 and functions as both a folate hydrolase and a neuropeptidase. Inhibition of brain GCPII may have therapeutic potential in the treatment of certain disease states arising from pathologically overactivated glutamate receptors. Recently, we reported that certain urea-based structures act as potent inhibitors of GCPII (J. Med. Chem. 2001, 44, 298). However, many of the potent GCPII inhibitors prepared to date are highly polar compounds and therefore do not readily penetrate the blood-brain barrier. Herein, we elaborate on the synthesis of a series of potent, urea-based GCPII inhibitors from the lead compound 3 and provide assay data for these ligands against human GCPII. Moreover, we provide data revealing the ability of one of these compounds, namely, 8d, to reduce the perception of inflammatory pain. Within the present series, the gamma-tetrazole bearing glutamate isostere 7d is the most potent inhibitor with a K(i) of 0.9 nM. The biological evaluation of these compounds revealed that the active site of GCPII likely comprises two regions, namely, the pharmacophore subpocket and the nonpharmacophore subpocket. The pharmacophore subpocket is very sensitive to structural changes, and thus, it appears important to keep one of the glutamic acid moieties intact to maintain the potency of the GCPII inhibitors. The site encompassing the nonpharmacophore subpocket that binds to glutamate's alpha-carboxyl group is sensitive to structural change, as shown by compounds 6b and 7b. However, the other region of the nonpharmacophore subpocket can accommodate both hydrophobic and hydrophilic groups. Thus, an aromatic ring can be introduced to the inhibitor, as in 8b and 8d, thereby increasing its hydrophobicity and thus potentially its ability to cross the blood-brain barrier. Intrathecally administered 8d significantly reduced pain perception in the formalin model of rat sensory nerve injury. A maximal dose of morphine (10 mg) applied in the same experimental paradigm provided no significant increase in analgesia in comparison to 8d during phase 1 of this pain study and modestly greater analgesia than 8d in phase 2. These urea-based inhibitors of GCPII thus offer a novel approach to pain management.

Moderate hyperhomocysteinemia is associated with several diseases, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, and spina bifida. However, the mechanisms for their pathogenesis are unknown but could involve the interaction of homocysteine or its metabolites with molecular targets such as neurotransmitter receptors, channels, or transporters. We discovered that L-homocysteine sulfinic acid (L-HCSA), L-homocysteic acid, L-cysteine sulfinic acid, and L-cysteic acid are potent and effective agonists at several rat metabotropic glutamate receptors (mGluRs). These acidic homocysteine derivatives 1) stimulated phosphoinositide hydrolysis in the cells stably expressing the mGluR1, mGluR5, or mGluR8 (plus Galpha(qi9)) and 2) inhibited the forskolin-induced cAMP accumulation in the cells stably expressing mGluR2, mGluR4, or mGluR6, with different potencies and efficacies depending on receptor subtypes. Of the four compounds, L-HCSA is the most potent agonist at mGluR1, mGluR2, mGluR4, mGluR5, mGluR6, and mGluR8. The effects of the four agonists were selective for mGluRs because activity was not discovered when L-HCSA and several other homocysteine derivatives were screened against a large panel of cloned neurotransmitter receptors, channels, and transporters. These findings imply that mGluRs are candidate G-protein-coupled receptors for mediating the intracellular signaling events induced by acidic homocysteine derivatives. The relevance of these findings for the role of mGluRs in the pathogenesis of homocysteine-mediated phenomena is discussed.

Group II and group III metabotropic glutamate (mGlu) receptors are G protein-coupled receptors (GPCRs) that inhibit adenylyl cyclase via activation of Gαi/o. The purpose of this study was to design a universal method that overcomes previous challenges in consistently measuring group II and group III mGlu-receptor (mGluR) activation in stably transfected systems. In Chinese hamster ovary (CHO) cells stably transfected with the GloSensor cAMP biosensor, we optimized conditions for simple and highly reproducible (

Metabotropic glutamate 1 (mGlu) receptor has been proposed as a target for the treatment of metastatic melanoma. Studies have demonstrated that inhibiting the release of glutamate (the natural ligand of mGlu1 receptors), results in a decrease of melanoma tumor growth in mGlu1 receptor-expressing melanomas. Here we demonstrate that mGlu1 receptors, which have been previously characterized as oncogenes, also behave like dependence receptors by creating a dependence on glutamate for sustained cell viability. In the mGlu1 receptor-expressing melanoma cell lines SK-MEL-2 (SK2) and SK-MEL-5 (SK5), we show that glutamate is both necessary and sufficient to maintain cell viability, regardless of underlying genetic mutations. Addition of glutamate increased DNA synthesis, whereas removal of glutamate not only suppressed DNA synthesis but also promoted cell death in SK2 and SK5 melanoma cells. Using genetic and pharmacological inhibitors, we established that this effect of glutamate is mediated by the activation of mGlu1 receptors. The stimulatory potential of mGlu1 receptors was further confirmed in vivo in a melanoma cell xenograft model. In this model, subcutaneous injection of SK5 cells with short hairpin RNA-targeted downregulation of mGlu1 receptors resulted in a decrease in the rate of tumor growth relative to control. We also demonstrate for the first time that a selective mGlu1 receptor antagonist JNJ16259685 ((3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone) slows SK2 and SK5 melanoma tumor growth in vivo. Taken together, these data suggest that pharmacological inhibition of mGlu1 receptors may be a novel approach for the treatment of metastatic melanoma.

The chemical synthesis of a series of N 1 -substituted derivatives of (2 R ,4 R )-4-aminopyrrolidine-2,4-dicarboxylic acid [(2 R ,4 R )-APDC] as constrained analogues of γ-substituted glutamic acids is described. Appropriate substitution of the N 1 -position results in agonist, partial agonist, or antagonist activity at mGluR2, mGluR3, and/or mGluR6.

In CHO-K1 cells, heat shock strongly activated reporter-gene expression driven by the cytomegalovirus immediate-early (CMV-IE) promoter from adenoviral and plasmid vectors. Heat shock treatment (2 h at 42.5 °C) significantly enhanced the promoter DNA-binding activity in nuclear extracts. In CHO cells expressing mGluR1a and mGluR5a receptors under the control of the CMV promoter, heat shock increased receptor protein expression, mRNA levels and receptor function estimated by measurement of PI hydrolysis, intracellular Ca 2+ and cAMP. Hyperthermia increased average amplitudes of Ca 2+ responses, the number of responding cells, and revealed the toxic properties of mGluR1a receptor. Heat shock also effectively increased the expression of EGFP. Hence, heat shock effects on mGluR expression and function in CHO cells may be attributed to the activation of the CMV promoter. Moreover, this effect was not limited to CHO cells as heat shock also increased EGFP expression in PC-12 and HEK293 cells. Heat shock treatment may be a useful tool to study the function of proteins expressed in heterologous systems under control of the CMV promoter. It may be especially valuable for increasing protein expression in transient transfections, for enhancing receptor expression in drug screening applications and to control the expression of proteins endowed with toxic properties. This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’.