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Background Tumor-based classification of human glioma portends patient prognosis, but considerable unexplained survival variability remains. Host factors (eg, age) also strongly influence survival times, partly reflecting a compromised immune system. How blood epigenetic measures of immune characteristics and age augment molecular classifications in glioma survival has not been investigated. We assess the prognostic impact of immune cell fractions and epigenetic age in archived blood across glioma molecular subtypes for the first time. Methods We evaluated immune cell fractions and epigenetic age in archived blood from the University of California San Francisco Adult Glioma Study, which included a training set of 197 patients with IDH-wild type, 1p19q intact, TERT wild type (IDH/1p19q/TERT-WT) glioma, an evaluation set of 350 patients with other subtypes of glioma, and 454 patients without glioma. Results IDH/1p19q/TERT-WT patients had lower lymphocyte fractions (CD4+ T, CD8+ T, natural killer, and B cells) and higher neutrophil fractions than people without glioma. Recursive partitioning analysis delineated 4 statistically significantly different survival groups for patients with IDH/1p19q/TERT-WT based on an interaction between chronological age and 2 blood immune factors, CD4+ T cells, and neutrophils. Median overall survival ranged from 0.76 years (95% confidence interval = 0.55-0.99) for the worst survival group (n = 28) to 9.72 years (95% confidence interval = 6.18 to not available) for the best (n = 33). The recursive partitioning analysis also statistically significantly delineated 4 risk groups in patients with other glioma subtypes. Conclusions The delineation of different survival groups in the training and evaluation sets based on an interaction between chronological age and blood immune characteristics suggests that common host immune factors among different glioma types may affect survival. The ability of DNA methylation-based markers of immune status to capture diverse, clinically relevant information may facilitate noninvasive, personalized patient evaluation in the neuro-oncology clinic.

Background Glioblastoma is an incurable disease with a poor prognosis. For caregivers of people with glioblastoma, the burden of care can be high. Patients often present with different clinical characteristics, which may impact caregiver burden in different ways. This study aimed to evaluate associations between patient clinical characteristics and caregiver burden/quality of life (QoL). Methods Caregiver–patient dyads were enrolled at 7 academic cancer centers in the United States. Eligible caregiver participants were self-reported as the primary caregiver of an adult living with glioblastoma and completed a caregiver burden survey. Eligible patients were age ≥ 18 years at glioblastoma diagnosis and alive when their respective caregiver entered the study, with the presence of cognitive dysfunction confirmed by the caregiver. Data were analyzed with descriptive statistics and multivariable analyses. Results The final cohort included 167 dyads. Poor patient performance status resulted in patient difficulty with mental tasks, more caregiving tasks, and increased caregiving time. Language problems were reported in patients with left-sided lesions. Patient confusion was negatively associated with all caregiver domains: emotional health, social health, general health, ability to work, confidence in finances, and overall QoL. Better caregiver QoL was observed in patients with frontal lobe lesions versus non-frontal lobe lesions. Conclusion This study reinforced that patient performance status is a critical clinical factor that significantly affects caregiver burden, caregiving tasks, and caregiver time. Additionally, patient confusion affects multiple facets of caregiver burden/QoL. These results could be used to support guided intervention for caregiver support, customized to the patient experience.

Introduction Anaplastic oligodendrogliomas are high-grade gliomas defined molecularly by 1p19q co-deletion. There is no curative therapy, and standard of care includes surgical resection followed by radiation and chemotherapy. However, the benefit of up-front radiation with chemotherapy compared to chemotherapy alone has not been demonstrated in a randomized control trial. Given the potential long-term consequences of radiation therapy, such as cognitive impairment, arteriopathy, endocrinopathy, and hearing/visual impairment, there is an effort to balance longevity with radiation toxicity. Methods We performed a retrospective single institution analysis of survival of patients with anaplastic oligodendroglioma over 20 years. Results 159 patients were identified as diagnosed with an anaplastic oligodendroglioma between 1996 and 2016. Of those, 40 patients were found to have AO at original diagnosis and had documented 1p19q co-deletion with a median of 7.1 years of follow-up (range: 0.6–16.7 years). After surgery, 45 % of patients were treated with radiation and chemotherapy at diagnosis, and 50 % were treated with adjuvant chemotherapy alone. The group treated with chemotherapy alone had a trend of receiving more cycles of chemotherapy than patients treated with radiation and chemotherapy upfront (p = 0.051). Median overall survival has not yet been reached. The related risk of progression in the upfront, adjuvant chemotherapy only group was almost 5-fold higher than the patients who received radiation and chemotherapy (hazard ratio = 4.85 (1.74–13.49), p = 0.002). However, there was no significant difference in overall survival in patients treated with upfront chemotherapy compared to patients treated upfront with chemotherapy and radiation (p = 0.8). Univariate analysis of age, KPS, extent of resection, or upfront versus delayed radiation was not associated with improved survival. Conclusions Initial treatment with adjuvant chemotherapy alone, rather than radiation and chemotherapy, may be an option for some patients with anaplastic oligodendroglioma, as it is associated with similar overall survival despite shorter progression free survival.

Background Chemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas (LGGs), but a proportion of patients treated with temozolomide (TMZ) will develop recurrent tumors with TMZ-induced hypermutation. We aimed to determine the prevalence of TMZ-induced hypermutation at recurrence and prognostic implications. Methods We sequenced recurrent tumors from 82 patients with initially low-grade IDH-mutant gliomas who underwent reoperation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes. Results Hypermutation was associated with high-grade disease at the time of reoperation (OR 12.0 95% CI 2.5-115.5, P = .002) and was identified at transformation in 57% of recurrent LGGs previously exposed to TMZ. After anaplastic (grade III) transformation, hypermutation was associated with shorter survival on univariate and multivariate analysis (HR 3.4, 95% CI 1.2-9.9, P = .024), controlling for tumor grade, subtype, age, and prior radiotherapy. The effect of hypermutation on survival after transformation was validated in an independent, published dataset. Hypermutated (HM) tumors were more likely to develop discontiguous foci of disease in the brain and spine (P = .003). To estimate the overall incidence of high-grade transformation among low-grade IDH-mutant tumors, data from a phase II trial of TMZ for LGG were analyzed. Eight-year transformation-free survival was 53.8% (95% CI 42.8-69.2), and 61% of analyzed transformed cases were HM. Conclusions TMZ-induced hypermutation is a common event in transformed LGG previously treated with TMZ and is associated with worse prognosis and development of discontiguous disease after recurrence. These findings impact tumor classification at recurrence, prognostication, and clinical trial design.

Intrinsic brain tumors often occur within functional neural networks, leading to neurological impairment and disability of varying degrees. Advances in our understanding of tumor-network integration, human cognition and language processing, and multiparametric imaging, combined with refined intraoperative tumor resection techniques, have enhanced surgical management of intrinsic brain tumors within eloquent areas. However, cognitive symptoms impacting health-related quality of life, particularly processing speed, attention, concentration, working memory, and executive function, often persist after the postoperative recovery period and treatment. Multidisciplinary cognitive rehabilitation is the standard of care for addressing cognitive impairments in many neurological diseases. There is promising research to support the use of cognitive rehabilitation in adult brain tumor patients. In this review, we summarize the history and usefulness of postacute cognitive rehabilitation for adult brain tumor patients.

Outcomes for patients with lower-grade gliomas (LrGGs) continue to improve with advances in molecular characterization and treatment. However, cognitive sequela from the tumor and its treatment leave a significant impact on health-related quality of life for these patients. Several factors affect each patient’s cognition, such as tumor location, treatment, medication, and comorbidities. However, impairments of processing speed, attention, concentration, working memory, and executive function are common across LrGG patients. Cognitive rehabilitation strategies, well established in traumatic brain injury and stroke populations, are based on neural plasticity and functional reorganization. Adapting these strategies for implementation in patients with brain tumors is an active area of research. This article provides an overview of cognitive domains commonly impaired in LrGG patients and evidence for the use of cognitive rehabilitation strategies to address these impairments with the goal of improving health-related quality of life in this patient population.

In Bolton's pubs at the end of the 1930s, the research organization Mass Observation pursued answers to big abstract questions about time by studying small concrete actions. Drawing on field notes, draft manuscripts, and published works, this article sets out the different understandings and experiences of time documented by the team of investigators. Outside the ‘time-clock factory-whistle dimension of living’ and inside ‘pub-time’, individuals bought drinks for their companions, drank at the same pace, and engaged with everyone around them on an equal footing. Mass Observation presented such behaviours as proof that the pub fostered a socially harmonious, egalitarian community from a pre-industrial age. However, this article shows that the pub study's archive contains material that goes against the published findings. Observers turned in reports about authoritarian conduct, hierarchical power structures, and the intrusion of contemporary politics. Blurring the research subject and object, it was sometimes the investigators themselves who broke the spell of the pub. These moments of tension, confusion, and contradiction offer insights into the observers’ own perspectives on modern temporalities and subjective experiences of time. All the people in the pubs were caught up in a state of flux.

Under-enrollment in clinical trials significantly limits valid analyses of clinical interventions and generalizability of findings. Often it results in premature study termination, with estimates of 22% to 50% of clinical trials terminated due to poor accrual. Currently, there are limited reports addressing the influence of race/ethnicity and socioeconomic status on clinical trial enrollment in adult glioma patients. The goal of this study was to test the hypothesis that race and socioeconomic status negatively impact therapeutic clinical trial enrollment. 988 adult patients were identified from the UCSF Tumor Board Registry and analyzed to determine the rate of therapeutic clinical trial screening and study enrollment. At initial diagnosis, 43.6% and 17.5% of glioma patients were screened and enrolled in a therapeutic clinical trial, respectively. At recurrence, 49.8% and 26.3% of patients were screened and enrolled in a clinical trial, respectively. Thirty-three percent of the study population belonged to a NIH-designated underrepresented minority group; Asian/Pacific-Islander comprised 19.6% of the overall cohort. On univariate analysis, only in-state location, distance to the hospital, and WHO grade were associated with enrollment at initial diagnosis and recurrence. Minority status, insurance type, median household income, and percent below poverty were not associated with clinical trial enrollment. Minority and socioeconomic status did not impact adult glioma clinical trial enrollment. Proximity to the tertiary care cancer center may be an important consideration for minority patients. Patient screening should be carefully considered in order to avoid bias based on minority and socioeconomic status.

Venous thromboembolism (VTE) occurs in up to 30% of patients with high-grade glioma (HGG). Concern for increased risk of intracranial hemorrhage (ICH) with therapeutic anticoagulation (AC) complicates VTE treatment. Some retrospective studies have reported an increased risk of ICH associated with therapeutic AC; however, effective alternatives to AC are lacking. The aim of our study is to assess the risk of ICH in HGG patients with VTE on low molecular weight heparin (LMWH).We performed a retrospective matched cohort study of HGG patients from January 2005 to August 2016. Blinded review of neuroimaging for ICH was performed. For analysis of the primary endpoint, estimates of cumulative incidence (CI) of ICH were calculated using competing risk analysis with death as competing risk; significance testing was performed using the Gray's test. Median survival was estimated using the Kaplan-Meier method.Two hundred twenty patients were included, 88 (40%) with VTE treated with LMWH, 22 (10%) with VTE, not on AC, and 110 (50%) without VTE. A total of 43 measurable ICH was recorded: 19 (26%) in LMWH, 3 (14%) in VTE not on AC, and 21 (19%) in non-VTE cohort. No significant difference was observed in the 1-year CI of ICH in the LMWH cohort and non-AC with VTE group (17% vs 9%; Gray's test, P = .36). Among patients without VTE, the 1-year CI of ICH was 13%. Median survival was similar among all 3 cohorts.Our data suggest that therapeutic LMWH is not associated with substantially increased risk of ICH in HGG patients.

BACKGROUND Epigenetic inhibition of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has emerged as a clinically relevant prognostic marker in glioblastoma (GBM). Methylation of the MGMT promoter has been shown to increase chemotherapy efficacy. While traditionally reported as a binary marker, recent methodological advancements have led to quantitative approaches that measure methylation, providing clearer insights into methylation’s functional relationship with survival. METHODS A CLIA assay and bisulfite sequencing was utilized to develop a quantitative, 17-point MGMT promoter methylation index derived from the number of methylated CpG sites. Retrospective review of 240 newly diagnosed GBM patients was performed in order to discern how risk for mortality transforms as promoter methylation increases. Non-linearities were captured by fitting splines to Cox proportional hazard models, plotting smoothed residuals, and creating survival plots. Covariates included age, KPS, IDH1 mutation, and extent of resection. RESULTS Median follow-up time and progression free survival were 16 and 9 months, respectively. 176 subjects experienced death. A one-unit increase in CpG methylation on a scale of 1-17 resulted in a 4% reduction in hazard (95% CI 0.93–0.99, P< 0.005). Moreover, GBM patients with low-levels of methylation (1-6 CpG sites) fared markedly worse (HR=1.62, 95% CI 1.03-2.54, P< 0.036) than individuals who were unmethylated (reference group). Subjects with medium-levels of methylation (7-12 CpG sites) had the greatest reduction in hazard (HR=0.48, 95% CI 0.29-0.80, P< 0.004), followed by individuals in the highest methylation tertile (HR=0.62, 95% CI 0.40-0.97, P< 0.035). CONCLUSION This novel approach offers greater bisulfite conversion efficiency when compared to alternative methods, reducing the likelihood of false positives. Analysis of the resulting methylation index scores demonstrates a non-linear relationship between MGMT methylation and survival, suggesting conformation of the marker’s protective effect. These findings challenge the current understanding of MGMT’s functional form and underline why implementing an “optimal cutoff point” may be disadvantageous.

BACKGROUND Gliomas are devastating primary tumors of the central nervous system that often present with difficult to manage symptoms in addition to the antineoplastic tumor itself. Due to recent increase in popularity and societal acceptance of cannabis products, their use by glioma patients has increased. METHODS We conducted a single center, prospective study: patients with glioma answered a locally validated survey to inquire about their cannabis use at baseline and every three months. Quality of Life was measured using the EORTC QLQ-C30, its complementary module BN-20 and the EQ-5D-5L instrument. Eligible participants were classified as cannabis users or non-users. We performed linear regression clustered by subjects to see differences by user group and trends overtime. RESULTS To date, 89 patients agreed to participate, enrolled, and answered the baseline questionnaires, and 64 have answered the 3 month follow up survey. The mean age was 49.7(SD 13.74), 55 were male, 55 were cannabis users at baseline (61.8%) and 34 at 3 months (53.13%). Patients who were cannabis users scored 11.73 lower points at baseline when compared to non-users (79.65 [SD 18.93] vs 67.92 [SD 19.22]) in the QLQ-C30 instrument. Similarly, cannabis users recorded 9.624 lower points at 3 months compared to non-users (70.1 [SD 21.33] vs 79.72 [SD13.95]). The difference-in-difference estimator was 2.108 (p< 0.7). CONCLUSION Although we observed cannabis users scoring lower QoL measurements (p< 0.05) at baseline and 3 months, we observed a slight improvement in QoL of cannabis users while observing no change or decline (in some measures) among non-users. Our findings provide insight to the impact that cannabis has in QoL over time. While not conclusive, these preliminary results need to be studied on a longer-term basis with a larger sample size in order to detect trends on quality of life among patients with different tumor types.

The neutrophil dexamethasone methylation index (NDMI) is an algorithm-based biomarker to assess individuals’ exposures to dexamethasone, a synthetic glucocorticoid commonly administered for inflammation. Cortisol is the main endogenous glucocorticoid that controls vital processes including the immune response and lipid and carbohydrate metabolism. Variations in the NDMI score reflect individuals’ sensitivities of exposures to both exogenous and endogenous glucocorticoids, and this biomarker was trained using elastic net regression on Illumina’s most recent DNA methylation beadarray, the EPIC array, which contains 850,000 cytosine-guanine (CpG) sites. While technology for microarray research continues to advance over time, researchers are capable of conducting more comprehensive epigenome-wide association studies (EWAS). However, many studies are still run and archived using Illumina’s historical 450K platform with approximately 450,000 CpGs, and there are fewer published databases using the 850K EPIC array. To evaluate the cross-platform bioinformatic comparability, we performed elastic net regression modeling using predictors available in the 450K to train the NDMI. Among the 135 pre-surgery glioma cases from the UCSF Immune Profiles Study (IPS), NDMI scores between the 450K and 850K model were strongly correlated (r = 0.99, p < 0.0001). In the 311 controls from the UCSF Adult Glioma Study (AGS), similar correlations were observed (r = 0.96, p < 0.0001). We observe that NDMI remains a robust tool using historical 450K data and conclude that this algorithmic tool is capable of detecting the variations in individuals’ responses to dexamethasone.

BACKGROUND Patients with high-grade glioma (HGG), WHO grade 3 or 4, have substantial palliative care needs. As evidence suggests early palliative care consultation (PCC) yields improved quality of life in advanced cancer, our aim was to determine the occurrence, timing, and factors associated with PCC in HGG. METHODS Adults with HGG diagnosed between 8/3/2011 and 1/23/2020 were identified retrospectively from a large, academic, multi-center health system cancer registry. Patients were stratified by any prior PCC (yes/no), and timing of PCC by disease phase: (1) diagnosis (before radiation), (2) initial treatment (first-line chemotherapy/radiation), (3) second-line treatment (second-line to last chemotherapy), and (4) end-of-life (after last chemotherapy). Univariate analyses (e.g., Chi-square test) were conducted to compare PCC to non-PCC groups, based on data distribution. RESULTS Of 621 HGG patients, 134 (21.58%) received PCC, with 14 (10.45%) referred during phase 1; 35 (26.12%) in phase 2; 20 (14.93%) in phase 3; and 65 (48.51%) in phase 4 with a median of 74 days (IQR 15, 277) from initial PCC to death. The majority of referrals were inpatient (111 (82.84%)). The PCC group did not differ significantly from non-PCC in age, sex, language, race, or ethnicity, but did differ by marital status: single (263 (42.35%) vs 187 (38.4%)), divorced/separated (37 (27.61%) vs 107 (21.97%)), married/civil union (17 (12.69%) vs 154 (31.62%)); (Chi-square p < .01). Compared to non-PCC, more patients in the PCC group had glioblastoma histopathology (89.55% vs. 82.14%, p = .04). CONCLUSION A minority of HGG patients ever received PCC, which primarily occurred in the inpatient setting, and half of those referred for PCC received it during the end-of-life phase. Thus, only about one in 10 patients in the entire cohort potentially received the benefits of early PCC. Further studies should elucidate barriers and facilitators to early palliative care in HGG.

BACKGROUND Exercise has proven benefit in patients with cancer with most studies focused on patients with high functional and neurocognitive status. Patients with brain tumors, however, frequently have deficits in cognition, motor, balance, or other symptoms that are further exacerbated by surgery and adjuvant treatment. We sought to determine providers’ knowledge, attitudes, motivating factors and preferences for integrating exercise into the treatment of patients with brain tumors. METHODS We surveyed multidisciplinary providers in Neurosurgery, Radiation Oncology and Neuro-Oncology from a single, quaternary medical center. Questions assessed demographics, current practices, attitudes, knowledge, motivating factors and barriers for integrating exercise into treatment. Questions were extrapolated from existing published questionnaires and sent electronically. RESULTS Most providers (92%) reported that exercise was important for patients' lifestyle and 80% felt it should be integrated into the treatment of patients with primary brain tumors. Nighty-six percent felt that exercise improved quality of life, decreased fatigue (100%) and reduced treatment related side effects (92%) yet only 57% of providers initiated a conversation about exercise with patients. Top motivating factors for promoting exercise were perceived benefit to patients’ quality of life and disease outcomes. Barriers to provider/patient discussions about exercise included, lack of time or appropriate expertise to discuss exercise with patients, and concern that patients have competing priorities. Some providers (23%) were concerned about potential limitations/complications with patients exercising including inability to participate from side effects of treatment (38%), physical deficits (61%) and fatigue (42%). CONCLUSION Understanding barriers for providers to incorporate exercise into their patients’ treatment regimens is critical to strategizing best practices. Findings from this study help to expand our understanding of barriers and facilitators to incorporating exercise interventions into brain cancer treatment and will assist with the implementation of a structured exercise program to enhance physical health for our patients.

BACKGROUND Monitoring lower-grade gliomas (LrGGs) for disease progression is made difficult by the limits of anatomical MRI to distinguish treatment-related tissue changes from tumor progression. MR spectroscopic imaging (MRSI) offers additional metabolic information that can help address these challenges. The goal of this study was to compare longitudinal changes in multiparametric MRI, including diffusion-weighted imaging, perfusion imaging, and 3D MRSI, for LrGG patients who progressed at the final time point and those who remained clinically stable. METHODS Forty-one patients with LrGG who were clinically stable were longitudinally assessed for progression. Changes in anatomical, diffusion, perfusion, and MRSI data were acquired and compared between patients who remained clinically stable and those who progressed. RESULTS Thirty-one patients remained stable, and 10 patients progressed. Over the study period, progressed patients had a significantly greater increase in normalized choline, choline-to-N-acetylaspartic acid index (CNI), normalized creatine, and creatine-to-N-acetylaspartic acid index (CRNI), than stable patients. CRNI was significantly associated with progression status and WHO type. Progressed astrocytoma patients had greater increases in CRNI than stable astrocytoma patients. CONCLUSIONS LrGG patients in surveillance with tumors that progressed had significantly increasing choline and creatine metabolite signals on MRSI, with a trend of increasing T2 FLAIR volumes, compared to LrGG patients who remained stable. These data show that MRSI can be used in conjunction with anatomical imaging studies to gain a clearer picture of LrGG progression, especially in the setting of clinical ambiguity.

BACKGROUND Grade 2 and 3 glioma survivors (LrGG) are living longer, yet experience cognitive impairments with diminished quality of life (QOL). We present a novel multimodal study of three cognitive rehabilitation interventions in stable LrGG survivors. METHODS Participants were radiologically stable adult LrGG patients who were off medical treatment for ≥ 6 months with subjective and objective cognitive impairments ( >1SD in 2 or more domains). Patients were offered either In-person cognitive rehabilitation (strategy training including telehealth), or randomized to App-based cognitive rehabilitation (retraining and strategy training) versus Text messaging (strategy training). Intervention duration was 3 months. Neuropsychological testing (with parallel forms) and QOL assessments were conducted at baseline (T1), immediate post intervention (T2), and 6-month follow-up (T3), and analyzed with repeated measures regression or Wilcoxon signed rank tests. RESULTS Of the 33 analyzed (enrollment ongoing); 15/17 In-person, 5/8 App-based, and 8/8 Texting completed ≥ 80% or greater of interventions. Demographic and clinical characteristics were similar between cohorts. Median age was 48 years (range 27-63), 58% astrocytoma, 30% oligodendroglioma, 15% other (1 pilocytic astrocytoma, 4 diffuse glioma NOS), and 76% had prior radiotherapy. Rehabilitation interventions showed improvements in auditory working memory (T1-T2 In-person p= 0.02, eta2= 0.32-medium effect), verbal learning (T1-T3 App-based p= .06, eta2= 0.54-large effect; T1-T3 Texting p= .01, eta2= 0.75-large effect), and verbal memory (T1-T3 App-based p= .06, rho=0.31-medium effect). CONCLUSION Significant improvements in cognitive impairments were found with medium to large treatment effects within each cohort. Cognitive rehabilitation via In-person and Texting showed strongest feasibility and acceptability. In-person cognitive rehab showed earlier posttreatment improvements whereas treatment effects for App-based and Texting were noted, but took longer to realize gains. These interventions may show promise for addressing cognitive impairments in LrGG survivors and warrant further investigation.

Author(s): Sloan, Emily A; Cooney, Tabitha; Oberheim Bush, Nancy Ann; Buerki, Robin; Taylor, Jennie; Clarke, Jennifer L; Torkildson, Joseph; Kline, Cassie; Reddy, Alyssa; Mueller, Sabine; Banerjee, Anu; Butowski, Nicholas; Chang, Susan; Mummaneni, Praveen V; Chou, Dean; Tan, Lee; Theodosopoulos, Philip; McDermott, Michael; Berger, Mitchel; Raffel, Corey; Gupta, Nalin; Sun, Peter P; Li, Yi; Shah, Vinil; Cha, Soonmee; Braunstein, Steve; Raleigh, David R; Samuel, David; Scharnhorst, David; Fata, Cynthia; Guo, Hua; Moes, Gregory; Kim, John YH; Koschmann, Carl; Van Ziffle, Jessica; Onodera, Courtney; Devine, Patrick; Grenert, James P; Lee, Julieann C; Pekmezci, Melike; Phillips, Joanna J; Tihan, Tarik; Bollen, Andrew W; Perry, Arie; Solomon, David A

Background Optimal techniques and patient selection for salvage reirradiation of high-grade glioma (HGG) are unclear. In this study, we identify prognostic factors for freedom from progression (FFP) and overall survival (OS) after reirradiation, risk factors for high-grade toxicity, and validate clinical prognostic scores. Methods A total of 116 patients evaluated between 2000 and 2018 received reirradiation for HGG (99 WHO grade IV, 17 WHO grade III). Median time to first progression after initial therapy was 10.6 months. Salvage therapies before reirradiation included surgery (31%) and systemic therapy (41%). Sixty-five patients (56%) received single-fraction stereotactic radiosurgery (SRS) as reirradiation. The median biologically effective dose (BED) was 47.25 Gy, and the median planning target volume (PTV) was 4.8 cc for SRS and 95.0 cc for non-SRS treatments. Systemic therapy was given concurrently to 52% and adjuvantly to 74% of patients. Results Median FFP was 4.9 months, and median OS was 11.0 months. Significant multivariable prognostic factors for FFP were performance status, time to initial progression, and BED; for OS they were age, time to initial progression, and PTV volume at recurrence. High-grade toxicity was correlated to PTV size at recurrence. Three-level prognostic scores were generated for FFP and OS, with cross-validated receiver operating characteristic area under the curve (AUC) of 0.640 and 0.687, respectively. Conclusions Clinical variables at the time of reirradiation for HGG can be used to prognosticate FFP and OS.

Glioblastoma is an incurable disease with a poor prognosis. For caregivers of people with glioblastoma, the burden of care can be high. Patients often present with different clinical characteristics, which may impact caregiver burden in different ways. This study aimed to evaluate associations between patient clinical characteristics and caregiver burden/quality of life (QoL).Caregiver-patient dyads were enrolled at 7 academic cancer centers in the United States. Eligible caregiver participants were self-reported as the primary caregiver of an adult living with glioblastoma and completed a caregiver burden survey. Eligible patients were age ≥ 18 years at glioblastoma diagnosis and alive when their respective caregiver entered the study, with the presence of cognitive dysfunction confirmed by the caregiver. Data were analyzed with descriptive statistics and multivariable analyses.The final cohort included 167 dyads. Poor patient performance status resulted in patient difficulty with mental tasks, more caregiving tasks, and increased caregiving time. Language problems were reported in patients with left-sided lesions. Patient confusion was negatively associated with all caregiver domains: emotional health, social health, general health, ability to work, confidence in finances, and overall QoL. Better caregiver QoL was observed in patients with frontal lobe lesions versus non-frontal lobe lesions.This study reinforced that patient performance status is a critical clinical factor that significantly affects caregiver burden, caregiving tasks, and caregiver time. Additionally, patient confusion affects multiple facets of caregiver burden/QoL. These results could be used to support guided intervention for caregiver support, customized to the patient experience.

BACKGROUND Novel therapies are needed in newly diagnosed glioblastoma as nearly all patients experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ), including patients with tumors with methylated MGMT promoter, a positive prognostic factor and predictor of benefit with TMZ. Here, we report the final analysis of progression-free survival (PFS), overall survival (OS), and safety from an international randomized, single-blind phase-3 study of nivolumab (NIVO)+RT+TMZ in patients with newly diagnosed glioblastoma with methylated/indeterminate MGMT promoter (CheckMate 548; NCT02667587). METHODS Patients (N=716) aged ≥ 18y were randomized 1:1 regardless of tumor PD-L1 expression to NIVO (240 mg Q2W×8, then 480 mg Q4W) + RT (60 Gy over 6 weeks) + TMZ (75 mg/m2 QD during RT, then 4-week break, then 150–200 mg/m2 QD on days 1–5 of every 28-day cycle for 6 cycles) or placebo (PBO)+RT+TMZ. The dual-primary endpoints were PFS by blinded independent central review and OS, both overall and without baseline corticosteroids. RESULTS As of December 22, 2020, median PFS was 10.6 months (95% CI, 8.9–11.8) with NIVO+RT+TMZ and 10.3 months (95% CI, 9.7–12.5) with PBO+RT+TMZ (HR, 1.06 [95% CI, 0.90–1.25]). Median OS was 28.9 months (95% CI, 24.4–31.6) with NIVO+RT+TMZ and 32.1 months (95% CI, 29.4–33.8) with PBO+RT+TMZ (HR, 1.10 [95% CI, 0.91–1.33]). Among patients without baseline corticosteroids, median OS was 31.3 months (95% CI, 28.6–34.8) with NIVO+RT+TMZ and 33.0 months (95% CI, 31.0–35.1) with PBO+RT+TMZ (HR, 1.12 [95% CI, 0.87–1.43]). Grade 3–4 treatment-related adverse events were 52.4% and 33.6% with NIVO+RT+TMZ and PBO+RT+TMZ, respectively. CONCLUSIONS NIVO added to RT+TMZ did not improve survival in patients with newly diagnosed glioblastoma with methylated/indeterminate MGMT promoter. No new safety signals were observed with NIVO. The role of immunotherapy in this treatment landscape remains an area for further investigation.

BACKGROUND Survival outcomes for patients with lower grade gliomas (LrGG) are improving. However, injury from tumor growth and consequences of treatment often leads to impaired cognition, particularly in cognitive domains reliant on distributed functional networks and intact white-matter tracts. Resting state functional MRI (rsfMRI) is a method of investigating the integrity of these functional networks. METHODS This study investigated rsfMRI connectivity in 21 patients with clinically stable LrGG compared to age- and gender-matched healthy controls, and associated imaging measures with cognitive outcomes. Data were acquired for 12 cognitive tests administered within one week of imaging. RsfMRI and T1-weighted images for 21 research controls were acquired from OpenNeuro datasets. RsfMRI data were processed and analyzed using the CONN toolbox using CONN’s standard regions of interest (ROI) for the 8 canonical networks as seeds, and cognitive test scores as covariates, with a threshold for T tests of p< .001 uncorrected. RESULTS Median age was 48 years old (range 27-67). There were 6 astrocytomas, IDHmut; 3 astrocytomas IDH-wt, 8 oligodendrogliomas, and 4 NOS. Thirteen had left hemisphere tumors (8 frontal, 3 parietal, 2 temporal), and 6 right (5 frontal, 1 temporal). Fourteen had previously recieved radiotherapy. There was significantly lower connectivity in frontoparietal executive control and the salience networks in LrGG patients versus controls. Within patients, lower executive control network connectivity covaried with worse performance on executive measures (FAS, Tower of London, Trails-A, Animal Naming, FrSBe), and attention and working memory measures (Digit Symbol, HVLT). Lower salience network connectivity covaried with poorer performance on executive measures (FrSBe, FAS) and attention and working memory measures (Digit Span, HVLT, WAIS-WM). CONCLUSION In clinically stable LrGG, rsfMRI measures of network connectivity are potentially useful markers to monitor and track, given the concordance with cognition, and could help guide cognitive assessment and rehabilitation.

Background Amino acid PET imaging of brain tumors has been shown to play an important role in predicting tumor grade, delineation of tumor margins, and differentiating tumor recurrence from the background of postradiation changes, but is not commonly used in clinical practice because of high cost. We propose that PET/MRI imaging of patients grouped to the day of tracer radiosynthesis will significantly decrease the cost of PET imaging, which will improve patient access to PET. Methods Seventeen patients with either primary brain tumors or metastatic brain tumors were recruited for imaging on 3T PET/MRI and were scanned on 4 separate days in groups of 3 to 5 patients. The first group of consecutively imaged patients contained 3 patients, followed by 2 groups of 5 patients, and a last group of 4 patients. Results For each of the patients, standard of care gadolinium-enhanced MRI and dynamic PET imaging with 18F-FDOPA amino acid tracer was obtained. The total cost savings of scanning 17 patients in batches of 4 as opposed to individual radiosynthesis was 48.5% ($28 321). Semiquantitative analysis of tracer uptake in normal brain were performed with appropriate accumulation and expected subsequent washout. Conclusion Amino acid PET tracers have been shown to play a critical role in the characterization of brain tumors but their adaptation to clinical practice has been limited because of the high cost of PET. Scheduling patient imaging to maximally use the radiosynthesis of imaging tracer significantly reduces the cost of PET and results in increased availability of PET tracer use in neuro-oncology.

BackgroundIt remains unknown how the COVID-19 pandemic has changed neuro-oncology clinical practice, training, and research efforts.MethodsWe performed an international survey of practitioners, scientists, and trainees from 21 neuro-oncology organizations across 6 continents, April 24–May 17, 2020. We assessed clinical practice and research environments, institutional preparedness and support, and perceived impact on patients.ResultsOf 582 respondents, 258 (45%) were US-based and 314 (55%) international. Ninety-four percent of participants reported changes in their clinical practice. Ninety-five percent of respondents converted at least some practice to telemedicine. Ten percent of practitioners felt the need to see patients in person, specifically because of billing concerns and pressure from their institutions. Sixty-seven percent of practitioners suspended enrollment for at least one clinical trial, including 62% suspending phase III trial enrollments. More than 50% believed neuro-oncology patients were at increased risk for COVID-19. Seventy-one percent of clinicians feared for their own personal safety or that of their families, specifically because of their clinical duties; 20% had inadequate personal protective equipment. While 69% reported increased stress, 44% received no psychosocial support from their institutions. Thirty-seven percent had salary reductions and 63% of researchers temporarily closed their laboratories. However, the pandemic created positive changes in perceived patient satisfaction, communication quality, and technology use to deliver care and mediate interactions with other practitioners.ConclusionsThe pandemic has changed treatment schedules and limited investigational treatment options. Institutional lack of support created clinician and researcher anxiety. Communication with patients was satisfactory. We make recommendations to guide clinical and scientific infrastructure moving forward and address the personal challenges of providers and researchers.

Changes in glioma patients’ immune profiles over the course of disease may predict outcomes. DNA based immunomethylomics quantifies blood immune cells based on cell specific DNA methylation signatures. To assess changes in immune profiles, we are longitudinally collecting blood samples from glioma patients pre-surgery and at other clinically relevant time points. Here we report patients’ pre-surgery immune profiles. All patients underwent biopsy or resection of a presumed new glioma or recurrent lower grade glioma. Blood DNA methylation was assessed with Illumina EPIC methylation arrays. Relative cell fractions of CD4, CD8, B-cells, natural killer cells, monocytes, and neutrophils, were estimated via our validated deconvolution algorithm. Total nucleated cell counts from Nexcelom cytometry were used to compute absolute cell counts. Other measures include total lymphocytes, CD4/CD8 ratio, neutrophil to lymphocyte ratio (NLR), and lymphocyte to monocyte ratio (LMR)). The first 125 participants includes 56 newly diagnosed glioblastomas (GBM), 28 newly diagnosed grade II-III gliomas, and 41 recurrent grade II-III gliomas. Median patient age is 49 years. 53 (43%) had recent dexamethasone exposure. In overall non-parametric analyses, most cell subsets, especially CD4, differed across grade, diagnosis group, WHO classification and dexamethasone exposure. In post-hoc pairwise analyses, immune profiles of IDH wildtype GBM patients who had taken dexamethasone differed from patients with GBM or grade II-III glioma who had not taken dexamethasone; they had clinically relevant and statistically significantly lower absolute CD4 counts, total white cell counts, and percent of total lymphocytes, and higher absolute neutrophil counts, NLR and LMR. However, some dexamethasone naïve GBM patients also had altered immune profiles. Comparisons of relative immune cell fractions with those from 454 non-glioma controls from the UCSF Adult Glioma Study showed that across grade and WHO classification, for the most part, immune profiles of glioma patients not exposed to dexamethasone did not differ from controls.

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma (PA), dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined, nor are the histopathologic features of pilocytic astrocytomas with FGFR1 alterations versus those harboring the more common BRAF mutations or fusions. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and PA are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis refines the classification and histopathologic spectrum of LGNET with FGFR1 alterations.

BACKGROUND Glioblastoma (GBM) patients fall within NCCN and ASCO guidelines for early palliative care (PC). However, data suggests they are less likely than systemic cancers to be referred to PC and often later in their illness. This results in potential missed opportunities, both for improving symptom control and earlier completion of important tasks, like advance care planning. Data on how to best incorporate comprehensive PC into routine neuro-oncology (NO) patient care is needed. METHODS We piloted a program embedding a PC physician into UCSF’s NO clinic one half-day per week. NO physicians were encouraged to refer GBM patients within 3 months of diagnosis and other patients with PC needs. PC visits were offered in-person, by telemedicine, or at home. PC physician and NO social worker made joint visits when possible; chaplaincy support was available by telemedicine. Data was collected using Palliative Care Quality Network (PCQN) database and patient satisfaction survey. RESULTS To date, 37 patients have been referred resulting in 103 visits (average 2.8 visits/person): 25% in-person; 68% telemedicine; 6% at home. PC physician and NO social worker met jointly with 46% visits. Median age was 58 years, 41% female, 81% non-Hispanic white, 84% GBM, median 9 months from diagnosis, and 73% receiving first line treatment. Interventions addressed across visits: 94% non-pain symptoms, 76% psychosocial needs; 71% pain; and 70% GOC. Results from satisfaction survey demonstrated 79% would recommend seeing PC embedded in NO to others and highest benefits were attention to practical considerations to staying healthy at home, discussing preferences for future medical care, and help with coping. CONCLUSIONS Embedding PC into NO clinics is a unique model for addressing symptoms and GOC early, is well received by patients and caregivers, and provides opportunities for collaboration and PC physicians to specialize in caring for needs of NO patients.

Lineage-specific DNA methylation marks differentiate leukocyte cell types while individual biological aging mechanisms impact other methylation alterations. Human glioma incidence and survival times have been shown to be associated with aberrant immune profiles and have a strong dependency on age. Here we developed a single epigenetic analysis framework to evaluate both immune cell fractions and epigenetic age in peripheral blood. We examined these measures in archived blood from 197 triple-negative glioma patients (TNG; IDH wildtype, 1p19q intact and TERT wildtype) and 312 frequency-matched controls from the SF Bay Area Adult Glioma Study (AGS). Significant differences were observed with TNG cases having lower CD4 and CD8 T cell, natural killer, and B cell fractions, and higher neutrophil fractions than controls. TNG cases were significantly older than controls in two of three epigenetic age estimates; however, there was no difference in epigenetic age acceleration once immune cell proportions were considered. For the TNG cases, we augmented results from several machine learning methods to delineate risk groups of TNG patients with significantly different overall survival. We compared survival models built by recursive partitioning, random forest, and elastic net methods. The final model was chosen by repeated bootstrap sampling via the Brier score loss function and validated in an independent set of 72 IDH-mutant only or TERT-mutant only glioma patients also from the AGS. The final model indicated important interactions between immune cell fractions (including CD4 and CD8 T cells and neutrophils) and treatment, age, and dexamethasone status when adjusted for the main effects of epigenetic age, glioblastoma status, and the neutrophil-to-lymphocyte ratio. The capacity of immunomethylomics to capture diverse, clinically relevant information and the simplicity of its implementation make this a powerful tool for personalized patient evaluation in the neuro-oncology clinic.

BACKGROUND The overall prognostic significance of maximal surgical resection in patients with diffuse low-grade glioma has been well established. Nonetheless, prior studies omit the combined importance of molecular subclass, patient characteristics, and chemoradiation. Similar to findings recently published in newly diagnosed glioblastoma, incorporation of these interactive factors may redefine the relative benefit of cytoreductive surgery. METHODS We examine the interactive effects of volumetric extent of resection with molecular and clinical factors to develop a new roadmap for cytoreductive surgery. Based on a 20-year retrospective cohort of 556 patients with WHO II diffuse low-grade glioma treated with surgery at UCSF 444 had complete records for survival modeling and recursive partitioning (RPA) to investigate multivariate relationships of overall and progression free survival. RESULTS Regardless of molecular subtype, patients with tumor volume under 55cm3 and postoperative volume of residual under 1.9cm3 experience the longest OS (median OS: not reached). Patients with volume of residual over 1.9cm3 experience a OS similar to that of patients with large (over 55cm3) oligodendrogliomas (median OS: not reached). Patients faring worst have large (over 55cm3) astrocytic gliomas (median OS: 84.8 months). Patients not treated with chemotherapy and either ATRX wild-type tumors or ATRX-mutant tumors with small (under 1cm3) volume of residual have the longest PFS together with chemotherapy treated patients who receive either no radiation or radiation for p53-mutant tumors under 30cm3 (median PFS 119 months). Patients with the shortest PFS are under 32-years with larger volume of residual (>1cm3), who receive no chemotherapy for ATRX-mutant tumors together with patients who receive both chemoradiation for larger (>30cm3) p53 mutant tumors (median PFS 30.8 months). CONCLUSION This is the first study to combine extent of resection with molecular and clinical information which paves the way for rethinking surgical strategies for individual patients with newly diagnosed low-grade gliomas.

Background “Diffuse midline glioma (DMG), H3 K27M-mutant” is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited. Methods Patient demographics, radiologic and pathologic characteristics, treatment course, progression, and patient survival were collected for 60 adult patients with DMG, H3 K27M-mutant. A subset of tumors also underwent next-generation sequencing. Analysis of progression-free survival and overall survival was conducted using Kaplan–Meier modeling, and univariate and multivariate analysis. Results Median patient age was 32 years (range 18–71 years). Tumors were centered in the thalamus (n = 34), spinal cord (10), brainstem (5), cerebellum (4), or other midline sites (4), or were multifocal (3). Genomic profiling revealed p.K27M mutations exclusively in the H3F3A gene and an absence of mutations in HIST1H3B or HIST1H3C, which are present in approximately one-third of pediatric DMGs. Accompanying mutations in TP53, PPM1D, FGFR1, NF1, and ATRX were frequently found. The overall survival of this adult cohort was 27.6 months, longer than historical averages for both H3 K27M-mutant DMG in children and IDH-wildtype glioblastoma in adults. Conclusions Together, these findings indicate that H3 K27M-mutant DMG represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in adults versus children.

Background Primary CNS tumors constitute a heterogeneous group of neoplasms that share a considerable morbidity and mortality rate. To help control tumor growth and clinical outcomes (overall survival, progression-free survival, quality of life) symptoms, patients often resort to alternative therapies, including the use of cannabis. Despite rapidly growing popularity, cannabis and its impact on patients with primary malignant CNS tumors is understudied. Methods To shed light on the lack of scientific evidence in this field, in November 2018 we conducted a search and examination of cannabis in neuro-oncology in major journal databases and bibliographies of selected articles, and through abstracts of annual meetings using prespecified criteria in line with the Cochrane Collaboration guidelines. Results We identified 45 publications, of which 9 were selected. Five studies were included. Publication dates ranged from 2004 to 2018 and included varying histologies of primary brain tumors. The average survival at 1 year was 56.09% (95% CI: 48.28-63.9). There was no difference in risk ratio (RR) for death at 1 year between groups (RR: 1.069 [95% CI: 0.139-8.25]). We found strong evidence of heterogeneity (Q = 74.0%; P = .021). We found no statistical evidence of publication bias (P = .117; SD = 1.91). Conclusions There was limited moderate-quality evidence that supports the use of cannabinoids as adjuvant to the standard of care in the treatment of brain and CNS tumors. There was very low-quality evidence suggesting that cannabinoids were associated with adult-onset gliomas. Further prospective clinical trials are necessary to adequately evaluate the impact of cannabinoids on CNS tumors, specifically on survival and quality of life.

TheFGFR1gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activatingFGFR1alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often withTACC1as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these differentFGFR1events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET withFGFR1alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET withFGFR1alterations, and is uniquely characterized byFGFR1kinase domain hotspot missense mutations in combination with eitherPIK3CAorPIK3R1mutation, often with accompanyingNF1orPTPN11mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized byFGFR1-TACC1fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanyingNF1orPTPN11mutation, but lacking the accompanyingPIK3CAorPIK3R1mutation that characterizes RGNT. The glial component of LGNET withFGFR1alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas withFGFR1alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas withBRAFmutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET withFGFR1alterations.

Importance Per the World Health Organization 2016 integrative classification, newly diagnosed glioblastomas are separated into isocitrate dehydrogenase gene 1 or 2 (IDH)–wild-type andIDH-mutant subtypes, with median patient survival of 1.2 and 3.6 years, respectively. Although maximal resection of contrast-enhanced (CE) tumor is associated with longer survival, the prognostic importance of maximal resection within molecular subgroups and the potential importance of resection of non–contrast-enhanced (NCE) disease is poorly understood. Objective To assess the association of resection of CE and NCE tumors in conjunction with molecular and clinical information to develop a new road map for cytoreductive surgery. Design, Setting, and Participants This retrospective, multicenter cohort study included a development cohort from the University of California, San Francisco (761 patients diagnosed from January 1, 1997, through December 31, 2017, with 9.6 years of follow-up) and validation cohorts from the Mayo Clinic (107 patients diagnosed from January 1, 2004, through December 31, 2014, with 5.7 years of follow-up) and the Ohio Brain Tumor Study (99 patients with data collected from January 1, 2008, through December 31, 2011, with a median follow-up of 10.9 months). Image accessors were blinded to patient groupings. Eligible patients underwent surgical resection for newly diagnosed glioblastoma and had available survival, molecular, and clinical data and preoperative and postoperative magnetic resonance images. Data were analyzed from November 15, 2018, to March 15, 2019. Main Outcomes and Measures Overall survival. Results Among the 761 patients included in the development cohort (468 [61.5%] men; median age, 60 [interquartile range, 51.6-67.7] years), younger patients withIDH–wild-type tumors and aggressive resection of CE and NCE tumors had survival similar to that of patients withIDH-mutant tumors (median overall survival [OS], 37.3 [95% CI, 31.6-70.7] months). Younger patients withIDH–wild-type tumors and reduction of CE tumor but residual NCE tumors fared worse (median OS, 16.5 [95% CI, 14.7-18.3] months). Older patients withIDH–wild-type tumors benefited from reduction of CE tumor (median OS, 12.4 [95% CI, 11.4-14.0] months). The results were validated in the 2 external cohorts. The association between aggressive CE and NCE in patients withIDH–wild-type tumors was not attenuated by the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. Conclusions and Relevance This study confirms an association between maximal resection of CE tumor and OS in patients with glioblastoma across all subgroups. In addition, maximal resection of NCE tumor was associated with longer OS in younger patients, regardless ofIDHstatus, and among patients withIDH–wild-type glioblastoma regardless of the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. These conclusions may help reassess surgical strategies for individual patients with newly diagnosed glioblastoma.

Author(s): Calixto-Hope, Lucas; Lee, Julieann; Sloan, Emily; Hofmann, Jeffrey; Van Ziffle, Jessica; Onodera, Courtney; Grenert, James; Devine, Patrick; Kline, Cassie; Banerjee, Anu; Clarke, Jennifer; Taylor, Jennie; Ann Oberheim-Bush, Nancy; Buerki, Robin; Butowski, Nicholas; Chang, Susan; McDermott, Mike; Aghi, Manish; Theodosopoulos, Philip; Hervey-Jumper, Shawn; Berger, Mitchel; Raffel, Corey; Gupta, Nalin; Kleinschmidt-DeMasters, Bette; Wood, Matthew; Grafe, Marjorie; Guo, Hua; Sun, Peter; Torkildson, Joseph; Cooney, Tabitha; Fata, Cynthia; Scharnhorst, David; Samuel, David; Bannykh, Serguei; Khatib, Ziad; Maher, Ossama; Chamyan, Gabriel; Pelaez, Liset; Brathwaite, Carole; Jin, Lee-way; Lechpammer, Mirna; Born, Donald; Vogel, Hannes; Lee, Han; Phillips, Joanna; Pekmezci, Melike; Bollen, Andrew; Tihan, Tarik; Perry, Arie; Solomon, David | Abstract: Abstract BACKGROUND Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component. METHODS We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway. RESULTS The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia. CONCLUSION Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation.

BACKGROUND Ivosidenib (AG-120, IVO) is a first-in-class oral inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), and vorasidenib (AG-881, VOR) is an oral, potent, brain-penetrant inhibitor of mIDH1/2. Both have been evaluated in glioma patients in ongoing phase 1 studies. In orthotopic glioma models, IVO and VOR reduced 2-hydroxyglutarate (2-HG) levels by 85% and 98%, respectively, despite different brain-to-plasma ratios (< 0.04 vs 1.33). METHODS Patients with recurrent, nonenhancing, WHO-2016 grade 2/3, mIDH1-R132H oligodendroglioma or astrocytoma undergoing craniotomy were randomized 2:2:1 to IVO 500mg QD, VOR 50mg QD, or no treatment (cohort 1), or 1:1 to IVO 250mg BID or VOR 10mg QD (cohort 2), for 4 weeks preoperatively. Postoperatively, patients continued receiving IVO or VOR (control patients were randomized 1:1 to IVO or VOR). Tumors were assessed for mIDH1 status, cellularity, and 2-HG and drug concentrations. Treated subjects were compared with controls and mIDH1/wild-type banked reference samples. Primary endpoint: tumor 2-HG concentration following IVO or VOR. RESULTS As of March 1, 2019, 27 patients (18 men; 25/2 grade 2/3) were randomized preoperatively in cohort 1 (IVO 10, VOR 12, untreated 5): 27 received drug (IVO 13, VOR 14); 1 discontinued VOR postoperatively due to disease progression. Of 26 tumors analyzed, 22 were evaluable. Mean brain-to-plasma ratios: 0.13 IVO, 1.59 VOR. Relative to untreated samples, IVO and VOR reduced tumor 2-HG by 92.0% (95% CI 73.2, 97.4) and 92.5% (95% CI 78.1, 97.7), respectively. Common (≥ 4 patients) TEAEs (all cohort 1 patients, all grades): diarrhea (37.0%), constipation, hypocalcemia, and nausea (each 18.5%), anemia, hyperglycemia, pruritus, headache, and fatigue (each 14.8%). Cohort 2 has completed accrual, with analyses ongoing. CONCLUSIONS In cohort 1 of this phase 1 perioperative study, IVO and VOR demonstrated brain penetrance and lowered 2-HG compared with controls. Updated data from both cohorts will be presented.

The design and evaluation of immunotherapies in IDH-mutant lower grade gliomas (LGG) is hindered by a poor understanding of the LGG T-cell repertoire. We present data on the temporal evolution, intratumoral spatial distribution, and prognostic value of the T-cell repertoire in IDH-mutant LGGs. We performed immunogenomic profiling using T-cell receptor beta-chain sequencing of 163 glioma and peripheral blood samples from 33 immunotherapy-naive glioma patients (22 astrocytomas, 11 oligodendrogliomas). T-cell repertoire evolution was analyzed in a subset of 26 patients (69 samples) with matched primary (WHO grade II) and recurrent (WHO grade II-IV) glioma samples. T-cell repertoire diversity was defined as the number of unique T-cell clonotypes by V-gene, J-gene, and CDR3 nucleotide sequences. Malignant transformed (Grade III or IV) recurrent gliomas demonstrated increased T-cell repertoire diversity compared to their patient-matched primary tumors (p=0.0023), but grade II recurrences did not show the same increased diversity (p=0.26). This increase in T-cell repertoire diversity was greater in patients who underwent transformation in the context of TMZ-associated hypermutation compared to spontaneously transformed counterparts (p=0.035). In grade II primary astrocytomas (n=17), T-cell repertoire diversity above the median (186 unique T-cell clonotypes per sample) was associated with worse transformation-free (HR=4.2, p=0.045) and overall survival (HR=6.4, p=0.025). Next, we evaluated intratumoral immune heterogeneity in 7 patients by sampling from up to 10 distinct and maximally-separated intratumoral sites per LGG (64 samples). Eighty-two to 96% of unique clonotypes within a given tumor were present only within a single sampled site. Despite this heterogeneity, six LGG patients harbored T-cell clonotypes present tumor-wide across all sampled sites within a given tumor. Ten of 24 (42%) tumor-wide T-cell clonotypes were enriched in the glioma compared to matched peripheral blood, suggesting glioma-specificity. Taken together, T-cell receptor profiling in LGGs may have utility both as a prognostic biomarker and to identify glioma-specific T-cells.

BACKGROUND Nearly 80,000 new cases of primary brain tumors are expected to be diagnosed this year, 32% of CNS tumors are malignant. Anecdotally, patients who report use of cannabis, frequently describe higher quality of life scores (QOL) in standardized instruments. However, the lack of available tools that allow systematic documentation of cannabis use results in a barrier to accurately assess efficacy, potential benefits and risks. METHODS We conducted a single center, observational study: patients with primary brain tumors answered a previously validated instrument to explore cannabis use. QOL was assessed using the instruments from the European Organisation for Research and Treatment of Cancer: QLQ-C30 and its complementary module BN-20 as well as the EuroQol instrument EQ-5D-5L. Eligible participants were identified as cannabis users or non-users, completing the instruments in a self-administered fashion. RESULTS To date, 51 patients who signed informed consent were enrolled and answered the questionnaires, mean age was 51 (SD 12.95) years, 34 were male, 30 were considered active cannabis users (66.6% males and 33.3% females). The mean global health score in the QLQ-C30 instrument was 68.4 (SD: 20.7) among cannabis users and 82.2 (SD: 17.5) among non-users. The mean difference in QOL scores between users and non-users was 13.8 (95%CI: 2.8, 24.8; p=0.01). In contrast the difference between cannabis users and non-users in QOL index in the EQ-5D-5L instrument was 0.13 (95% CI: 0.06, 0.2; p=0.001). Among cannabis users, patients perceive their symptoms as moderate before using cannabis and mild after using cannabis (p >0.001) CONCLUSIONS In our analysis, patients who use cannabis reported, on average, lower QOL scores. Potentially, sicker patients resort to cannabis to improve their symptoms and ultimately quality of life. The perception of patients is that cannabis usage improves overall quality of life. Findings provide support to perform prospective studies.

BACKGROUND GBM is an aggressive cancer with poor prognosis. We explored impact of disease on caregivers by characterizing caregiver burden and QOL associated with patient characteristics. METHODS Primary caregivers of living adult GBM patients with cognitive dysfunction completed a GBM-specific caregiver burden survey and the validated Caregiver Quality of Life Index–Cancer Scale (CQOLC). Patient data were abstracted from medical records (7/2018-4/2019). Patient characteristics were compared between highest and lowest tertile of CQOLC scores (range 0–140); higher scores suggest better QOL. RESULTS There were 140 patient-caregiver dyads enrolled in the study. Mean patient age was 57 years (range 24–63); majority white males (62.9%), unifocal lesion (90%) and normal activity level at diagnosis. Forty-percent had methylated MGMT promoter status. Caregivers were mostly white (61.4%), college-educated female spouses of similar age; 87.8% were caregiving for >6 months. Median CQOLC score was 82 (tertiles: < 76 and >92). More caregivers in the lowest vs highest CQOLC tertile reported ‘not employed due to caregiving’ (52.4% vs 12%, P< 0.01), ‘changes in patients’ personality’ (73.3% vs 42.6%, P< 0.01), ‘patient memory problems’ (93.5% vs 77.1%, P=0.02), and caring for patient with recurrence treated with ‘chemotherapy other than temozolomide’ ([TMZ], 27.7% vs 8.3%, P=0.01). There was > 10% difference in proportion of caregivers in the lowest vs highest CQOLC tertile for the following patient characteristics: largest lesion in right temporal lobe at baseline and partial resection at initial treatment. Conversely, there was > 10% difference in the highest vs lowest CQOLC tertile for Karnofsky score (> 80), largest lesion in right frontal lobe at baseline, surgical clean margins, TMZ for initial treatment, and surgery for recurrence. CONCLUSION Unemployment, patient personality/memory changes, and chemotherapy other than TMZ use had significant impact on caregiver burden/QoL. This may help identify caregivers to receive support and intervention.

Information is limited on the impact of glioblastoma (GBM) on patient employment and caregiver time commitments. This observational multisite study evaluated the impact of GBM on patients’ employment and on caregivers’ ability to work and perform daily activities. A total of 180 adults diagnosed with GBM and their caregivers were stratified across 4 groups representing specific stages in the disease course: Group 1=newly diagnosed; 2=postradiation; 3=stable disease; 4=recurrence. We assessed the impact of GBM on employment status and self-reported cognitive function in patients (EORTC QLQ-C30) and in caregivers (Work Productivity and Activity Impairment Questionnaire). Prior to diagnosis, 64% of all patients (74% < 65 years old) were employed, while only 22% (26% for those < 65 years old) were employed after diagnosis. Though not reaching significance, newly diagnosed patients and those with stable disease reported higher mean cognitive function scores (72.0 and 71.9) than other groups (61.1 and 61.3; P=0.227). At study enrollment, 56% of all caregivers were employed, while 41% had left their jobs to care for their patients. The impact on caregiver work productivity varied with a higher percentage of caregivers of newly diagnosed patients and those with recurrent disease missing work (45% and 24%, respectively) and experiencing work impairment (54% and 36%, respectively) than the other groups (P< 0.05). Forty-one percent of caregivers of newly diagnosed patients to 25% of patients with stable disease reported impairment of daily activities. GBM had a significant impact on patient and caregiver employment from the time of diagnosis. High cognitive burden among patients might have impacted their employment. Overall work and activity impairment for caregivers was evident in all groups with a notable impact at the time of first diagnosis and recurrence of disease. Future studies will explore the impact of these findings in a longitudinal cohort.

BACKGROUND The prognosis of WHO grade II low-grade gliomas (LGG) is varied with potential for long survival.Given their relatively intact immune system and slow growth rate, vaccines are an attractive treatment strategy for LGG in an attempt to defer more toxic treatments. The goals of this pilot study were to evaluate safety and immunological effects of vaccination with GBM6-AD, an allogeneic glioblastoma stem cell line lysate, with poly-ICLC in LGG. METHODS Eligible patients were ≥ 18 years old, ≥ 70 KPS, with recurrent LGG or imaging consistent with LGG, and amenable to resection. Patients were randomized to vaccine prior to surgery (Arm 1) or not (Arm 2) and all received adjuvant vaccine. Co-primary outcomes were safety and immune response in the tumor, with exploratory outcomes of survival and immunologic effects in peripheral blood. RESULTS A total of 17 eligible patients were evaluable – nine into Arm 1 and eight into Arm 2. Median age was 33 years, with median time from initial diagnosis of 4.7 years (0 – 20). Two patients (11.8%) previously received radiotherapy and seven (41.2%) prior systemic therapy. No dose limiting toxicities or grade 3 AEs were observed. Neoadjuvant vaccination induced up regulation of type-1 cytokines and chemokines in peripheral blood, and CD8+ T cell clones that reacted to the vaccine were also detected in the tumor. Median follow-up time from first post-operative vaccine was 20.8 months with median PFS of 11.0 months and time to change in therapy of 23.7 months. Of the six patients to receive additional treatment, three had second surgery only one confirming malignant progression to anaplastic oligodendroglioma. CONCLUSION Treatment was well-tolerated with no regimen-limiting toxicity. GBM6-AD plus poly-ICLC induced effector CD8+ T cell response in peripheral blood and enables some vaccine-reactive CD8+ T cells to migrate into the TME. Further investigation is warranted.

Angiogenesis is a central feature of glioblastoma (GBM), with contribution from several mechanisms and signaling pathways to produce an irregular, poorly constructed, and poorly connected tumor vasculature. Targeting angiogenesis has been efficacious for disease control in other cancers, and given the (I) highly vascularized environment in GBM and (II) correlation between glioma grade and prognosis, angiogenesis became a prime target of therapy in GBM as well. Here, we discuss the therapies developed to target these pathways including vascular endothelial growth factor (VEGF) signaling, mechanisms of tumor resistance to these drugs in the context of disease progression, and the evolving role of anti-angiogenic therapy in GBM.

Background Epigenetic inhibition of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has emerged as a clinically relevant prognostic marker in glioblastoma (GBM). Methylation of the MGMT promoter has been shown to increase chemotherapy efficacy. While traditionally reported as a binary marker, recent methodological advancements have led to quantitative methods of measuring methylation, allowing for clearer insights into methylation’s functional relationship with survival. Methods A CLIA assay and bisulfite sequencing was utilized to develop a quantitative, 17-point MGMT promoter methylation index derived from the number of methylated CpG sites. Retrospective review of 242 newly diagnosed GBM patients was performed in order to discern how risk for mortality transforms as promoter methylation increases. Non-linearities were captured by fitting splines to Cox proportional hazard models, plotting smoothed residuals, and creating survival plots. Covariates included age, KPS, IDH1 mutation, and extent of resection. Results Median follow-up time and progression free survival were 15.9 and 9 months, respectively. 176 subjects experienced death. A one-unit increase in CpG methylation resulted in a 4% reduction in hazard (95% CI 0.93–0.99, P Conclusion The extent of MGMT methylation shares a non-linear relationship with survival, suggesting conformation of the marker’s protective effect. This finding challenges the current understanding of MGMT and underlines the clinical importance of determining its prognostic utility. Potential limitations include censoring, sample size, and extraneous mutations. Future research is warranted to examine whether the location of CpG site methylation contributes to a reduction in mortality hazard.

BACKGROUND Patients with lower grade (2 and 3) gliomas (LrGG) are living longer, but often with cognitive impairments from their tumor and treatments. However, cognitive assessments and access to cognitive rehabilitation are not a standard part of care. We present preliminary results of a pilot study investigating feasibility and efficacy of three cognitive rehabilitation strategies for stable LrGG patients – in-person manualized cognitive rehabilitation; iPad based cognitive rehabilitation program of retraining and compensation strategies (ReMind); or daily instructional text messages (Healthy SMS). METHODS Eligible patients were adults with clinically and radiologically stable LrGG, > 6 months from last treatment, and ≥1 standard deviation (SD) below normal on ≥ 2 domains of neuropsychological assessments. Patients were first offered in-person cognitive rehabilitation or randomized to ReMind or Healthy SMS if unable to attend in-person. Interventions lasted 3 months. Neuropsychological and HRQOL assessments, using PROMIS NeuroQOL, were conducted at baseline, 3, and 6 months post-intervention. Feasibility was defined as attending ≥80% of in-person sessions; completing ≥80% of ReMind tasks; or not opting out of Healthy SMS texts. RESULTS To date 23/60 patients have enrolled: 11 in-person and 12 randomized to ReMind (5) or Healthy SMS (7). Demographic and clinical characteristics were similar between cohorts. Median age at testing was 46 years, with 65% female, and 78% having received prior radiation (median 4.1 years, range 3.2 – 11.5). At baseline, processing speed was the most common domain of impairment with 43% ≥ 1.5 SD below normal and 36% patients reporting subjective cognitive impairment on HROQL assessment. Feasibility was 71% for in-person rehabilitation; 50% for ReMind; and 100% for Health SMS. CONCLUSION These preliminary results demonstrate that stable LrGG patients with subjective and objective cognitive impairments can reasonably engage in cognitive rehabilitation interventions. Updated data including post-intervention neuropsychological and HROQL related changes will be presented.

2045 Background: Recurrence of GBM after initial treatment with surgery, radiation, and chemotherapy is nearly universal. Salvage therapies have limited efficacy with median overall survival (OS) of approximately 9 months and 6-month-progression-free survival (PFS-6) of 10-25% for both targeted and traditional therapies. Given GBM’s molecular heterogeneity, targeting a single molecular abnormality in isolation has consistently failed as a strategy, and precision combination approaches are needed. Methods: The primary objective was to demonstrate the feasibility of implementing a personalized drug regimen for patients (pts) with surgically resectable recurrent GBM within 35 days of surgery. Secondary objectives included safety and efficacy. Eligible pts signed consent before surgery, and tumor tissue was analyzed using the CLIA-approved “UCSF500” next-generation sequencing panel with paired tumor/germline sequencing. A specialized genomic tumor board made individualized treatment recommendations incorporating sequencing results of the recurrent tumor and clinical history for each pt, using up to 4 FDA-approved drugs in combination (all drugs provided by study). Correlative studies will be reported separately. Results: 19 pts signed consent and 16 pts had surgery on trial, 1 with pathology showing treatment effect only. The remaining 15 pts were all genetically profiled and successfully started their individualized treatment within 35 days of surgery, meeting the primary feasibility endpoint. Conclusions: Implementation of an individualized treatment regimen was feasible in a timely fashion in surgically resectable recurrent GBM pts, with encouraging preliminary efficacy results. Further investigation is warranted, both to validate efficacy and to streamline this approach in larger pt populations. Clinical trial information: NCT03681028. [Table: see text]

BACKGROUND Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is common in patients with low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. METHODS Fifty-eight patients with pathologic evidence of recurrence after they had initially been diagnosed with World Health Organization (WHO) grade II gliomas were enrolled into a prospective phase 2 clinical trial and received daily everolimus (RAD001) for 1 year or until progression. Tissue at the time of enrollment was analyzed for markers of PI3K/mTOR pathway activation. Thirty-eight patients underwent serial multiparametric magnetic resonance imaging, with the tumor volume and the perfusion metrics (the fractional blood volume [fBV] for capillary density and the transfer coefficient [Kps ] for vascular permeability) measured during treatment. The primary endpoint was progression-free survival at 6 months (PFS-6) in patients with WHO II disease at enrollment. RESULTS For patients with WHO II gliomas at enrollment, the PFS-6 rate was 84%, and this met the primary endpoint (P

Computed tomography (CT) and magnetic resonance (MR) imaging have been widely used for visualizing the inside of the human body. However, in many cases, pathological diagnosis is conducted through a biopsy or resection of an organ to evaluate the condition of tissues as definitive diagnosis. To provide more advanced information onto CT or MR image, it is necessary to reveal the relationship between tissue information and image signals. We propose a registration scheme for a set of PT images of divided specimens and a 3D-MR image by reference to an optical macro image (OM image) captured by an optical camera. We conducted a fundamental study using a resected human brain after the death of a brain cancer patient. We constructed two kinds of registration processes using the OM image as the base for both registrations to make conversion parameters between the PT and MR images. The aligned PT images had shapes similar to the OM image. On the other hand, the extracted cross-sectional MR image was similar to the OM image. From these resultant conversion parameters, the corresponding region on the PT image could be searched and displayed when an arbitrary pixel on the MR image was selected. The relationship between the PT and MR images of the whole brain can be analyzed using the proposed method. We confirmed that same regions between the PT and MR images could be searched and displayed using resultant information obtained by the proposed method. In terms of the accuracy of proposed method, the TREs were 0.56±0.39mm and 0.87±0.42mm. We can analyze the relationship between tissue information and MR signals using the proposed method.