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Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas. The first harbored biallelic NF1 inactivation only, occurred primarily during childhood, followed a more indolent clinical course, and had a unique epigenetic signature for which we propose the terminology “pilocytic astrocytoma, arising in the setting of NF1”. The second subgroup harbored additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, occurred primarily during adulthood, followed a more aggressive clinical course, and was epigenetically diverse, with most tumors aligning with either high-grade astrocytoma with piloid features or various subclasses of IDH-wildtype glioblastoma. Several patients were treated with small molecule MEK inhibitors that resulted in stable disease or tumor regression when used as a single agent, but only in the context of those tumors with NF1 inactivation lacking additional oncogenic alterations. Together, these findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.

Background Terminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (1) explore the prognostic utility of the classification system and (2) define how much removed non-CE tumor translates into a survival benefit. Methods The international RANO resect group retrospectively searched previously compiled databases from 7 neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and postoperative MRI were collected. Results We collected 1,008 patients with newly diagnosed IDHwt glioblastoma. 744 IDHwt glioblastomas were treated with radiochemotherapy per EORTC-26981/22981 (TMZ/RT→TMZ) following surgery. Among these homogenously treated patients, lower absolute residual tumor volumes (in cm3) were favorably associated with outcome: patients with “maximal CE resection” (class 2) had superior outcome compared to patients with “submaximal CE resection” (class 3) or “biopsy” (class 4). Extensive resection of non-CE tumor (≤5 cm3 residual non-CE tumor) was associated with better survival among patients with complete CE resection, thus defining class 1 (“supramaximal CE resection”). The prognostic value of the resection classes was retained on multivariate analysis when adjusting for molecular and clinical markers. Conclusions The proposed “RANO categories for extent of resection in glioblastoma” are highly prognostic and may serve for stratification within clinical trials. Removal of non-CE tumor beyond the CE tumor borders may translate into additional survival benefit, providing a rationale to explicitly denominate such “supramaximal CE resection.”

OBJECTIVES To assess impact and implementation of remote delivery of a parenting program following suspension of in-person visits during the coronavirus disease 2019 pandemic. METHODS Impact of remote delivery of the Reach Up parenting program on parenting practices was evaluated by randomized trial in Jamaica. Mothers with children aged 5 to 24 months who met 1 of 7 at-risk criteria were enrolled at health centers. Participants were randomly assigned to intervention or control using random number tables generated by a statistician. Intervention comprised a manual for parents with illustrated play activities, phone calls, and short message service messages. The control group received usual care. Parent practices were measured using an adapted Family Care Indicators telephone-administered questionnaire by interviewers unaware of group assignment. Qualitative interviews were conducted with staff and parents in Jamaica and Brazil and staff in Ecuador to identify facilitators and barriers to remote delivery of Reach Up. RESULTS Two hundred forty-seven participants were assessed at endline (control n = 130; intervention n = 117). Intervention increased parent activities that support child development, effect size 0.34 SD (95% confidence interval 0.03–0.53), and use of praise, odds 2 times higher with intervention. There were no benefits to interactive language or play materials. Qualitative results showed parents appreciated program continuation and felt motivated to help their child, and methods were acceptable to staff. Barriers included poor mobile phone access, difficulty contacting parents, and feedback limitations without in-person contact. CONCLUSIONS Remote delivery methods have potential to contribute to scaling of parenting programs.

Although tumor-propagating cells can be derived from glioblastomas (GBM) of the proneural and mesenchymal subtypes, a glioma stem-like cell (GSC) of the classic subtype has not been identified. It is unclear whether mesenchymal GSCs (mGSC) and/or proneural GSCs (pGSC) alone are sufficient to generate the heterogeneity observed in GBM. We performed single-cell/single-nucleus RNA sequencing of 28 gliomas, and single-cell ATAC sequencing for 8 cases. We found that GBM GSCs reside on a single axis of variation, ranging from proneural to mesenchymal. In silico lineage tracing using both transcriptomics and genetics supports mGSCs as the progenitors of pGSCs. Dual inhibition of pGSC-enriched and mGSC-enriched growth and survival pathways provides a more complete treatment than combinations targeting one GSC phenotype alone. This study sheds light on a long-standing debate regarding lineage relationships among GSCs and presents a paradigm by which personalized combination therapies can be derived from single-cell RNA signatures, to overcome intratumor heterogeneity.Significance:Tumor-propagating cells can be derived from mesenchymal and proneural glioblastomas. However, a stem cell of the classic subtype has yet to be demonstrated. We show that classic-subtype gliomas are comprised of proneural and mesenchymal cells. This study sheds light on a long-standing debate regarding lineage relationships between glioma cell types.See related commentary by Fine, p. 1650.This article is highlighted in the In This Issue feature, p. 1631

Table S1: Clinical and molecular characteristics of the glioma cases profiled by scRNA-seq.

Supplementary Figures

mp3 file (11 MB). In the May edition of the Cancer Discovery podcast, Science Writer Elizabeth McKenna talks with Ingo K. Mellinghoff about his paper, which suggests that the disappointing clinical activity of first-generation EGFR inhibitors in glioblastoma versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these two cancer types.

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Purpose Prognostically favorable IDH-mutant gliomas are known to produce oncometabolite D-2-hydroxyglutarate (2HG). In this study, we investigated metabolite-based features of patients with grade 2 and 3 glioma using 2HG-specific in vivo MR spectroscopy, to determine their relationship with image-guided tissue pathology and predictive role in progression-free survival (PFS). Methods Forty-five patients received pre-operative MRIs that included 3-D spectroscopy optimized for 2HG detection. Spectral data were reconstructed and quantified to compare metabolite levels according to molecular pathology (IDH1R132H, 1p/19q, and p53); glioma grade; histological subtype; and T2 lesion versus normal-appearing white matter (NAWM) ROIs. Levels of 2HG were correlated with other metabolites and pathological parameters (cellularity, MIB-1) from image-guided tissue samples using Pearson’s correlation test. Metabolites predictive of PFS were evaluated with Cox proportional hazards models. Results Quantifiable levels of 2HG in 39/42 (93%) IDH+ and 1/3 (33%) IDH– patients indicated a 91.1% apparent detection accuracy. Myo-inositol/total choline (tCho) showed reduced values in astrocytic (1p/19q-wildtype), p53-mutant, and grade 3 (vs. 2) IDH-mutant gliomas (p p p p p p = 0.002), total NAA (R = − 0.61; p = 0.002) and cellularity (R = 0.37; p = 0.04) but not MIB-1. Increasing levels of 2HG/tCr (p = 0.0007, HR 5.594) and thresholding (≥ 0.905, median value; p = 0.02) predicted adverse PFS. Conclusion In vivo 2HG detection can reasonably be achieved on clinical scanners and increased levels may signal adverse PFS.

Study Workflow Diagram. Key steps in the study are outlined, including the number of patients at each stage. BEV: bevacizumab.

PDF file, 48K, Overall Survival Characteristics of Treated Patients.

PDF file, 406KB, Supplementary Table 1.115 TCGA SOC sample IDs used in the validation phase.; Supplementary Table 2. Proportionality tests based on the scaled Schoenfeld residules for the SNP effect in the log-additive Cox Proportional Hazards model adjusted for age and sex.; Supplementary Table 3. Validation of survival association with three SNPs in glioblastoma multiforme patients from three independent studies (Mayo Clinic10, GliomaSE11 and The Cancer Genome Atlas (TCGA17); Supplementary Table 4. Imputation analyiss of SSBP2 region:chr5: 80,680,000 -- 80,980,000, University of California, San Francisco Adult Glioma Study (AGS), Mayo Clinic, and The MACH, Hapmap 2, human genome build 18, 3 sites (University of California, San Francisco, Mayo Clinic and The Cancer Genome Atlas).

PDF file, 9905K, Representative phenotypic analysis of circulating lymphocytes in a clinical responder (Patient #009).

Purpose: Cancer immunotherapy offers hope of a highly specific nontoxic adjuvant treatment. Heat shock protein peptide complexes (HSPPCs) found in cancer cells carry tumor-specific antigenic proteins and can facilitate adaptive and innate immune responses. Here we show that peptides bound to a 96 kD chaperone protein (HSP-96) from brain tissue containing glioblastoma multiforme (GBM) can be used to safely immunize patients with recurrent GBM.Experimental Design: Multimodality immunomonitoring was completed on 12 patients with recurrent GBM before and after immunization with an autologous HSPPC vaccine derived from surgically resected tumor. Clinical endpoints included safety assessments and overall survival.Results: No adverse events attributable to the vaccine were found. Testing of peripheral blood leukocytes before and after vaccination revealed a significant peripheral immune response specific for the peptides bound to HSP-96, in 11 of the 12 patients treated. Brain biopsies of immune responders after vaccination revealed focal CD4, CD8, and CD56 IFNγ positive cell infiltrates, consistent with tumor site specific immune responses. Immune responders had a median survival of 47 weeks after surgery and vaccination, compared with 16 weeks for the single nonresponder.Conclusions: These data provide the first evidence in humans of individual patient-specific immune responses against autologous tumor derived peptides bound to HSP-96. Clin Cancer Res; 19(1); 205–14. ©2012 AACR.

Purpose: Glioblastoma is a devastating, incurable disease with few known prognostic factors. Here, we present the first genome-wide survival and validation study for glioblastoma.Experimental Design: Cox regressions for survival with 314,635 inherited autosomal single-nucleotide polymorphisms (SNP) among 315 San Francisco Adult Glioma Study patients for discovery and three independent validation data sets [87 Mayo Clinic, 232 glioma patients recruited from several medical centers in Southeastern United States (GliomaSE), and 115 The Cancer Genome Atlas patients] were used to identify SNPs associated with overall survival for Caucasian glioblastoma patients treated with the current standard of care, resection, radiation, and temozolomide (total n = 749). Tumor expression of the gene that contained the identified prognostic SNP was examined in three separate data sets (total n = 619). Genotype imputation was used to estimate hazard ratios (HR) for SNPs that had not been directly genotyped.Results: From the discovery and validation analyses, we identified a variant in single-stranded DNA-binding protein 2 (SSBP2) on 5q14.1 associated with overall survival in combined analyses (HR, 1.64; P = 1.3 × 10−6). Expression of SSBP2 in tumors from three independent data sets also was significantly related to patient survival (P = 5.3 × 10−4). Using genotype imputation, the SSBP2 SNP rs17296479 had the strongest statistically significant genome-wide association with poorer overall patient survival (HR, 1.79; 95% CI, 1.45-2.22; P = 1.0 × 10−7).Conclusion: The minor allele of SSBP2 SNP rs17296479 and the increased tumor expression of SSBP2 were statistically significantly associated with poorer overall survival among glioblastoma patients. With further confirmation, previously unrecognized inherited variations influencing survival may warrant inclusion in clinical trials to improve randomization. Unaccounted for genetic influence on survival could produce unwanted bias in such studies. Clin Cancer Res; 18(11); 3154–62. ©2012 AACR.

PDF file, 17162K, Model of HSPPC-96 mechanism of action.

Purpose: Glioblastoma is an aggressive and molecularly heterogeneous cancer with few effective treatment options. We hypothesized that next-generation sequencing can be used to guide treatment recommendations within a clinically acceptable time frame following surgery for patients with recurrent glioblastoma.Experimental Design: We conducted a prospective genomics-informed feasibility trial in adults with recurrent and progressive glioblastoma. Following surgical resection, genome-wide tumor/normal exome sequencing and tumor RNA sequencing were performed to identify molecular targets for potential matched therapy. A multidisciplinary molecular tumor board issued treatment recommendations based on the genomic results, blood–brain barrier penetration of the indicated therapies, drug–drug interactions, and drug safety profiles. Feasibility of generating genomics-informed treatment recommendations within 35 days of surgery was assessed.Results: Of the 20 patients enrolled in the study, 16 patients had sufficient tumor tissue for analysis. Exome sequencing was completed for all patients, and RNA sequencing was completed for 14 patients. Treatment recommendations were provided within the study's feasibility time frame for 15 of 16 (94%) patients. Seven patients received treatment based on the tumor board recommendations. Two patients reached 12-month progression-free survival, both adhering to treatments based on the molecular profiling results. One patient remained on treatment and progression free 21 months after surgery, 3 times longer than the patient's previous time to progression. Analysis of matched nonenhancing tissue from 12 patients revealed overlapping as well as novel putatively actionable genomic alterations.Conclusions: Use of genome-wide molecular profiling is feasible and can be informative for guiding real-time, central nervous system–penetrant, genomics-informed treatment recommendations for patients with recurrent glioblastoma. Clin Cancer Res; 24(2); 295–305. ©2017 AACR.See related commentary by Wick and Kessler, p. 256

PDF file, 8781K, Representative phenotypic analysis of circulating lymphocytes in a clinical non-responder (Patient #003).

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PDF file, 80K, Supplementary Table 1: Temozolomide 150 mg/m2 Pharmacokinetic Parameters (first cycle).

PDF file, 62K, Supplementary Table 2: Grade 3 or 4 events with relationship unrelated to unlikely to combination therapy (Vorinostat + TMZ).

PDF file, 29K, Vaccine Administration Schedule and Characteristics of Adverse Events.

Purpose: A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG).Experimental Design: This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m2/day for 5 days every 28 days. Part 2 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m2/day for 5 days of the first cycle and 200 mg/m2/day for 5 days of the subsequent 28-day cycles.Results: In part 1, the MTD of vorinostat administered on days 1 to 7 and 15 to 21 of every 28-day cycle, in combination with TMZ, was 500 mg daily. Dose-limiting toxicities (DLT) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In part 2, the MTD of vorinostat on days 1 to 7 and 15 to 21 of every 28-day cycle, combined with TMZ, was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells.Conclusion: Vorinostat in combination with temozolomide is well tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway. Clin Cancer Res; 18(21); 6032–9. ©2012 AACR.

Central nervous system (CNS) tumor patients commonly undergo multimodality treatment in the course of their disease. Adverse effects and complications from these interventions have not been systematically studied, but pose significant challenges in clinical practice and impact function and quality of life, especially in the management of long-term brain tumor survivors. Here, the European Association of Neuro-Oncology (EANO) has developed recommendations to prevent, diagnose, and manage adverse effects and complications in the adult primary brain CNS tumor (except lymphomas) patient population with a specific focus on surgery, radiotherapy, and pharmacotherapy. Specifically, we also provide recommendations for dose adaptations, interruptions, and reexposure for pharmacotherapy that may serve as a reference for the management of standard of care in clinical trials. We also summarize which interventions are unnecessary, inactive or contraindicated. This consensus paper should serve as a reference for the conduct of standard therapy within and outside of clinical trials.

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

Isocitrate dehydrogenase (IDH) mutant gliomas are the most common adult, malignant primary brain tumors diagnosed in patients younger than 50, constituting an important cause of morbidity and mortality. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors, sparking multiple efforts to improve their diagnosis and treatment. In this consensus review from the Society for Neuro-Oncology (SNO), the current diagnosis and management of IDH-mutant gliomas will be discussed. In addition, novel therapies, such as targeted molecular therapies and immunotherapies, will be reviewed. Current challenges and future directions for research will be discussed.

BACKGROUND There is little evidence on adult benefits from early childhood interventions in low and middle-income countries. We assessed adult cognition, psychosocial skills and behaviour from a stimulation trial conducted in Jamaica. METHODS Children with stunted growth (height-for age

Mutations in the TERT promoter represent the genetic underpinnings of tumor cell immortality. Beyond the two most common point mutations, which selectively recruit the ETS factor GABP to activate TERT, the significance of other variants is unknown. In seven cancer types, we identify duplications of wildtype sequence within the core promoter region of TERT that have strikingly similar features including an ETS motif, the duplication length and insertion site. The duplications recruit a GABP tetramer by virtue of the native ETS motif and its precisely spaced duplicated counterpart, activate the promoter and are clonal in a TERT expressing multifocal glioblastoma. We conclude that recurrent TERT promoter duplications are functionally and mechanistically equivalent to the hotspot mutations that confer tumor cell immortality. The shared mechanism of these divergent somatic genetic alterations suggests a strong selective pressure for recruitment of the GABP tetramer to activate TERT.

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

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.

INTRODUCTION Hyperpolarized carbon-13 (HP-13C) MR enables rapid dynamic imaging of metabolic pathways in the human brain using non-toxic, non-radioactive metabolites as tracers. This study presents our unique experience on the benefit of using [1-13C]pyruvate and [2-13C]pyruvate MR for evaluating patients with glioma. METHODS 132 scans (71 using an integrated 13C /1H coil) including steady-state 1H-MRSI (~10 min) and dynamic HP-13C imaging (60 sec) following injection of HP [1-13C]pyruvate (N=125) or [2-13C]pyruvate (N=7) were acquired from 46 patients with glioma (18F/28M; 15 IDH-mutant, 27 IDH-wildtype, 4 IDH-status-unknown). Maps of temporally-summed 13C-metabolite signals, ratios, and kinetic rate constants were calculated for contrast-enhancing, nonenhancing, and normal-appearing-white-matter (NAWM) regions and compared to steady-state metabolic metrics. RESULTS The only adverse event, in a single patient, was a burning sensation after the injection that resolved after saline flush. The mean time-to-injection of HP probes was 58.6±14.0 sec. Signal-to-noise ratios of [1-13C]lactate and [13C]bicarbonate within the NAWM from the HP [1-13C]pyruvate data were 53±39 and 13±6, respectively. The SD/mean of repeated injections (N=3) for lactate/pyruvate and pyruvate-to-lactate conversion rates were 3.8±3.1% and 6.5±3.1% in the NAWM, respectively. Patients with progressive GBM had significantly higher lactate/pyruvate and lower bicarbonate/lactate (p< 0.05) in contrast- and non-enhancing lesions compared to NAWM. Significantly elevated lactate/pyruvate and reduced bicarbonate/lactate (p< 0.01) were found in contrast-enhancing compared to nonenhancing regions, whereas choline/NAA and steady-state 1H-lactate levels were similar. HP [2-13C]pyruvate data showed reduced glutamate/pyruvate and pyruvate-to-glutamate conversion rates in T2 lesions compared to contralateral normal-appearing brain in IDH-mutant gliomas, consistent with known metabolic reprogramming. CONCLUSION This study demonstrates the potential benefit of dynamic HP-13C MRI for evaluating patients with glioma, which provides unique and spatially distinct contrast compared to steady-state metabolic imaging. Ongoing studies will further characterize dynamic metabolism in specific glioma subtypes and provide biomarkers for evaluating responses to treatment.

Although physiologic (diffusion-weighted and perfusion-weighted) MRI has shown promise in identifying regions of recurrent tumor (rTumor) in patients with glioblastoma suspected of progression, distinguishing treatment-induced effects (TxE) from rTumor on anatomical MRI remains a challenge. Whereas prior larger-scale machine learning (ML)-based studies mostly utilize anatomical imaging alone and/or perform lesion-level predictions, this study aimed to develop a non-invasive, radiopathomic tool for regional probabilistic mapping of TxE using 208 tissue-samples (55 pathologically-confirmed TxE, 153 recurrent glioblastoma) acquired from 107 patients with known spatial coordinates on pre-surgical MRI. We tested the hypothesis that applying a deep-learning (DL) model that included physiological MRI can: 1) more accurately identify areas of TxE that mimic rTumor on anatomical MRI and 2) better generalize to an independent test set than ML-models or a DL-model that uses anatomical MRI alone. An 80/20 split for training/validation was used after 1/3 of the patients were withheld for testing. Oversampling of TxE samples was employed to address class imbalance and an equal proportion of TxE samples was maintained across all datasets. Three ML-models, their ensemble, and a deep 4D-convolutional-neural-network were trained based on normalized anatomical (post-contrast T1, T2-FLAIR), diffusion-weighted (ADC, FA), and DSC perfusion-weighted (PeakHeight, %recovery) images cropped to 10mm-cubic patches centered on the coordinates from where tissue was obtained. Although Random Forest and voting-ensembled ML-models using all imaging and the anatomical DL-model had the best validation performance (AUC=0.81-0.82), these models did not generalize (test AUC=0.58-0.59). The DL-model including physiologic images had slightly lower validation AUC (0.78) but the best overall test AUC (0.795), indicating superior generalizability. Elevated blood volume (nPeakHeight) was the most important feature. Our DL-model’s interpretability was also demonstrated by disrupting class separation after shuffling voxels within each input patch. These results suggest that using deep-learning with physiologic MRI can improve intratumoral classification of TxE from rTumor.

Real-time metabolic conversion of intravenously-injected hyperpolarized [1-Dynamic HP-Both denoising methods improved metabolite SNR and regional signal coverage. In patient data, the average increase in peak dynamic metabolite SNR was 2-fold using TRI and 4-5 folds using GL-HOSVD denoising compared to acquired data. Denoising reduced kPost-processing denoising methods significantly improved the SNR of dynamic HP

Background Genomic profiling studies of diffuse gliomas have led to new improved classification schemes that better predict patient outcomes compared to conventional histomorphology alone. One example is the recognition that patients with IDH-wildtype diffuse astrocytic gliomas demonstrating lower-grade histologic features but genomic and/or epigenomic profile characteristic of glioblastoma typically have poor outcomes similar to patients with histologically diagnosed glioblastoma. Here we sought to determine the clinical impact of prospective genomic profiling for these IDH-wildtype diffuse astrocytic gliomas lacking high-grade histologic features but with molecular profile of glioblastoma. Methods Clinical management and outcomes were analyzed for 38 consecutive adult patients with IDH-wildtype diffuse astrocytic gliomas lacking necrosis or microvascular proliferation on histologic examination that were genomically profiled on a prospective clinical basis revealing criteria for an integrated diagnosis of “diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV” per cIMPACT-NOW criteria. Results We identified that this diagnosis consists of two divergent clinical scenarios based on integration of radiologic, histologic, and genomic features that we term “early/evolving” and “undersampled” glioblastoma, IDH-wildtype. We found that prospective genomically guided identification of early/evolving and undersampled IDH-wildtype glioblastoma resulted in more aggressive patient management and improved clinical outcomes compared to a biologically matched historical control patient cohort receiving standard-of-care therapy based on histomorphologic diagnosis alone. Conclusions These results support routine use of genomic and/or epigenomic profiling to accurately classify glial neoplasms, as these assays not only improve diagnostic classification but critically lead to more appropriate patient management that can improve clinical outcomes.

Background Molecular testing (MT) is utilized in neuro-oncology with increasing frequency. The aim of this study was to determine clinical practice patterns to acquire this information, interpret and utilize MT for patient care, and identify unmet needs in the practical clinical application of MT. Methods We conducted a voluntary online survey of providers within the Society for Neuro-Oncology (SNO) membership database between March and April 2019. Results We received 152 responses out of 2022 SNO members (7.5% of membership). 88.8% of respondents routinely order MT for newly diagnosed gliomas. Of those who do not, testing is preferentially performed in younger patients or those with midline tumors. 82.8% use MT in recurrent gliomas. Other common indications included: metastatic tumors, meningioma, and medulloblastoma. Many providers utilize more than one resource (36.0%), most frequently using in-house (41.8%) over commercially available panels. 78.1% used the results for clinical decision-making, with BRAF, EGFR, ALK, and H3K27 mutations most commonly directing treatment decisions. Approximately, half (48.5%) of respondents have molecular tumor boards at their institutions. Respondents would like to see SNO-endorsed guidelines on MT, organized lists of targeted agents available for specific mutations, a database of targetable mutations and clinical trials, and more educational programs on MT. Conclusion This survey was marked by several limitations including response rate and interpretation of MT. Among respondents, there is routine use of MT in Neuro-Oncology, however, there remains a need for increased guidance for providers to effectively incorporate the expanding genomic data resulting from MT into daily Neuro-Oncology practice.