Mechanisms and therapeutic implications of hypermutation in gliomas.

A high tumour mutational burden (hypermutation) is observed in some gliomas1-5; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.

Brain Tumor Imaging in Adolescents and Young Adults: 2021 WHO Updates for Molecular-based Tumor Types.

Published in 2021, the fifth edition of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS) introduced new molecular criteria for tumor types that commonly occur in either pediatric or adult age groups. Adolescents and young adults (AYAs) are at the intersection of adult and pediatric care, and both pediatric-type and adult-type CNS tumors occur at that age. Mortality rates for AYAs with CNS tumors have increased by 0.6% per year for males and 1% per year for females from 2007 to 2016. To best serve patients, it is crucial that both pediatric and adult radiologists who interpret neuroimages are familiar with the various pediatric- and adult-type brain tumors and their typical imaging morphologic characteristics. Gliomas account for approximately 80% of all malignant CNS tumors in the AYA age group, with the most common types observed being diffuse astrocytic and glioneuronal tumors. Ependymomas and medulloblastomas also occur in the AYA population but are seen less frequently. Importantly, biologic behavior and progression of distinct molecular subgroups of brain tumors differ across ages. This review discusses newly added or revised gliomas in the fifth edition of the CNS WHO classification, as well as other CNS tumor types common in the AYA population.

Pediatric-type low-grade gliomas in adolescents and young adults-challenges and emerging paradigms.

Pediatric-type low-grade glioma (PLGG) encompasses a heterogeneous group of WHO grade 1 or 2 tumors and is the most common central nervous system tumor found in children. PLGG extends beyond pediatrics, into adolescents and young adults (AYA, ages 15-40). PLGG represents 25% of all gliomas diagnosed in AYA with differences in tumor location and molecular alterations compared to children, resulting in improved outcome for AYAs. Long-term outcome is excellent, though patients may suffer significant morbidity depending on tumor location. There are differences in treatment practices with radiation used to treat PLGG in AYAs more often than in children. Most PLGG in AYA harbor an alteration in the RAS/MAPK pathway, with limited insight into response to targeted therapy in this age group. This review discusses the epidemiology, current therapeutic approaches, and challenges in the management of PLGG in AYA.

Dose-dependent efficacy of bevacizumab in recurrent glioblastoma.

BACKGROUND: Bevacizumab (BEV), at a standard dose of 10 mg/kg every 2 weeks is associated with prolonged progression-free survival (PFS) but no improvement in overall survival (OS) in recurrent glioblastoma (rGBM). Few studies have examined the potential dose-dependent efficacy of BEV. In Ontario, reimbursement for the costs of BEV varies, and as a result, our practice began to routinely use lower dose regimens. The main aim of this study was to ensure that there was no harm to patients who received the low dose protocol. METHODS: A single-center retrospective study of patients given BEV for rGBM between 2015 and 2020 was performed. Clinical and treatment data including BEV dose regimen [SD (10 mg/kg every 2 weeks) vs. LD (5 mg/kg every 2-3 weeks or 10 mg/kg every 3 weeks)] received at the time of rGBM diagnosis were captured. Overall survival (OS) and progression-free survival (PFS) on BEV were compared using the Kaplan-Meier product-limit method. Log-rank test was used to compare potential predictive factors. Cox regression model was performed for multivariable analysis of OS and PFS. RESULTS: A total of 96 patients were included with a median follow-up duration of 6.84 months (range 1.12-50.63 months) from the date of the first infusion. The LD group consisted of 55 of the 96 patients. By virtue of funding mechanisms for BEV, the median age in the LD group was significantly higher (62 vs. 54 years p = 0.009). There was no difference in MGMT status between the two groups (p = 0.60). The LD group had prolonged median PFS (5.89 months versus 3.22 months; p = 0.0112) and OS (10.23 months versus 6.28 months; p = 0.0010). Multivariable analysis including the dose of BEV, the extent of resection, gender, and age revealed that standard dose of BEV, subtotal resection, and female sex were associated with worse overall survival. Nine patients in the SD group vs. 18 patients in the LD group reported an adverse event related to BEV. CONCLUSION: For patients with recurrent GBM, we found that a low dose regimen of BEV was associated with prolonged OS and PFS compared to the standard dose regimen. Lower dose schedules may be a better and more cost-effective option for patients with rGBM. Lower costs might provide more equitable access to this very important palliative drug.

Re-irradiation for recurrent high-grade glioma: an analysis of prognostic factors for survival and predictors of radiation necrosis.

PURPOSE: Recurrent high-grade glioma (rHGG) is a heterogeneous population, and the ideal patient selection for re-irradiation (re-RT) has yet to be established. This study aims to identify prognostic factors for rHGG patients treated with re-RT. METHODS: We retrospectively reviewed consecutive adults with rHGG who underwent re-RT from 2009 to 2020 from our institutional database. The primary objective was overall survival (OS). Secondary endpoints included prognostic factors for early death (< 6 months after re-RT) and predictors of radiation necrosis (RN). RESULTS: For the 79 patients identified, the median OS after re-RT was 9.9 months (95% CI 8.3-11.6). On multivariate analyses, re-resection at progression (HR 0.56, p = 0.027), interval from primary treatment to first progression ≥ 16.3 months (HR 0.61, p = 0.034), interval from primary treatment to re-RT ≥ 23.9 months (HR 0.35, p < 0.001), and re-RT PTV volume < 112 cc (HR 0.27, p < 0.001) were prognostic for improved OS. Patients who had unmethylated-MGMT tumours (OR 12.4, p = 0.034), ≥ 3 prior systemic treatment lines (OR 29.1, p = 0.022), interval to re-RT < 23.9 months (OR 9.0, p = 0.039), and re-RT PTV volume ≥ 112 cc (OR 17.8, p = 0.003) were more likely to die within 6 months of re-RT. The cumulative incidence of RN was 11.4% (95% CI 4.3-18.5) at 12 months. Concurrent bevacizumab use (HR < 0.001, p < 0.001) and cumulative equivalent dose in 2 Gy fractions (EQD2, α/ß = 2) < 99 Gy2 (HR < 0.001, p < 0.001) were independent protective factors against RN. Re-RT allowed for less corticosteroid dependency. Sixty-six percent of failures after re-RT were in-field. CONCLUSION: We observe favorable OS rates following re-RT and identified prognostic factors, including methylation status, that can assist in patient selection and clinical trial design. Concurrent use of bevacizumab mitigated the risk of RN.

Brain Tumors in Adolescents and Young Adults: A Review.

Brain tumors account for the majority of cancer-related deaths in adolescents and young adults (AYAs), defined as individuals aged 15 to 39. AYAs constitute a distinct population in which both pediatric- and adult-type central nervous system (CNS) tumors can be observed. Clinical manifestations vary depending on tumor location and often include headaches, seizures, focal neurological deficits, and signs of increased intracranial pressure. With the publication of the updated World Health Organization CNS tumor classification in 2021, diagnoses have been redefined to emphasize key molecular alterations. Gliomas represent the majority of malignant brain tumors in this age group. Glioneuronal and neuronal tumors are associated with longstanding refractory epilepsy. The classification of ependymomas and medulloblastomas has been refined, enabling better identification of low-risk tumors that could benefit from treatment de-escalation strategies. Owing to their midline location, germ cell tumors often present with oculomotor and visual alterations as well as endocrinopathies. The management of CNS tumors in AYA is often extrapolated from pediatric and adult guidelines, and generally consists of a combination of surgical resection, radiation therapy, and systemic therapy. Ongoing research is investigating multiple agents targeting molecular alterations, including isocitrate dehydrogenase inhibitors, SHH pathway inhibitors, and BRAF inhibitors. AYA patients with CNS tumors should be managed by multidisciplinary teams and counselled regarding fertility preservation, psychosocial comorbidities, and risks of long-term comorbidities. There is a need for further efforts to design clinical trials targeting CNS tumors in the AYA population.

Current state of therapeutic focused ultrasound applications in neuro-oncology.

INTRODUCTION: Despite manifold advances in oncology, cancers of the central nervous system remain among the most lethal. Unique features of the brain, including distinct cellular composition, immunological privilege, and physical barriers to therapeutic delivery, likely contribute to the poor prognosis of patients with neuro-oncological disease. Focused ultrasound is an emerging technology that allows transcranial delivery of ultrasound energy to focal brain targets with great precision. METHODS: A review of the clinical and preclinical focused ultrasound literature was performed to obtain data regarding the current state of the focused ultrasound in context of neuro-oncology. A narrative review was then constructed to provide an overview of current and future applications of this technology. RESULTS: Focused ultrasound can facilitate direct control of tumors by thermal or mechanical ablation, as well as enhance delivery of diverse therapeutics by disruption of the blood-brain barrier without local tissue damage. Indeed, ultrasound-sensitive drug formulations or sonosensitizers may be combined with ultrasound blood-brain barrier disruption to achieve high local drug concentration while limiting systemic exposure to therapeutics. Furthermore, focused ultrasound can induce radiosensitization, immunomodulation, and neuromodulation. Here we review applications of focused ultrasound with a focus on approaches currently under clinical investigation for the treatment of neuro-oncological disease, such as blood-brain barrier disruption for drug delivery and thermal ablation. We also discuss design of clinical trials, selection of patient cohorts, and emerging approaches to improve the efficacy of transcranial ultrasound, such as histotripsy, as well as combinatorial strategies to exploit synergistic biological effects of existing cancer therapies and ultrasound. CONCLUSIONS: Focused ultrasound is a promising and actively expanding therapeutic modality for diverse neuro-oncological diseases.

Clinical, radiological and genomic features and targeted therapy in BRAF V600E mutant adult glioblastoma.

PURPOSE: Although uncommon, detection of BRAF V600E mutations in adult patients with glioblastoma has become increasingly relevant given the widespread application of molecular diagnostics and encouraging therapeutic activity of BRAF/MEK inhibitors. METHODS: We performed a retrospective study of adult glioblastoma patients treated at Dana-Farber Cancer Institute/Brigham and Women's Hospital or Massachusetts General Hospital from January 2011 to July 2019 with an identified BRAF V600E mutation by either immunohistochemistry or molecular testing. Patient characteristics, molecular genomics, and preoperative MRI were analyzed. RESULTS: Nineteen glioblastoma patients were included, with median age at diagnosis of 41-years-old (range 22-69). Only 1/18 was IDH1/2-mutant; 10/17 had MGMT unmethylated tumors. The most common additional molecular alterations were CDKN2A/2B biallelic loss/loss-of-function (10/13, 76.9%), polysomy 7 (8/12, 66.7%), monosomy 10 (5/12, 41.7%), PTEN biallelic loss/loss-of-function (5/13, 38.5%) and TERT promoter mutations (5/15, 33.3%). Most tumors were well-circumscribed (11/14) and all were contrast-enhancing on MRI. Twelve patients eventually developed subependymal or leptomeningeal dissemination. Six patients were treated with BRAF/MEK inhibition following disease progression after standard of care therapy, with 4/6 patients showing partial response or stable disease as best response. Median time to progression after BRAF/MEK inhibition was 6.0 months (95% CI 1.2-11.8). Grade 1 skin rash was present in 2 patients, but no other adverse events were reported. Median OS for the entire cohort was 24.1 months (95% CI 15.7-38.9). CONCLUSION: Understanding the natural history and features of BRAF V600E glioblastoma may help better identify patients for BRAF/MEK inhibition and select therapeutic strategies.

Myelopathies from Neoplasms.

Benign and malignant tumors can be an important cause of myelopathy. Patients may present with a wide range of neurologic symptoms including back and neck pain, weakness, sensory abnormalities, and bowel and bladder dysfunction. Management can be challenging depending on the location and underlying biology of the tumor. Neuroimaging of the spine is an important component of diagnostic evaluation and patient management both during initial evaluation and when monitoring after treatment. This article provides a systematic and practical review of neoplasms that can cause myelopathy. Unique imaging and biological features of distinct tumors are discussed, and their management strategies are reviewed.

Bevacizumab in Recurrent High-Grade Gliomas: A Canadian Retrospective Study.

BACKGROUND: Bevacizumab has been used in recurrent glioblastoma (rGBM) since 2010 in Canada. Given its cost, potential toxicities, and unclear efficacy, further studies are required to better define suitable candidates for therapy. METHODS: A single-center retrospective review of patients started on bevacizumab for rGBM from 2012 to 2015 was performed. Patient demographics, tumor characteristics, treatment regimen, and dates of clinical progression and death were collected. Overall survival (OS) and progression-free survival (PFS) were used as clinical outcomes and estimates. Radiological response was assessed using modified Response Assessment in Neuro-Oncology criteria. RESULTS: A total of 80 patients were included. There were 67 reported deaths, and the median OS was 9.2 months (95% confidence interval [CI 95%]=7.0-10.1 months), with a 12-month OS of 31% (CI 95%=21.9-43.5%). Some 79 patients were included for analysis of clinical progression, among whom 61 had documented clinical progression. The median clinical PFS was 4.6 months (CI 95%=3.8-6.4 months), and the 6-month clinical PFS was 39% (CI 95%=29.0-52.9%). Addition of chemotherapy did not improve clinical outcomes. A total of 68 patients were included for radiological progression analysis, with 58 radiological progressions. The median radiological PFS was 5.8 months (CI 95%=4.2-6.7 months), and the 6-month radiological PFS was 46% (CI 95%=35.6-60.0%). CONCLUSIONS: This is the first reported Canadian experience with bevacizumab for rGBM. Our clinical outcomes are consistent with published data from multicenter phase II and III trials on bevacizumab in rGBM. More research is required to determine which subtype(s) of patients with rGBM could benefit from bevacizumab upon recurrence.

Treatment Outcomes in 1p19q Co-deleted/Partially Deleted Gliomas.

BACKGROUND: Radiotherapy with procarbazine, lomustine, and vincristine improves overall survival (OS) in patients with 1p19q co-deleted anaplastic oligodendroglioma/anaplastic oligoastrocytoma. METHODS: This retrospective analysis investigated outcomes in patients with 1p19q co-deleted/partially deleted oligodendroglioma, oligoastrocytoma, anaplastic oligodendroglioma, or anaplastic oligoastrocytoma. OS and progression-free survival (PFS) were analyzed using the Kaplan-Meier method and prognostic factors using the Cox proportional hazard model. RESULTS: A total of 106 patients (between December 1997 and December 2013) were included. Median age was 40 years (19-66), 58 were male (55%), Eastern Cooperative Oncology Group performance status was 0 in 80 patients (75%). 1p19q status was co-deleted in 66 (62%), incompletely co-deleted in 27 (25%), and 1p or 19q loss alone in four (4%) and nine (8%) patients, respectively. Isocitrate dehydrogenase-1 R132H mutation was found in 67 of 85 patients with sufficient material. Upfront treatment was given in 72 (68%) patients and temozolomide alone in 52 (49%). Median time to radiotherapy in 47 patients (44%) was 34.7 months and 41.2 months in 9 patients with co-deleted/incompletely co-deleted anaplastic oligodendroglioma/anaplastic oligoastrocytoma who received upfront temozolomide alone. Median OS was not reached and 5-year OS was 91% for all groups (median follow-up, 5.1 years). On multivariable analysis for all patients, receipt of therapy upfront versus none (p=0.04), PS 1 versus 0 (p<0.001) and 1p19q co-deletion/incomplete deletion versus 1p or 19q loss alone (p=0.005) were prognostic for PFS. Isocitrate dehydrogenase-1 status was not prognostic for PFS. CONCLUSIONS: With similar survival patterns in low-grade/anaplastic gliomas, molecular characteristics may be more important than histological grade. Longer follow-up and results of prospective trials are needed for definitive guidance on treatment of these patients.

MEK Inhibition in a Pilocytic Astrocytoma With a Rare KRAS Q61R Mutation in a Young Adult Patient: A Case Report.

This case illustrates the utility and impact of molecular testing and molecular tumor board discussion in the management of AYA patients with brain tumors.

Dose-Escalated Radiation Therapy Is Associated With Improved Outcomes for High-Grade Meningioma.

PURPOSE: The optimal modern radiation therapy (RT) approach after surgery for atypical and malignant meningioma is unclear. We present results of dose escalation in a single-institution cohort spanning 2000 to 2021. METHODS AND MATERIALS: Consecutive patients with histopathologic grade 2 or 3 meningioma treated with RT were reviewed. A dose-escalation cohort (≥66 Gy equivalent dose in 2-Gy fractions using an α/ß = 10) was compared with a standard-dose cohort (<66 Gy). Outcomes were progression-free survival (PFS), cause-specific survival, overall survival (OS), local failure (LF), and radiation necrosis. RESULTS: One hundred eighteen patients (111 grade 2, 94.1%) were identified; 54 (45.8%) received dose escalation and 64 (54.2%) standard dose. Median follow-up was 45.4 months (IQR, 24.0-80.0 months) and median OS was 9.7 years (Q1: 4.6 years, Q3: not reached). All dose-escalated patients had residual disease versus 65.6% in the standard-dose cohort (P < .001). PFS at 3, 4, and 5 years in the dose-escalated versus standard-dose cohort was 78.9%, 72.2%, and 64.6% versus 57.2%, 49.1%, and 40.8%, respectively, (P = .030). On multivariable analysis, dose escalation (hazard ratio [HR], 0.544; P = .042) was associated with improved PFS, whereas ≥2 surgeries (HR, 1.989; P = .035) and older age (HR, 1.035; P < .001) were associated with worse PFS. The cumulative risk of LF was reduced with dose escalation (P = .016). Multivariable analysis confirmed that dose escalation was protective for LF (HR, 0.483; P = .019), whereas ≥2 surgeries before RT predicted for LF (HR, 2.145; P = .008). A trend was observed for improved cause-specific survival and OS in the dose-escalation cohort (P < .1). Seven patients (5.9%) developed symptomatic radiation necrosis with no significant difference between the 2 cohorts. CONCLUSIONS: Dose-escalated RT with ≥66 Gy for high-grade meningioma is associated with improved local control and PFS with an acceptable risk of radiation necrosis.

NANO-LM: An updated scorecard for the clinical assessment of patients with leptomeningeal metastases.

BACKGROUND: There are no validated tools for the clinical neurological assessment of patients with leptomeningeal metastases (LM). However, clinical examination during the course of the disease guides medical management and is part of response assessment in clinical trials. Because neuroimaging may not always be obtained owing to rapid clinical deterioration, clinical neurological assessment of LM is essential, and standardization Is important to minimize rater disagreement. METHODS: The RANO-LM group launched a 2-steps process, aiming at improving and standardizing the clinical assessment of patients with LM. We report here on the first step: the establishment of a consensus scorecard. The task force had 9 virtual meetings to define general recommendations on neurological assessment and selected domains of interest that should be tested. RESULTS: Fourteen domains of neurological symptoms and signs were selected: level of consciousness, cognition, nausea and vomiting, vision, eye movement, facial strength, hearing, swallowing, speech, limb strength, limb ataxia, walking, bladder bowel functions. For each item, a clear instruction on how to perform the assessment is provided with scoring criteria between 0 and 2. The general clinical status of the patient and use of steroids, pain medications, and anti-emetics should be documented. Neurological sequelae from previous brain metastases or cancer treatment should be rated at the baseline evaluation; it should be specified when symptoms or signs may be related to a condition other than LM. DISCUSSION: A revised NANO-LM consensus scorecard for clinical assessment has been established. An international prospective validation study of the proposal is currently ongoing (NCT06417710).

Gadolinium Enhanced T2 FLAIR is an Imaging Biomarker of Radiation Necrosis and Tumor Progression in Patients with Brain Metastases.

BACKGROUND AND PURPOSE: Differentiating radiation necrosis (RN) from tumor progression (TP) after radiotherapy for brain metastases is an important clinical problem requiring advanced imaging techniques which may not be widely available and are challenging to perform at multiple time points. The ability to leverage conventional MRI for this problem, could have meaningful clinical impact. The purpose of this study was to explore contrast enhanced T2 FLAIR (T2FLAIRc) as a new imaging biomarker of RN and TP. MATERIALS AND METHODS: This single-institution retrospective study included patients with treated brain metastases undergoing DSC-MRI between January 2021 and June 2023. Reference standard assessment was based on histopathology or serial follow-up including results of DSC-MRI for a minimum of 6 months from the first DSC-MRI. The index test was implemented as part of the institutional brain tumor MRI protocol and preceded the first DSC-MRI. T2FLAIRc and gadolinium enhanced T1 MPRAGE (T1c) signal were normalized against normal brain parenchyma and expressed as z-score. Mean signal intensity of enhancing disease for RN and TP groups were compared using unpaired t-test. Receiver operator characteristic (ROC) curves and area under the ROC curve (AUC) were derived by bootstrapping. DeLong test was used to compare AUC. RESULTS: 56 participants (mean age, 62 years +/-12.7 [SD]; 39 females); 28 RN, 28 TP were evaluated. The index MRI was performed on average 73 days +/-34 [SD] before the first DSC-MRI. Significantly higher z-scores were found for RN using T2FLAIRc (8.3 versus 5.8, p<0.001) and T1c (4.1 versus 3.5, p=0.02). AUC for T2FLAIRc (0.83, 95% CI, 0.72-0.92) was greater than T1c (0.70, 95% CI, 0.560.83) (p = 0.04). The AUC of DSC derived rCBV (0.82, 95% CI, 0.70-0.93) was not significantly different from T2FLAIRc (p = 0.9). CONCLUSIONS: A higher normalized T1c and T2FLAIRc signal intensity was found for RN. In a univariable test, mean T2FLAIRc signal intensity of enhancing voxels showed good discrimination performance for distinguishing RN from TP. The results of this work demonstrate the potential of T2FLAIRc as an imaging biomarker in the work-up of RN in patients with brain metastases. ABBREVIATIONS: AUC = area under the receiver operating characteristic curve; RN = radiation necrosis; ROC = receiver operating characteristic; SRS = stereotactic radiosurgery; T1c = contrast enhanced T1; T2FLAIRc = contrast enhanced T2 FLAIR; TP = tumor progression.

Predictors of Tumor Dynamics Over a 6-Week Course of Concurrent Chemoradiotherapy for Glioblastoma and the Effect on Survival.

PURPOSE: We present the final analyses of tumor dynamics and their prognostic significance during a 6-week course of concurrent chemoradiotherapy for glioblastoma in the Glioblastoma Longitudinal Imaging Observational study. METHODS AND MATERIALS: This is a prospective serial magnetic resonance imaging study in 129 patients with glioblastoma who had magnetic resonance imaging obtained at radiation therapy (RT) planning (F0), fraction 10 (F10), fraction 20 (F20), and 1-month post-RT. Tumor dynamics assessed included gross tumor volume relative to F0 (Vrel) and tumor migration distance (dmigration). Covariables evaluated included: corpus callosum involvement, extent of surgery, O6-methylguanine-DNA-methyltransferase methylation, and isocitrate dehydrogenase mutation status. RESULTS: The median Vrel were 0.85 (range, 0.25-2.29) at F10, 0.79 (range, 0.09-2.22) at F20, and 0.78 (range, 0.13-4.27) at 1 month after completion of RT. The median dmigration were 4.7 mm (range, 1.1-20.4 mm) at F10, 4.7 mm (range, 0.8-20.7 mm) at F20, and 6.1 mm (range, 0.0-45.5 mm) at 1 month after completion of RT. Compared with patients who had corpus callosum involvement (n = 26), those without corpus callosum involvement (n = 103) had significant Vrel reduction at F20 (P = .03) and smaller dmigration at F20 (P = .007). Compared with patients who had biopsy alone (n = 19) and subtotal resection (n = 71), those who had gross total resection (n = 38) had significant Vrel reduction at F10 (P = .001) and F20 (P = .001) and a smaller dmigration at F10 (P = .03) and F20 (P = .002). O6-Methylguanine-DNA-methyltransferase methylation and isocitrate dehydrogenase mutation status were not significantly associated with tumor dynamics. The median progression-free survival and overall survival (OS) were 8.5 months (95% CI, 6.9-9.9) and 20.4 months (95% CI, 17.6-25.2). In multivariable analyses, patients with Vrel ≥ 1.33 at F10 had worse OS (hazard ratio [HR], 4.6; 95% CI, 1.8-11.4; P = .001), and patients with dmigration ≥ 5 mm at 1-month post-RT had worse progression-free survival (HR, 1.76; 95% CI, 1.08-2.87) and OS (HR, 2.2; 95% CI, 1.2-4.0; P = .007). CONCLUSIONS: Corpus callosum involvement and extent of surgery are independent predictors of tumor dynamics during RT and can enable patient selection for adaptive RT strategies. Significant tumor enlargement at F10 and tumor migration 1-month post-RT were associated with poorer OS.

Canadian Consensus for Treatment of BRAF V600E Mutated Pediatric and AYA Gliomas.

Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods: Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results: A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm.

Clinical and Genomic Predictors of Adverse Events in Newly Diagnosed Glioblastoma.

PURPOSE: Adverse clinical events cause significant morbidity in patients with GBM (GBM). We examined whether genomic alterations were associated with AE (AE) in patients with GBM. EXPERIMENTAL DESIGN: We identified adults with histologically confirmed IDH-wild-type GBM with targeted next-generation sequencing (OncoPanel) at Dana Farber Cancer Institute from 2013 to 2019. Seizure at presentation, lymphopenia, thromboembolic events, pseudoprogression, and early progression (within 6 months of diagnosis) were identified as AE. The biologic function of genetic variants was categorized as loss-of-function (LoF), no change in function, or gain-of-function (GoF) using a somatic tumor mutation knowledge base (OncoKB) and consensus protein function predictions. Associations between functional genomic alterations and AE were examined using univariate logistic regressions and multivariable regressions adjusted for additional clinical predictors. RESULTS: Our study included 470 patients diagnosed with GBM who met the study criteria. We focused on 105 genes that had sequencing data available for ≥ 90% of the patients and were altered in ≥10% of the cohort. Following false-discovery rate (FDR) correction and multivariable adjustment, the TP53, RB1, IGF1R, and DIS3 LoF alterations were associated with lower odds of seizures, while EGFR, SMARCA4, GNA11, BRD4, and TCF3 GoF and SETD2 LoF alterations were associated with higher odds of seizures. For all other AE of interest, no significant associations were found with genomic alterations following FDR correction. CONCLUSIONS: Genomic biomarkers based on functional variant analysis of a routine clinical panel may help identify AE in GBM, particularly seizures. Identifying these risk factors could improve the management of patients through better supportive care and consideration of prophylactic therapies.

Is pulsed saturation transfer sufficient for differentiating radiation necrosis from tumor progression in brain metastases?

Background: Stereotactic radiosurgery (SRS) for the treatment of brain metastases delivers a high dose of radiation with excellent local control but comes with the risk of radiation necrosis (RN), which can be difficult to distinguish from tumor progression (TP). Magnetization transfer (MT) and chemical exchange saturation transfer (CEST) are promising techniques for distinguishing RN from TP in brain metastases. Previous studies used a 2D continuous-wave (ie, block radiofrequency [RF] saturation) MT/CEST approach. The purpose of this study is to investigate a 3D pulsed saturation MT/CEST approach with perfusion MRI for distinguishing RN from TP in brain metastases. Methods: The study included 73 patients scanned with MT/CEST MRI previously treated with SRS or fractionated SRS who developed enhancing lesions with uncertain diagnoses of RN or TP. Perfusion MRI was acquired in 49 of 73 patients. Clinical outcomes were determined by at least 6 months of follow-up or via pathologic confirmation (in 20% of the lesions). Results: Univariable logistic regression resulted in significant variables of the quantitative MT parameter 1/(RA·T2A), with 5.9 ±â€…2.7 for RN and 6.5 ±â€…2.9 for TP. The highest AUC of 75% was obtained using a multivariable logistic regression model for MT/CEST parameters, which included the CEST parameters of AREXAmide,0.625µT (P = .013), AREXNOE,0.625µT (P = .008), 1/(RA·T2A) (P = .004), and T1 (P = .004). The perfusion rCBV parameter did not reach significance. Conclusions: Pulsed saturation transfer was sufficient for achieving a multivariable AUC of 75% for differentiating between RN and TP in brain metastases, but had lower AUCs compared to previous studies that used a block RF approach.