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Adolescent and young adult (AYA) patients with glioma have historically had poorer outcomes than similar patients of younger or older age, a disparity thought to be attributable to the social and economic challenges faced by this group in the transition from childhood to adult life, delays in diagnosis, low participation of AYA patients in clinical trials, and the lack of standardized treatment approaches specific to this patient group. Recent work from many groups has informed a revision of the World Health Organization classification schema for gliomas to identify biologically divergent pediatric- and adult-type tumors, both types of which may occur in AYA patients, and revealed exciting opportunities for the use of targeted therapies for many of these patients. In this review, the authors focus on the glioma types of specific concern to practitioners caring for AYA patients and the factors that should be considered in the development of multidisciplinary teams to facilitate their care.

Introduction: Leptomeningeal disease (LMD) is a late complication of metastatic cancer that significantly limits patient survival. LMD is most prevalent in patients with melanoma, lung, and breast cancer, with incidence reaching 24.1% among those treated for brain metastases with both surgery and radiotherapy. As systemic treatment advances in oncology continue to improve patient survival, the incidence of LMD is expected to rise. This necessitates increased efforts to identify effective LMD therapies. Further, recent reporting of focal LMD in asymptomatic patients indicates that unique categories of LMD exist which may not necessarily portend a dismal prognosis. Unfortunately, exclusion of these patients from clinical trials has resulted in a paucity of high-quality evidence to guide management in this patient population. We therefore conducted a systematic review to determine the proportion and characteristics of phase III randomized clinical trials in breast cancer, lung cancer, and melanoma that included patients with LMD and/or included LMD-specific outcomes. Methods: The online ClinicalTrials.gov database was searched on December 22, 2020 for eligible phase III randomized control trials. No time limits were applied. The 1619 search results were screened by two independent reviewers for randomized, multi-arm therapeutic trials in advanced breast cancer, lung cancer, or melanoma. Results: 245 trials were included in this review, 75/245 (30.6%) of which included LMD-specific enrollment criteria. 67/245 (27.3%) trials explicitly excluded all patients with LMD, while 8 trials (3.3%) allowed conditional enrollment of patients with LMD; these stipulated that LMD must be asymptomatic/stable, and in some cases, treated. All 8 trials which conditionally allowed LMD patients to enroll were lung cancer trials. No temporal trend towards LMD inclusion was noted. CNS-specific outcomes, which did not include specific mention of LMD, were noted in 13/245 (5.4%) trials, 2 (15.4%) of which used standardized response criteria. No trials included LMD-specific outcomes. Conclusion: In this review, high rates of LMD exclusion and a complete lack of LMD-specific outcomes were noted in phase III trials for advanced breast cancer, lung cancer, and melanoma, despite these cancers carrying the highest risks of LMD. Lung cancer trials were most likely to include patients with LMD; this may be due to differences in tumor biology, drug penetration in the CNS and drug efficacy. Standardized and validated measures should be integrated into clinical trial design to facilitate inclusion of these patients when feasible and allow for meaningful assessment of LMD response to therapy. Table 1: Trial factors associated with exclusion of patients with leptomeningeal metastases a.based on study start date listed on clinicaltrials.gov, defined as “the actual date on which the first participant was enrolled in a clinical study.” b.based on studies with known location. Statistical test was between intercontinental versus single continent studies. Citation Format: Alisha Sharma, Kathryn Corbett, Maleeha Qazi, Hany Soliman, Arjun Sahgal, Sunit Das, Mary Jane Lim-Fat, Gregory R. Pond, Katarzyna Jerzak. Inclusion of Patients with Leptomeningeal Disease in Phase III Randomized Clinical Trials of Patients with Advanced Breast Cancer, Lung Cancer, and Melanoma: A Systematic Review [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-13-04.

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 2015–2020 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 2 groups (p = 0.60). Eight patients received lomustine with BEV (3 from the SD and 5 from the LD. 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. Conclusions 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.

PURPOSE The Response Assessment in Neuro-Oncology (RANO) criteria are widely used in high-grade glioma clinical trials. We compared the RANO criteria with updated modifications (modified RANO [mRANO] and immunotherapy RANO [iRANO] criteria) in patients with newly diagnosed glioblastoma (nGBM) and recurrent GBM (rGBM) to evaluate the performance of each set of criteria and inform the development of the planned RANO 2.0 update. MATERIALS AND METHODS Evaluation of tumor measurements and fluid-attenuated inversion recovery (FLAIR) sequences were performed by blinded readers to determine disease progression using RANO, mRANO, iRANO, and other response assessment criteria. Spearman's correlations between progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS Five hundred twenty-six nGBM and 580 rGBM cases were included. Spearman's correlations were similar between RANO and mRANO (0.69 [95% CI, 0.62 to 0.75] v 0.67 [95% CI, 0.60 to 0.73]) in nGBM and rGBM (0.48 [95% CI, 0.40 to 0.55] v 0.50 [95% CI, 0.42 to 0.57]). In nGBM, requirement of a confirmation scan within 12 weeks of completion of radiotherapy to determine progression was associated with improved correlations. Use of the postradiation magnetic resonance imaging (MRI) as baseline scan was associated with improved correlation compared with use of the pre-radiation MRI (0.67 [95% CI, 0.60 to 0.73] v 0.53 [95% CI, 0.42 to 0.62]). Evaluation of FLAIR sequences did not improve the correlation. Among patients who received immunotherapy, Spearman's correlations were similar among RANO, mRANO, and iRANO. CONCLUSION RANO and mRANO demonstrated similar correlations between PFS and OS. Confirmation scans were only beneficial in nGBM within 12 weeks of completion of radiotherapy, and there was a trend in favor of the use of postradiation MRI as the baseline scan in nGBM. Evaluation of FLAIR can be omitted. The iRANO criteria did not add significant benefit in patients who received immune checkpoint inhibitors.

Purpose:Dexamethasone, a uniquely potent corticosteroid, is frequently administered to patients with brain tumors to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in patients with glioblastoma (GBM), particularly in the context of immunotherapy.Experimental Design:We evaluated the dose-dependent effects of dexamethasone when administered with programmed cell death 1 (PD-1) blockade and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 and CT-2A GBM tumors. Clinically, the effect of dexamethasone on survival was evaluated in 181 patients with isocitrate dehydrogenase (IDH) wild-type GBM treated with PD-(L)1 blockade, with adjustment for relevant prognostic factors.Results:Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti–PD-1 therapy reduced survival in a dose-dependent manner. Concurrent dexamethasone also abrogated survival following anti–PD-1 therapy with or without radiotherapy in immune-resistant CT-2A models. Dexamethasone decreased T-lymphocyte numbers by increasing apoptosis, in addition to decreasing lymphocyte functional capacity. Myeloid and natural killer cell populations were also generally reduced by dexamethasone. Thus, dexamethasone appears to negatively affect both adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive patients with IDH wild-type GBM treated with PD-(L)1 blockade revealed poorer survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone administration was the strongest predictor of poor survival [reference, no dexamethasone; P = 0.003 and ≥2 mg HR, 1.97; 95% CI, 1.23–3.16; P = 0.005].Conclusions:Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for patients with GBM.

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Background The incidence and biology of IDH1/2 mutations in pediatric gliomas are unclear. Notably, current treatment approaches by pediatric and adult providers vary significantly. We describe the frequency and clinical outcomes of IDH1/2-mutant gliomas in pediatrics. Methods We performed a multi-institutional analysis of the frequency of pediatric IDH1/2-mutant gliomas, identified by next-generation sequencing (NGS). In parallel, we retrospectively reviewed pediatric IDH1/2-mutant gliomas, analyzing clinico-genomic features, treatment approaches, and outcomes. Results Incidence: Among 851 patients with pediatric glioma who underwent NGS, we identified 78 with IDH1/2 mutations. Among patients 0–9 and 10–21 years old, 2/378 (0.5%) and 76/473 (16.1%) had IDH1/2-mutant tumors, respectively. Frequency of IDH mutations was similar between low-grade glioma (52/570, 9.1%) and high-grade glioma (25/277, 9.0%). Four tumors were graded as intermediate histologically, with one IDH1 mutation. Outcome: Seventy-six patients with IDH1/2-mutant glioma had outcome data available. Eighty-four percent of patients with low-grade glioma (LGG) were managed observantly without additional therapy. For low-grade astrocytoma, 5-year progression-free survival (PFS) was 42.9% (95%CI:20.3–63.8) and, despite excellent short-term overall survival (OS), numerous disease-related deaths after year 10 were reported. Patients with high-grade astrocytoma had a 5-year PFS/OS of 36.8% (95%CI:8.8–66.4) and 84% (95%CI:50.1–95.6), respectively. Patients with oligodendroglioma had excellent OS. Conclusions A subset of pediatric gliomas is driven by IDH1/2 mutations, with a higher rate among adolescents. The majority of patients underwent upfront observant management without adjuvant therapy. Findings suggest that the natural history of pediatric IDH1/2-mutant glioma may be similar to that of adults, though additional studies are needed.

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. 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. 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. Focused ultrasound is a promising and actively expanding therapeutic modality for diverse neuro-oncological diseases.

This systematic review examines the proportion of patients with leptomeningeal disease included in phase 3 randomized clinical trials for patients with metastatic breast cancer, lung cancer, and melanoma.

Brain metastases (BM) are perceived as a rare complication of prostate cancer associated with poor outcome. Due to limited published data, we conducted a literature review regarding incidence, clinical characteristics, treatment options, and outcomes of patients with prostate cancer BM. A literature analysis of the PubMed, MEDLINE, and EMBASE databases was performed for full-text published articles on patients diagnosed with BM from prostate cancer. Eligible studies included four or more patients. Twenty-seven publications were selected and analyzed. The sources of published patient cohorts were retrospective chart reviews, administrative healthcare databases, autopsy records, and case series. BM are rare, with an incidence of 1.14% across publications that mainly focus on intraparenchymal metastases. Synchronous visceral metastasis and rare histological prostate cancer subtypes are associated with an increased rate of BM. Many patients do not receive brain metastasis-directed local therapy and the median survival after BM diagnosis is poor, notably in patients with multiple BM, dural-based metastases, or leptomeningeal dissemination. Overall, prostate cancer BM are rare and associated with poor prognosis. Future research is needed to study the impact of novel prostate cancer therapeutics on BM incidence, to identify patients at risk of BM, and to characterize molecular treatment targets.

Recent discoveries elucidating the genetic underpinnings of glial neoplasms have revealed myriad recurrent alterations that have clinical value by improving accuracy of diagnosis and prognosis. Furthermore, this wealth of genomic information provides the basis for targeted therapies and the subsequent design of biomarker-based clinical trials. This review summarizes the current landscape of clinically relevant molecular alterations in gliomas and describes the role of routine molecular testing in context of treatment planning for standards of care and clinical trials.

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. Temozolomide therapy seems to lead to mismatch repair deficiency and hypermutation in gliomas, but not to an increase in response to immunotherapy.

Background Targeted gene NGS testing is available through many academic institutions and commercial entities and is increasingly incorporated in practice guidelines for glioblastoma (GBM). This single-center retrospective study aimed to evaluate the clinical utility of incorporating NGS results in the management of GBM patients at a clinical trials-focused academic center. Methods We identified 1011 consecutive adult patients with pathologically confirmed GBM (IDHwt or IDHmut) who had somatic tumor sequencing (Oncopanel, ~500 cancer gene panel) at DFCI from 2013–2019. Clinical records of all IDHwt GBM patients were reviewed to capture clinical trial enrollment and off-label targeted therapy use based on NGS results. Results Of the 557 IDHwt GBM patients with sequencing, 182 entered clinical trials at diagnosis (32.7%) and 213 (38.2%) entered after recurrence. Sequencing results for 130 patients (23.3%) were utilized for clinical trial enrollment for either targeted therapy indications (6.9 % upfront and 27.7% at recurrent clinical trials and 3.1% for off-label targeted therapy) or exploratory studies (55.4% upfront and 6.9% recurrent clinical trials). Median overall survival was 20.1 months with no survival difference seen between patients enrolled in clinical trials compared to those who were not, in a posthoc analysis. Conclusions While NGS testing has become essential for improved molecular diagnostics, our study illustrates that targeted gene panels remain underutilized for selecting therapy in GBM-IDHwt. Targeted therapy and clinical trial design remain to be improved to help leverage the potential of NGS in clinical care.

Purpose To quantitatively compare the recurrence pattern of glioblastoma (IDH-wild type) versus grade 4 IDH-mutant astrocytoma (herein referred to as wtIDH and mutIDH, respectively) following primary chemoradiation. Methods Twenty-two wtIDH and 22 mutIDH patients matched by sex, extent of resection, and corpus callosum involvement were enrolled. The recurrent gross tumor volume (rGTV) was compared with both the gross tumor volume (GTV) and clinical target volume (CTV) from radiotherapy planning. Failure patterns were quantified by the incidence and volume of the rGTV outside the GTV and CTV, and positional differences of the rGTV centroid from the GTV and CTV. Results The GTV was smaller in wtIDH compared to the mutIDH group (mean±SD: 46.5±26.0 cm3 v. 72.2±45.4 cm3, p=0.026). The rGTV was 10.7±26.9 cm3 and 46.9±55.0 cm3 smaller than the GTV for the same groups (p=0.018). The rGTV extended outside the GTV in 22 (100%) and 15 (68%) (p=0.009) of wtIDH and mutIDH patients, respectively; however, the volume of rGTV outside the GTV was not significantly different (12.4±16.1 cm3 vs. 8.4±14.2 cm3, p=0.443). The rGTV metrics extending outside the CTV was not different between the groups. The rGTV centroid was within 5.7 mm of the closest GTV edge for 21 (95%) and 22 (100%) of wtIDH and mutIDH patients, respectively. Conclusion The rGTV extended beyond the GTV less often in mutIDH patients, suggesting limited margin radiotherapy could be beneficial in this group. The results support the study of small margin adaptive radiotherapy per the ongoing UNITED MR-Linac 5 mm CTV trial (NCT04726397).

BACKGROUND Accurate response criteria are crucial for determining treatment efficacy. The response assessment in neuro-oncology (RANO) criteria was developed to standardize response assessment in neuro-oncology. Modified RANO (m-RANO) criteria were recently proposed to address some limitations of the initial criteria including the use of a post-radiation baseline and an additional scan to confirm progression. We sought to identify differences in the association of progression-free survival (PFS) and overall survival (OS) using RANO and m-RANO criteria. METHODS We conducted a retrospective review of newly diagnosed glioblastoma (GBM) patients treated at Dana-Farber Cancer Institute from January 2013 until December 2019. Patients with available clinical and imaging data obtained before initiation of treatment, after radiation completion and at intervals of 1 to 3 months were included. MRIs were evaluated by two independent readers, and PD dates determined using RANO and m-RANO criteria. RESULTS 552 patients were included. 97.1% of the tumors were IDH wild-type. MGMT promoter was unmethylated in 51.4%, methylated in 35.1% and undetermined in 8.5%. Median OS among patients was 18.1 months. 72 patients (13%) did not have PD at the end of the study. 83 patients had treatment change while being clinically stable and without a confirmation scan and were excluded from the final analysis. PFS was 8.2 months with RANO and 8.4 months with mRANO. Difference in PD dates between RANO and m-RANO was detected in 76 patients (14%), where PFS was 3.5 months with RANO and 5.1 months with m-RANO. These patients had a worse median OS than those with identical RANO and m-RANO PD dates (15.2 vs. 22.4 months, p< 0.0001). CONCLUSION RANO and m-RANO criteria resulted in identical PFS for most patients. 14% of patients had discordant PD dates and a worse prognosis. These patients progressed early, and their PD was identified sooner with RANO criteria.

BACKGROUND Given the rarity of medulloblastoma in adults (fewer than 50 incident cases annually across Canada), the optimal chemotherapy strategy in this population is unknown. The management of adult medulloblastomas is thought to vary from institution to institution. Guidelines often omit suggestions for specific chemotherapy regimens, reflecting the lack of high quality evidence in this population. We sought to understand Canadian adult medulloblastoma practice patterns, hoping to inform future quality metrics and guidelines. METHODS In March 2022 a 30-question survey was sent out to 71 adult neuro-oncology clinicians on the Canadian Adolescent and Young Adult national rounds mailing list. Snowball sampling was permitted. RESULTS There were 25 responses (up to 35% response rate). Radiation oncologists (11), neuro-oncologists (8), medical oncologists (4), and neurosurgeons (2) responded from 6/10 Canadian provinces. They each treated on average 1.6 medulloblastoma patients per year. Most (61% of respondents) said that medulloblastoma molecular subgrouping was always done at their centre. Half (50%) indicated that cerebrospinal fluid testing was always done at diagnosis. The most common (64%) radiation regimen was 36 Gy (in 20 fractions) craniospinal irradiation + 18 Gy (in 10 fractions) boost. Concomitant chemotherapy was rarely given (75% of respondents included chemotherapy less than half of the time). Adjuvant chemotherapy was frequently administered (79% of respondents give it more than half of the time). The most common adjuvant chemotherapy was Cisplatin/Lomustine/Vincristine (57%), but other regimens included Cisplatin/Lomustine/Vincristine alternating with Cyclophosphamide/Vincristine (21%), Cisplatin/Cyclophosphamide/Vincristine (14%), and carboplatin-based regimens (14%). Respondents noted challenges prescribing chemotherapy in this population: drug toxicities, limited resources, and clinical uncertainty. There was support for standard of care adult medulloblastoma guidelines in 92% of respondents. CONCLUSIONS There is significant practice variation among Canadian neuro-oncology centres treating adult medulloblastoma. This variation can serve as an opportunity for quality improvement and clinical research.

OBJECTIVE Gliomas in adolescents and young adults (AYA) are commonly treated with a standard chemo-radiation approach. Molecular alterations have not been comprehensively described to date. METHODS We compiled a multi-institutional cohort of patients diagnosed with glioma between 15-39.9 years over 20 years. Molecular analysis, therapeutic data and outcome was collected. For specific alterations, analysis included patients aged 0-39.9 years. RESULTS A total of 1900 patients with 876 AYA gliomas were included. Ongoing analysis reveals genetic alterations in 95% of available tumours. IDH p.R132H was found in 49% of tumours, while non-canonical IDH mutations were found in 7%. Paediatric-type mutations were found in 33% of AYA tumours with IDH-WT GBM accounting for the remaining 11%. The most common paediatric alterations in AYAs included BRAF p.V600E (11%) and FGFR alterations (7%) while BRAF fusions, H3 p.K27M and H3.3 p.G34R were rarely observed (4%, 4% and 1% respectively). BRAF fused tumours with non-canonical binding partners were enriched in AYAs. Analysis of BRAF-V600E gliomas between ages 0-40 revealed increased tendency for malignant tumours in patients > 20 years suggesting malignant transformation possibly due to higher rate of secondary hits. This resulted in worse overall-survival for AYA patients with BRAF-V600E glioma when compared to children under 20 years (p=0.0032). Ten-year OS of 100%, 90% and 95% was seen for BRAF fused, BRAF-V600E and FGFR-altered AYA low grade glioma respectively, compared to 14% and 25% for BRAF-V600E and FGFR-altered high grade glioma. In contrast, continuous decline was observed in the IDH-mutant gliomas with 10-year OS of 50% which declined to 29% at 15 years. CONCLUSIONS Gliomas in AYA often have non-canonical alterations that may evade standard molecular analysis. They are enriched for paediatric-type alterations with distinct molecularly-based outcomes. These tumours may respond to targeted inhibitors and would benefit from comprehensive diagnostic and therapeutic approaches.

BACKGROUND Adverse events (AE) including seizures cause significant morbidity in patients with GBM. We propose a novel method for assessing genomic predictors of AEs using results from a clinical targeted sequencing platform with variant function analysis. METHODS We identified 1,011 consecutive adult patients with newly diagnosed, histologically confirmed IDH-wildtype GBM with targeted exome NGS (Oncopanel) at Dana-Farber Cancer Institute from 2013-2019. Seizure at presentation was retrospectively identified as an AE. Biologic function (high loss, low loss, neutral, low gain and high gain) was assigned to variants using a three-tiered approach leveraging a genetic variant database (OncoKB), followed by analysis using protein prediction tools (Sift, Polyphen2 and Provean). Univariate logistic regression was performed for each relevant altered gene against the outcome of interest with false-discovery rate correction. Genes associated with seizure at presentation were included iteratively in a multivariate logistic model including other predictors of the outcome. RESULTS Our analysis included 470 GBM patients with 107 genes and 12 whole chromosome or arm level candidate variants covered by all versions of Oncopanel and with >10% alteration. Seizure at presentation occurred in 143/463 patients (31%) and was associated with EGFR amplification (high gain) (OR: 2.76, 95% CI: 1.4-5.3, p = 0.04). In a multivariate analysis (including age, sex, and preoperative tumor volume), EGFR amplification remained statistically significant (OR: 1.5, 95% CI: 1.0-2.2, p = 0.03). CONCLUSION Genomic biomarkers based on functional variant analysis of a routine clinical panel may predict adverse events in GBM. Seizure at presentation was independently associated with EGFR amplification. Our ongoing analysis will look at predictors of myelosuppression, thromboembolism, pseudoprogression and early progression using a similar approach. Identifying molecular risk factors could improve the management of patients through supportive care and consideration of prophylactic therapies.

Mismatch repair deficiency (MMRD) is a pan-cancer mechanism resulting in universal hypermutation and aggressive cancers that are resistant to chemoradiation yet sensitive to immunotherapy. MMRD mutations can occur somatically or be inherited as a part of Lynch Syndrome or Constitutional Mismatch Repair Deficiency (CMMRD). Although MMRD affects children, adolescents and young adults (CAYA, ages 0-40) with gliomas, its prevalence and impact of germline inheritance is unknown. Given that high microsatellite instability (MSI) is a key characteristic of MMRD, we previously developed a robust low-coverage whole genome-based tool to quantify MSI, which allows for accurate MMRD detection. We are therefore performing a large-scale MMRD screen of CAYA high grade gliomas (HGGs) and utilizing data from the International Replication Repair Deficiency Consortium (IRRDC) to determine the impact of germline mutations in MMRD gliomas. Ongoing data on 346 HGGs from CAYA patients reveals that MMRD is identified in 6% of HGGs and is not present in tumors with pediatric type alterations. Moreover, of MMRD tumors with IDH1 mutations, none harbor 1p/19q co-deletions. Of patients with available information, all are diagnosed with Lynch Syndrome (69%) or CMMRD (31%), with all Lynch Syndrome diagnoses occurring in patients above 18 years of age. Complementary data from the IRRDC on 113 MMRD patients with gliomas reveal that the median age of glioma is 9.7 and 17.5 years in CMMRD and Lynch Syndrome, respectively (p < 0.001). Strikingly, CMMRD gliomas are enriched for secondary polymerase mutations (60%, p < 0.001) and exhibit ultra-hypermutation, while MMRD gliomas with Lynch Syndrome are enriched for IDH1 mutations (32%, p < 0.025) and harbor a lower mutational burden. Our data reveal a high prevalence of MMRD in CAYA HGGs with alarming impact of germline predisposition. These data can support universal screening for MMRD in high grade glioma diagnostics and identify patients for precision therapeutics.

BACKGROUND We sought to compare the Response Assessment in Neuro-Oncology (RANO), modified RANO (mRANO), and immunotherapy RANO (iRANO) in a large population of patients with newly diagnosed (nGBM) and recurrent (rGBM) glioblastoma. METHODS Bidimensional measurements of enhancing disease and FLAIR sequence evaluation were performed by two independent readers on brain MRIs of consecutive patients with IDH-wildtype nGBM and rGBM treated at a single institution. Discrepancies were evaluated by a third reader. Dates of disease progression (PD) were identified using RANO, mRANO, iRANO, and other response assessment criteria variations. Spearman’s correlations between PFS and OS were calculated using iterative multiple imputations for censored observations. RESULTS 526 nGBM and 580 rGBM cases were included. Spearman’s correlations were not significantly different between RANO and mRANO in nGBM (0.69 [95% CI 0.62 to 0.75] vs. 0.67 [0.60, 0.73]) and rGBM (0.48 [0.40, 0.55] vs. 0.50 [0.42, 0.57]). Evaluation of FLAIR did not improve the correlation in patients who received antiangiogenic therapy. Acquisition of confirmation scans was associated with increased correlation only when PD was identified within 12 weeks of completion of radiation in nGBM. The use of the post-radiation MRI as a baseline was associated with increased correlation compared to use of the pre-radiation MRI in nGBM (0.67 [0.60, 0.73] vs. 0.53 [0.42, 0.62]). The correlation with iRANO was similar to RANO and mRANO among 98 patients with nGBM and 175 patients with rGBM who received immunotherapy. CONCLUSIONS RANO and mRANO demonstrated similar correlations between PFS and OS. The evaluation of FLAIR can be omitted, while confirmation scans were only beneficial in nGBM in the first 12 weeks after completion of radiation. There was a trend in favor of the post-radiation MRI as the baseline scan in nGBM. The use of iRANO criteria did not add a significant benefit in patients who received immunotherapy.

BACKGROUND MGMT promoter methylation in IDH-mutant gliomas was associated with improved survival in a recent study (PMID 35386566) but did not account for the updated WHO classification of CNS tumors. We evaluated the prognostic value of MGMT methylation in IDH-mutant gliomas incorporating the 2021 WHO classification. METHODS We retrospectively identified 431 patients with IDH-mutant gliomas treated at a single institution from 2010-2020. Kaplan-Meier method was used to estimate OS and PFS rates. Log-Rank test was used to evaluate differences between groups. RESULTS Median age was 36.2 years. MGMT promoter was methylated in 49.6%, unmethylated in 17.2%, partially methylated in 6.7%, and untested in 26.5%. Histological diagnosis was consistent with astrocytoma in 45.7%, oligodendroglioma in 33.9%, glioblastoma in 16.4%, and oligoastrocytoma in 4%. After accounting for 1p/19q and CDKN2A statuses, 190 patients had an integrated diagnosis of astrocytoma, grade 2 or 3; 94 had astrocytoma, grade 4; and 147 had oligodendroglioma, grade 2 or 3. There were 101 death events. Median OS was 33.36 years and median PFS was 5.67 years in MGMT methylated gliomas, compared to median OS of 12.54 years (p=0.0064) and median PFS of 3.91 years (p=0.0034) in unmethylated tumors. Upon univariate subgroup analysis, MGMT methylation was associated with significantly longer OS in histological astrocytomas, grade 2 or 4. However, when stratifying patients according to 2021 WHO classification of CNS tumors, there was no significant difference in OS between MGMT methylated and unmethylated astrocytomas or oligodendrogliomas, irrespective of WHO grade. CONCLUSION MGMT promoter methylation was associated with prolonged OS in histological astrocytomas, IDH-mutant. However, MGMT status did not impact survival after incorporating 2021 WHO classification of CNS tumors, suggesting that 1p/19q co-deletion and CDKN2A homozygous deletion are stronger prognostic factors in our cohort. The number of survival events was limited; larger datasets are required for more definitive conclusions.

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.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.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.Focused ultrasound is a promising and actively expanding therapeutic modality for diverse neuro-oncological diseases.

OBJECTIVE: Gliomas in adolescents and young adults (AYA) are commonly treated with a standard chemo-radiation approach based on data from adults. The clinical impact of paediatric-type alterations in these tumours is unknown. METHODS: We compiled a multi-institutional cohort of patients diagnosed with glioma between 15-39.9 years over 20 years. Complete molecular analysis, therapeutic data and outcome was collected. For specific alterations, analysis included patients aged 0-39.9 years. RESULTS: A total of 1900 patients with 876 AYA gliomas were included. Ongoing analysis reveals genetic alterations in 95% of available tumours. IDH-mutant tumours account for only 53%, while paediatric-type mutations were found in 35% of AYA tumours with IDH-WT GBM accounting for the remaining 12%. The most common paediatric alterations in AYAs included BRAF p.V600E (11%) and FGFR alterations (6%) while BRAF fusions, H3 p.K27M and H3.3 p.G34R were rarely observed (4%, 4% and 1% respectively). BRAF fused tumours with non-canonical binding partners were enriched in AYAs. Analysis of BRAF-V600E gliomas between ages 0-40 revealed increased tendency for malignant tumours in patients >20 years suggesting malignant transformation possibly due to higher rate of secondary hits including TP53, CDKN2A and ATRX mutations. This resulted in worse overall-survival for AYA patients with BRAF-V600E glioma when compared to children under 20 years (p=0.0032). Ten-year OS of 100%, 90% and 95% was seen for BRAF fused, BRAF-V600E and FGFR-altered AYA low grade glioma respectively, compared to 14% and 25% for BRAF-V600E and FGFR-altered high grade glioma. In contrast, continuous decline was observed in the IDH-mutant gliomas with 10-year OS of 50% which declined to 29% at 15 years. CONCLUSIONS: Gliomas in AYA are enriched for paediatric-type alterations with distinct molecularly-based outcomes. As these tumours carry different outcomes than childhood glioma and may respond to targeted inhibitors, AYA gliomas would benefit from comprehensive diagnostic and therapeutic approaches.

2020 Background: The Response Assessment in Neuro-Oncology (RANO) and modified RANO (mRANO) criteria are the two most widely used criteria to evaluate treatment response in glioblastoma (GBM) clinical trials. Unlike RANO, mRANO omits the evaluation of FLAIR sequence and requires a repeat scan to confirm responses. It also uses the post-radiation (RT) MRI as a baseline MRI in the newly diagnosed setting instead of the pre-RT MRI used in RANO. We sought to compare the 2 response assessment criteria and evaluate the differences between them in a large patient population. We also sought to compare them to immunotherapy RANO (iRANO) in patients who received immunotherapy. Methods: We conducted a retrospective review of consecutive patients with newly diagnosed (nGBM) and recurrent (rGBM) IDH wild-type GBM treated at Dana-Farber Cancer Institute from 2014 to 2020. Bidimensional measurements of enhancing disease and evaluation of FLAIR sequences were performed by two independent readers on patients’ brain MRIs obtained before change of treatment, and discrepancies were evaluated by a third reader. Dates of disease progression (PD) were identified using RANO, mRANO, iRANO, and other response assessment criteria variations. Spearman’s correlations between PFS and OS were calculated using an iterative multiple imputation method to account for any right-censoring. Results: 526 and 580 patients were included in the newly diagnosed and recurrent cohorts, respectively. Spearman’s correlations were not significantly different between RANO and mRANO in the nGBM (0.69 [95% CI 0.62 to 0.75] vs. 0.67 [0.60, 0.73]) and rGBM (0.45 [0.37, 0.52] vs. 0.50 [0.42, 0.57]) cohorts. Evaluation of FLAIR sequences did not improve the correlation between PFS and OS in patients who received antiangiogenic therapy. Addition of confirmation scans was associated with stronger Spearman’s correlations only when PD was identified within 12 weeks of completion of RT in the nGBM cohort, but did not affect the Spearman’s correlations in the rGBM cohort. The use of the post-RT MRI as a baseline was associated with a higher Spearman’s correlation in nGBM than the use of pre-RT MRI (0.67 [0.60, 0.73] vs. 0.53 [0.42, 0.62]). Among 98 patients with nGBM and 175 patients with rGBM who received immunotherapy, the Spearman’s correlations (nGBM and rGBM) with iRANO (0.63 [0.44, 0.76] and 0.34 [0.17, 0.49]) were similar to RANO (0.73 [0.60, 0.82] and 0.42 [0.28, 0.54]) and mRANO (0.65 [0.48, 0.77] and 0.43 [0.28, 0.56]). Conclusions: RANO and mRANO demonstrated similar correlation between PFS and OS. The evaluation of FLAIR can be omitted, while confirmation scans appear to be only beneficial in the nGBM settings during the first 12 weeks of completion of RT. There was a nonsignificant trend in favor of the use of post-RT MRI as the baseline scan in the nGBM setting. The application of iRANO criteria did not add significant benefit in patients who received immunotherapy.

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.

PURPOSE/OBJECTIVE(S) While glioblastoma (GBM) is known to have increased incidence in males, recent work has identified possible sex-specific molecular differences that could be associated with improved clinical outcomes for female GBM patients. We evaluated sex-based differences in patient and tumor characteristics, and clinical outcomes in newly diagnosed GBM patients. MATERIALS/METHODS We reviewed 665 newly diagnosed adult IDH-wild type GBM patients with Karnofsky Performance Status (KPS) ≥60 who were treated at our institution from January 1, 2010 to May 30, 2019. Patient, tumor and treatment details were obtained from the electronic medical record. An unpaired t-test, Fisher's exact test and univariable/multivariable Cox proportional hazards modeling were used to evaluate associations, including progression free survival (PFS) and overall survival (OS). RESULTS In our GBM cohort, 384 (57.7%) were male and 281 (42.3%) were female. There were no significant differences in age (60.6 years in males vs. 60.0 years in females, P = 0.16), KPS (KPS ≥90 in 46.1% in males vs. 43.4% in females, P = 0.53), extent of resection (gross total resection in 44.8% in males vs. 47.7% in females, P = 0.48), or prevalence of MGMT methylation (37.8% in males vs. 43.4% in females, P = 0.11). There were also no differences in receipt of temozolomide (95.1% of males vs. 95.7% of females, P = 0.71), radiation dose (≥59.4 Gy in 85.2% in males vs. 87.5% in females, P = 0.43), or clinical trial enrollment (24.7% males vs. 21.0% females, P = 0.27). Median OS was 22.5 months for females and 19.3 months for males (hazard ratio [HR] 0.81, 95% CI 1.03-1.48, P = 0.02). On multivariable analysis adjusted for age (adjusted hazard ratio [AHR] 1.04, 95% CI [1.03-1.05], P < 0.001), KPS ≥90 (AHR 0.73, 95% CI [0.60-0.89], P = 0.002), extent of resection (AHR 1.12, 95% CI 0.92-1.37, P = 0.26), and MGMT methylation status (AHR 0.38, 95% CI [0.31-0.47], P < 0.001), female sex (AHR 0.78, 95% CI [0.64-0.95], P = 0.015) was associated with improved OS. Superior OS in females was observed in MGMT unmethylated patients (HR 0.69, 95% CI [0.54-0.90], P = 0.005) but not in MGMT methylated patients (HR 0.85, 95% CI [0.64-1.14], P = 0.28). While age (AHR 1.02, 95% CI [1.02-1.03], P < 0.001), KPS ≥90 (AHR 0.79, 95% CI [0.66-0.95], P = 0.01), and MGMT methylation (AHR 0.40, 95% CI [0.33-0.49], P < 0.001) were associated with PFS, biologic sex was not associated with PFS (AHR 0.94, 95% CI [0.78-1.12], P = 0.49). CONCLUSION Female sex was associated with improved survival after adjustment of known clinical covariates in newly diagnosed GBM patients. Further study is necessary to understand biologic mechanism for sex-based differences in clinical outcome given implications for therapy development and clinical trial design. AUTHOR DISCLOSURE D.D. Shi: None. M. Lim-Fat: None. G.C. Youssef: None. S. Whorral: None. M. Allen: None. D.N. Cagney: None. S. Tanguturi: None. D. Haas-Kogan: Research Grant; Novartis; Cellworks. A.A. Aizer: Research Grant; Varian. Consultant; Novartis. Advisory Board; Seattle Genetics. J. McFaline-Figueroa: None. U.N. Chukwueke: None. E.Q. Lee: None. D.A. Reardon: Research Grant; Celldex, Inovio, Midatech. Consultant; Amgen. Speaker's Bureau; Merck/Schering, Roche/Genentech. Advisory Board; AbbVie, Bristol Myers Squibb, Cavion, Celldex, EMD Serono, Juno Pharmaceuticals, Momenta Pharmaceuticals, Novartis, Novocure, Oxigene, Regeneron, Roche/Genentech, Stemline. L. Nayak: None. W.L. Bi: Research Grant; The Leukemia and Lymphoma Society, NIH/NCI.R. Beroukhim: Independent Contractor; Scorpion Therapeutics. Stock; Scorpion Therapeutics. K.L. Ligon: None. B.M. Alexander: Research Grant; Puma Biotechnology, Eli Lily, Celgene. Stock; Hoffman-La Roche. P.Y. Wen: None. R. Rahman: Research Grant; Project Data Sphere, LLC.

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.

Purpose: Dexamethasone, a uniquely potent corticosteroid, is frequently administered to patients with brain tumors to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in patients with glioblastoma (GBM), particularly in the context of immunotherapy. Experimental Design: We evaluated the dose-dependent effects of dexamethasone when administered with programmed cell death 1 (PD-1) blockade and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 and CT-2A GBM tumors. Clinically, the effect of dexamethasone on survival was evaluated in 181 patients with isocitrate dehydrogenase (IDH) wild-type GBM treated with PD-(L)1 blockade, with adjustment for relevant prognostic factors. Results: Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti–PD-1 therapy reduced survival in a dose-dependent manner. Concurrent dexamethasone also abrogated survival following anti–PD-1 therapy with or without radiotherapy in immune-resistant CT-2A models. Dexamethasone decreased T-lymphocyte numbers by increasing apoptosis, in addition to decreasing lymphocyte functional capacity. Myeloid and natural killer cell populations were also generally reduced by dexamethasone. Thus, dexamethasone appears to negatively affect both adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive patients with IDH wild-type GBM treated with PD-(L)1 blockade revealed poorer survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone administration was the strongest predictor of poor survival [reference, no dexamethasone; Conclusions: Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for patients with GBM.

BACKGROUND Comprehensive next generation sequencing (NGS) is available through many academic institutions and commercial entities, and is incorporated in practice guidelines for glioblastoma (GBM). We retrospective evaluated the practice patterns and utility of incorporating NGS data into routine care of GBM patients at a clinical trials-focused academic center. METHODS We identified 1,011 consecutive adult patients with histologically confirmed GBM with OncoPanel testing, a targeted exome NGS platform of 447 cancer-associated genes at Dana Farber Cancer Institute (DFCI), from 2013-2019. We selected and retrospectively reviewed clinical records of all IDH-wildtype GBM patients treated at DFCI. RESULTS We identified 557 GBM IDH-wildtype patients, of which 227 were male (40.7%). OncoPanel testing revealed 833 single nucleotide variants and indels in 44 therapeutically relevant genes (Tier 1 or 2 mutations) including PIK3CA (n=51), BRAF (n=9), FGFR1 (n=8), MSH2 (n=4), MSH6 (n=2) and MLH1 (n=1). Copy number analysis revealed 509 alterations in 18 therapeutically relevant genes including EGFR amplification (n= 186), PDGFRA amplification (N=39) and CDKN2A/2B homozygous loss (N=223). Median overall survival was 17.5 months for the whole cohort. Seventy-four therapeutic clinical trials accrued 144 patients in the upfront setting (25.9%) and 203 patients (36.4%) at recurrence. Altogether, NGS data for 107 patients (19.2%) were utilized for clinical trial enrollment or targeted therapy indications. High mutational burden (>17mutations/Mb) was identified in 11/464 samples (2.4%); of whom 3/11 received immune checkpoint blockade. Four patients received compassionate use therapy targeting EGFRvIII (rindopepimut, n=2), CKD4/6 (abemaciclib, n=1) and BRAFV600E (dabrafenib/trametinib, n=1). CONCLUSION While NGS has greatly improved diagnosis and molecular classification, we highlight that NGS remains underutilized in selecting therapy in GBM, even in a setting where clinical trials and off-label therapies are relatively accessible. Continued efforts to develop better targeted therapies and efficient clinical trial design are required to maximize the potential benefits of genomically-stratified data.

BACKGROUND Dexamethasone, a uniquely potent corticosteroid, is frequently administered to brain tumor patients to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in glioblastoma patients – particularly in the context of immunotherapy. METHODS We evaluated the dose-dependent effects of dexamethasone when administered with anti-PD-1 and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 or CT-2A glioblastoma tumors, including analyses of intracranial tumors, draining lymph nodes, and spleen. Clinically, the effect of dexamethasone on survival was additionally evaluated in 181 consecutive IDH-wildtype glioblastoma patients treated with anti-PD-(L)1, with adjustment for relevant prognostic factors. RESULTS Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy decreased survival in a dose-dependent fashion and decreased survival following anti-PD-1 plus radiotherapy in both GL261 and immunoresistant CT-2A models. Dexamethasone quantitatively decreased T lymphocytes by reducing the proliferation while increasing apoptosis. Dexamethasone also decreased lymphocyte functional capacity. Myeloid and NK cell populations were also generally reduced. Thus, dexamethasone negatively affects both the adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive IDH-wildtype glioblastoma patients treated with PD-(L)1 blockade revealed worse survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone use – regardless of dose – was the strongest predictor of poor survival (reference no dexamethasone; < 2mg HR 2.28, 95%CI=1.41–3.68, p=0.001; ≥2mg HR 1.97, 95%CI=1.27–3.07, p=0.003). CONCLUSIONS Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for glioblastoma patients. Our preclinical analyses also suggest that dexamethasone’s detrimental effects are dose-dependent, suggesting that the lowest possible dose should be used for patients when dexamethasone use is unavoidable. Careful evaluation of dexamethasone use is warranted for neuro-oncology patients undergoing immunotherapy clinical trials.

Background Increasing data indicate that corticosteroids can exert a detrimental effect on immunotherapy for oncology patients. Dexamethasone, a uniquely potent corticosteroid, is frequently administered to brain tumor patients to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in glioblastoma patients – particularly in the context of immunotherapy. Methods We evaluated the dose-dependent effects of dexamethasone when administered with PD-1 blockade and/or radiotherapy on survival and tumor response in immunocompetent C57BL/6 mice with syngeneic GL261 and CT-2A glioblastoma tumors. The immune microenvironment was comprehensively profiled using flow cytometry analysis. Clinically, the effect of dexamethasone on survival was evaluated in 181 IDH-wildtype glioblastoma patients treated with PD-(L)1 blockade, with adjustment for relevant prognostic factors using multivariable Cox regression. Results Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy reduced survival in a dose-dependent manner (figure 1). Concurrent dexamethasone also abrogated survival following anti-PD-1 with or without radiotherapy in immunoresistant CT-2A models (figure 2). Dexamethasone decreased T lymphocyte numbers (figure 3) by increasing apoptosis (figure 4), in addition to decreasing lymphocyte functional capacity (figure 3C/D). Myeloid and NK cell populations were also generally reduced by dexamethasone (figure 3). Thus, dexamethasone appears to negatively affect both adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive IDH-wildtype glioblastoma patients treated with PD-(L)1 blockade revealed poorer survival among those on baseline dexamethasone. Upon multivariable adjustment by relevant prognostic factors, baseline dexamethasone administration was the strongest predictor of poor survival, regardless of dose (referent no dexamethasone; Conclusions We demonstrate that concurrent dexamethasone administration, even at a low dose, limits the therapeutic benefit of anti-PD-1 therapy both in mouse glioblastoma models and in a retrospective cohort of 181 IDH-wildtype glioblastoma patients. Mechanistically, dexamethasone decreased intratumoral T cells and systemic levels of T cells, natural killer cells, and myeloid cells, while qualitatively impairing lymphocyte function. The mechanism of T cell depletion included induction of apoptosis. These findings indicate that dexamethasone hinders both adaptive and innate immune responses, intratumorally and systemically, and that its administration should be carefully assessed among glioblastoma patients undergoing second-generation immunotherapy clinical trials. Our findings also have ramifications for brain metastasis patients where immune checkpoint inhibitors are part of standard-of-care management. Acknowledgements We thank Min Wu for assistance in generating CT-2A luciferase-transduced cells, and Drs. Geoffrey Young, Lei Qin, Xin Chen, and Jing Li for assistance in evaluation of patients‘ radiographic imaging. Ethics Approval Approved under DFCI Institutional Review Board protocol 10-417.

Recent discoveries elucidating the genetic underpinnings of glial neoplasms have revealed myriad recurrent alterations that have clinical value by improving accuracy of diagnosis and prognosis. Furthermore, this wealth of genomic information provides the basis for targeted therapies and the subsequent design of biomarker-based clinical trials. This review summarizes the current landscape of clinically relevant molecular alterations in gliomas and describes the role of routine molecular testing in context of treatment planning for standards of care and clinical trials.

BACKGROUND: An optimal radiological surveillance plan is crucial for high-grade glioma (HGG) patients, which is determined arbitrarily in daily clinical practice. We propose the radiological assessment schedule using a parametric model of standardized progression-free survival (PFS) curves. METHODS: A total of 277 HGG patients (178 glioblastoma [GBM] and 99 anaplastic astrocytoma [AA]) from a single institute who completed the standard treatment protocol were enrolled in this cohort study and retrospectively analyzed. The patients were stratified into each layered risk group by genetic signatures and residual mass or through recursive partitioning analysis. PFS curves were estimated using the piecewise exponential survival model. The criterion of a 10% progression rate among the remaining patients at each observation period was used to determine the optimal radiological assessment time point. RESULTS: The optimal follow-up intervals for MRI evaluations of isocitrate dehydrogenase (IDH) wild-type GBM was every 7.4 weeks until 120 weeks after the end of standard treatment, followed by a 22-week inflection period and every 27.6 weeks thereafter. For the IDH mutated GBM, scans every 13.2 weeks until 151 weeks are recommended. The optimal follow-up intervals were every 22.8 weeks for IDH wild-type AA, and 41.2 weeks for IDH mutated AA until 241 weeks. Tailored radiological assessment schedules were suggested for each layered risk group of the GBM and the AA patients. CONCLUSIONS: The optimal schedule of radiological assessments for each layered risk group of patients with HGG could be determined from the parametric model of PFS.

BACKGROUND We evaluated sex-based differences in clinical outcomes and tumor genomics in patients with newly-diagnosed GBM. METHODS We reviewed 665 IDH-wild type GBM patients with Karnofsky Performance Status (KPS) ≥60 treated at our institution from 2010-2019 including; 585 patients with targeted exome sequencing of 447 cancer associated genes (OncoPanel). Deleterious mutations were defined as homozygous deletions or loss of function mutations of known tumor suppressors (as reported in TCGA, ≥ 3 times in the COSMIC database, or predicted as “damaging” in SIFT and/or “probably damaging” in Polyphen 2) or known oncogenic mutations in proto-oncogenes (reported in TCGA or ≥ 3 times in COSMIC). RESULTS There were 384 (57.7%) males and 281 (42.3%) females. Median OS was 22.5 months for females and 19.3 months for males (hazard ratio [HR] 0.81, 95% CI 1.03-1.48, p = 0.02). On multivariable analysis adjusted for age, KPS ≥90, extent of resection, and MGMT methylation status, female sex (adjusted hazard ratio 0.78, 95% CI [0.64-0.95], p = 0.015) was associated with improved OS. Superior OS in females was observed in MGMT-unmethylated patients (HR 0.69, 95% CI [0.54-0.90], p = 0.005) but not MGMT-methylated patients. Thirteen genes were deleteriously altered in ≥5% of our cohort: CDK4 (12.1% male vs. 7.8% female), CDKN2A (46.5% vs. 45.7%), CDKN2B (41.8% vs. 43.3%), EGFR (34.7% vs. 40.0%, MTAP (18.2% vs. 18.8%), NF1 (11.5% vs. 9.4%), PTEN (28.2% vs. 29.8%), TP53 (28.2% vs. 30.2%), RB1 (5.6% vs. 6.5%), MDM4 (6.2% vs. 5.7%), ATM (5.9% vs. 3.7%), MDM2 (7.4% vs. 4.1%), PIK3R1 (6.2% vs. 4.1%). There were no differences in frequency of mutations in these individual genes between males and females (χ 2 [1, N=585] = 0.05-2.86, p = 0.09-0.86). CONCLUSIONS Female sex is associated with improved survival. We did not identify sex-based differences in deleterious genomic alterations amongst commonly altered genes in GBM.

BACKGROUND Glioblastoma (GBM) patients are treated with radiation therapy (RT), temozolomide, and corticosteroids which can affect hematologic and immunologic parameters. We examined lymphocytes, neutrophil-to-lymphocyte ratio and platelet measurements and their association with progression-free survival (PFS) overall survival (OS). METHODS We identified 759 newly diagnosed adult GBM patients treated at our institution in the temozolomide (TMZ) era with blood counts that could be automatically extracted from the electronic medical record during chemoradiation (CRT, defined as within 42 days of RT) and at first recurrence. Linear regression and Cox modeling were used to evaluate outcomes. RESULTS Median age was 60.3 years; 87% had KPS ≥ 70, 37.5% had gross total resection, and 90% received TMZ. Prior to RT, 56.4% (375/665) patients had a lymphocyte measurement < 1.0 × 1000 cells [K]/μL. Within 42 days of CRT, 81.7% (536/656) had a lymphocyte measurement < 1.0 K/μL, 37.8% (248/656) < 0.5 K/μL. 10.7% (58/544) patients developed grade 2 or higher neutropenia, 9.1% (50/547) patients developed grade 2 or higher thrombocytopenia. On multivariable analysis (MVA), older age (AHR1.03, p< 0.001), unmethylated MGMT status (AHR2.56,p< 0.001), lower RT dose ( Older age (AHR1.01, p=0.02), unmethylated MGMT status (AHR2.44, p< 0.001), lower RT dose (AHR1.82, p=0.02), higher NLR during CRT (AHR1.03, p < 0.001) were significantly associated with worse PFS on MVA. At first recurrence, median lymphocyte count was 0.7 K/μL with 74% (348/468) patients < 1.0 K/μL and 27% < 0.5 K/μL. CONCLUSION Lymphopenia and higher neutrophil-to-lymphocyte ratio are associated with inferior outcomes. Persistent lymphopenia at time of first recurrence may have implications for clinical trial eligibility and immunotherapy approaches in recurrent GBM.

BACKGROUND The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in patients with brain tumors and complement radiographic assessment in defining overall outcome. The scale has been incorporated in clinical trials. Early data is suggestive of feasibility and that NANO contributes to overall outcome assessment. However, real-world use of the NANO scale to drive clinical-decision making and the predictive value of the NANO scale to determine overall survival remains unclear in IDH-wt GBM. METHODS We report on an ongoing study using the NANO scale to evaluate neurologic function in patients with IDH-wt GBM, seen at Dana-Farber Cancer Institute (DFCI). Patient demographics, tumor histology and molecular status, treatment history and progression dates are being captured. NANO score, as collected by a built-in scale in our institutional electronic medical record (EMR), functional status (Karnofsky performance status) and corticosteroid dose are collected at prespecified time points (prior to start of therapy, and during each subsequent MRI visit). Changes in the NANO score will be correlated to overall survival. Statistical analyses including descriptive data analysis and generalized linear models will be performed using R (version 3.4.3). RESULTS Since June 2020, 50 patients have been enrolled in this study, including 42 (84%) with ≥2 follow up visits. Study accrual was initially impacted by the COVID-19 pandemic, but adaptation to a virtual platform for NANO allowed for improved recruitment and follow up of patients. Study results will be available for discussion at the 2021 SNO conference. CONCLUSIONS Evaluation of neurologic function by NANO is feasible in a virtual framework in a prospective study in patients with GBM, aided by integration of the scale in our institutional EMR. NANO is able to objectively track neurologic function throughout disease course in IDH-wt GBM.