Primary CNS Tumors Research Articles

An expanded role for surgery in grade 3 1p/19q co-deleted oligodendroglioma.

Grade 3 1p/19q co-deleted oligodendroglioma is an uncommon primary CNS tumor with a high rate of progression and recurrence. This study examines the benefit of surgery after progression and identifies predictors of survival. This is a single-institution retrospective cohort study of consecutive adult patients with anaplastic or grade 3 1p/19q co-deleted oligodendroglioma diagnosed between 2001 and 2020. Eighty patients with 1p/19q co-deleted grade 3 oligodendroglioma were included. The median age was 47 years (interquartile range 38-56) and 38.8% were women. All patients underwent surgery, including gross total resection (GTR) for 26.3% of patients, subtotal resection (STR) for 70.0% of patients, and biopsy for 3.8% of patients. Forty-three cases (53.8%) progressed at a median of 5.6 years, and the median overall survival (OS) was 14.1 years. Among 43 cases of progression or recurrence, 21 (48.8%) underwent another resection. Patients who underwent a second operation had improved OS (P = .041) and survival after progression/recurrence (P = .012), but similar time to subsequent progression as patients who did not have repeat surgery (P = .50). Predictors of mortality at initial diagnosis included a preoperative Karnofsky Performance Status (KPS) under 80 (hazard ratio [HR] 5.4; 95% CI 1.5-19.2), an STR or biopsy rather than GTR (HR 4.1; 95% CI 1.2-14.2), and a persistent postoperative neurologic deficit (HR 4.0; 95% CI 1.2-14.1). Repeat surgery is associated with increased survival, but not time to subsequent progression for progressing or recurrent 1p/19q co-deleted grade 3 oligodendrogliomas recur. Mortality is associated with a preoperative KPS under 80, lack of GTR, and persistent postoperative neurologic deficits after the initial surgery.

Genetic Profile of Primary Brain Tumours and the Degree of Their Resection Versus Survival of Patients Undergoing Surgery and Complementary Oncological Treatment

Introduction. Recently, the incidence of brain glial tumours has increased significantly worldwide. Gliomas are among the most malignant types of tumours of the central nervous system. Patients diagnosed with glial tumours have a very unfavourable prognosis leading to death, and the course of the disease itself has a negative impact on their physical, mental and social condition. Aim. The aim of this study was to determine the effect of the results of histological and genetic tests as well as the degree of resection of primary CNS tumours on the survival of patients undergoing neurosurgery and complementary oncological treatment — pharmacology and radiotherapy. Material and Methods. The research was carried out on the basis of an analysis of medical records (2019–2021) of 63 adult patients from the Department of Neurosurgery of the Specialist Municipal Hospital of Nicolaus Copernicus in Toruń. The study group included patients who had been diagnosed with a primary brain tumour and had undergone neurosurgery and complementary oncological treatment. The analysis of medical documentation consisted in comparing the results of histopathological tests with the results of specialized molecular tests and correlating them with the survival time of patients. The statistical analysis was carried out using the Pearson correlation, statistical inference was made at the significance level of p=0.05. Results. Based on the obtained results, it was found that the presence of MGMT gene promoter methylation (r=0.30, p=0.018) and IDH mutation (r=0.38, p=0.002) correlated positively with survival. The extent of resection also had a significant impact on patient survival (r=0.55, p<0.001). Patients who underwent complete tumour resection survived an average of 19.34 months, while those who underwent biopsy survived for 7.94 months. Conclusions. The data collected during the conducted analyses may be important for the prognosis perspective and the selection of the optimal treatment strategy for both current and future patients. (JNNN 2022;11(4):162–166)

Entrectinib (Rozlytrek)


 CADTH recommends that Rozlytrek be reimbursed by public drug plans for the treatment of adults with unresectable locally advanced or metastatic extracranial solid tumours, including brain metastases, that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation if certain conditions are met.
 Rozlytrek should only be reimbursed to treat patients who have previously failed on all standard treatments for their current tumour site and who will be able to tolerate the treatment.
 Rozlytrek should only be reimbursed as a single-agent therapy and should not be initiated in patients who have primary CNS tumours or those who have received prior treatment with an NTRK inhibitor.

Glioma Stem Cells: Novel Data Obtained by Single-Cell Sequencing.

Glioma is the most common type of primary CNS tumor, composed of cells that resemble normal glial cells. Recent genetic studies have provided insight into the inter-tumoral heterogeneity of gliomas, resulting in the updated 2021 WHO classification of gliomas. Thorough understanding of inter-tumoral heterogeneity has already improved the prognosis and treatment outcomes of some types of gliomas. Currently, the challenge for researchers is to study the intratumoral cell heterogeneity of newly defined glioma subtypes. Cancer stem cells (CSCs) present in gliomas and many other tumors are an example of intratumoral heterogeneity of great importance. In this review, we discuss the modern concept of glioma stem cells and recent single-cell sequencing-driven progress in the research of intratumoral glioma cell heterogeneity. The particular emphasis was placed on the recently revealed variations of the cell composition of the subtypes of the adult-type diffuse gliomas, including astrocytoma, oligodendroglioma and glioblastoma. The novel data explain the inconsistencies in earlier glioma stem cell research and also provide insight into the development of more effective targeted therapy and the cell-based immunotherapy of gliomas. Separate sections are devoted to the description of single-cell sequencing approach and its role in the development of cell-based immunotherapies for glioma.

CTNI-58. IMPROVING TRIAL ACCESS FOR PEOPLE WITH RARE CNS TUMORS: AN NCI-CONNECT PHASE I/II TRIAL OF PLX038 IN TUMORS WITH MYC/MYCN AMPLIFICATIONS INCORPORATING CORRELATIVE STUDIES AND PATIENT REPORTED OUTCOMES

Abstract MYC genes encode transcription factors that regulate expression of genes involved in cell division. Supraphysiologic levels of MYC drive oncogenesis in many human cancers and induce the formation of topoisome complexes, essential to managing the torsional strain that would otherwise oppose transcription and replication. MYC/MYCN amplifications are seen in multiple primary CNS tumors including 30% of relapsed medulloblastomas (MB) and a subtype of ependymoma (EPN) where MYCN amplification defines the tumor. PLX038 is a PEGylated macromolecule containing the topoisomerase I inhibitor SN-38. PEGylations lead to longer half-life, tumor accumulation and decreased toxicity. We hypothesize that PLX038 will be efficacious in primary CNS tumors driven by MYC/MYCN amplifications by targeting the MYC-induced topoisome (Das, S.K. 2022 DOI10.1016/j.molcel.2021.11.016). METHODS Trial in development. Design/Objectives: Phase I (N = 12) – determine the maximum tolerated dose and recommended phase 2 dose of PLX038 in recurrent primary CNS tumors using TITE-BOIN design. Phase II - 3 independent cohorts, N = 30 for each group with interim analysis after 10 each: 2A - MYC-N amplified EPN post resection and radiotherapy (PFS); 2B - Recurrent MYCN amplified EPN or MYC/MYCN amplified MB (disease control rate, DCR); 2C - Other recurrent primary CNS tumors with MYC/MYCN amplifications (DCR). Additional measures: PROs from the Office of Patient-Centered Outcomes Research (OpCORe) web-based early phase trial endpoints; biomarkers of PLX038 distribution and response/resistance in peripheral blood, tumor tissue, hair follicles, and abdominal wall fat pad tissue. CONCLUSIONS NCI-CONNECT’s commitment to innovative designs can mitigate some of the barriers to access experimental therapy for people with rare CNS tumors. This basket trial will enroll participants with unifying molecular features and potential susceptibility to PLX038 despite different histological diagnoses. Furthermore, incorporation of comprehensive PROs will help identify clinical benefit and tolerability while correlative studies in tumor and other tissues will help identify biomarkers of response or resistance.

CNSC-37. ATYPICAL GERMLINE MUTATIONS AND PRIMARY CNS TUMORS: A SINGLE-CENTER CASE SERIES AND LITERATURE REVIEW

Abstract A growing spectrum of germline mutations and their association with primary CNS tumors has been described over the last decade. These germline mutations are implicated in regulation of DNA integrity and repair, telomere maintenance, and cell cycle regulation resulting in aberrant cellular proliferation and immune surveillance evasion. To date, there are no well-defined guidelines for primary CNS tumor surveillance for these patients. Moreover, the exact role of traditional chemotherapy, immunotherapy, and radiation is unclear. We present a single-institution case series of adult patients with primary CNS tumors with atypical germline mutations and literature review. The most common germline mutations encountered involved heterozygous mutations of one of the mismatch repair (MMR) genes (MSH2, PMS2, MLH1). All patients developed high-grade gliomas defined as astrocytoma or glioblastoma WHO grade 4 based on the WHO 2021 classification. Germline mutations involving RAD51C, POT1, IDH1/2, MutyH, NTHL1, PALB2, and CHEK2 were associated with gliomas of variable grades and molecular subtypes. Non-glial tumors, including atypical rhabdoid tumors, medulloblastomas, hemangioblastomas, and meningiomas were found in association with germline SMARCB1, ATM, BRCA1, and CHEK2 mutations respectively. Review of the existing literature and knowledge obtained from our case series suggests several important concepts: (1) there is an increased risk of both glioma and non-glial tumor types in several atypical germline mutations, (2) multiple risk genes or variants of unknown significance likely contribute to primary brain tumor formation, (3) germline MMR mutations associated with high-grade glioma may be MMR gene-specific with potential increased risk of resistance and/or disease progression in the presence of alkylating agents such as temozolomide, (4) several germline mutations may increase risk of secondary tumor development after radiation, and (5) the role of screening for atypical germline mutations and subsequent disease surveillance remain unanswered.

MODL-18. ORGANOTYPIC BRAIN SLICE CULTURES: A COMPREHENSIVE MODEL FOR PRIMARY CNS TUMOR STUDIES

Abstract Inducing an immunosuppressive environment has been one of the most notable subversive tactics employed by aggressive primary brain tumors like Glioblastoma (GBM). It is vital that we garner a better understanding of the cell-cell interactions occurring within the tumor microenvironment (TME) in situ. Current in vitro and in vivo models sorely limit our ability to study the cell-cell interactions within the TME while accounting for its complexity and the spatial orientation of its components. Unfilled, this gap in physiologically relevant models greatly hinders the translation of impactful research findings to successful treatment options for patients diagnosed with GBM and other primary CNS tumors. We have devised a novel organotypic brain slice culture (BSC) model study using tumor-bearing C57BL/6J mice which brings the potential to not only determine the cell-cell interactions within the TME but also investigate the underlined mechanisms which govern them. Obtaining BSCs from tumor-bearing mice at various time points post-implantation also allows for analysis of the trafficking of various immune cells across the blood-brain barrier (BBB). We demonstrated outcomes similar to those seen in vivo following the introduction of parallel conditions, further supporting the physiological relevancy of this model. Thus, organotypic brain slice cultures from tumor-bearing mouse models may serve as a credible and incredibly versatile model for the study of primary CNS tumors which may bridge the gap between in vitro and in vivo studies.

NCMP-03. HEADACHE IN PATIENTS WITH NON-CNS CANCER

Abstract BACKGROUND Almost everybody will experience at least one headache episode and almost 40% of the world-population will be diagnosed with some sort of cancer during their life; nevertheless, their association has scantly been measured. Aim: To identify if headache characteristics and/or accompanying signs were associated with brain metastases (BM) in patients with non-CNS cancer. METHODS Patients with systemic cancer and headache sent for evaluation between June 2012 and June 2018 were included. Hematologic or primary CNS tumors were excluded. Magnetic resonance imaging (MRI) was performed in most; the remaining were followed for at least a year. Logistic regression analyses were used to measure associations. RESULTS From 572 patients with cancer and headache, 216 (38%) were diagnosed with BM. Variables significantly (P < 0.05) associated with BM after multivariable analysis were male gender (OR 1.97), headache starting after cancer diagnosis (OR 21), oppressive type (OR 1.9), presence of vomiting (OR 5.78), not increased by changes in position (OR 2.2), and generalized location (OR 0.34). Having another symptom/sign other than headache was seen in 73% of patients with BM and was significantly associated with a higher risk of BM [OR 6.08 (9%%CI 2.1-17.3)], especially if patients presented with altered mental status (OR 15), visual complaint (OR 15), focal motor weakness (OR 11), seizures (OR 15), ataxia (OR 19), and/or vertigo (OR 3.8). CONCLUSION Headache in patients with cancer should be considered a warning sign, it′s characteristics and accompanying signs should be considered to assess individually the risk of being diagnosed with BM.

BIOS-04. CONTACT: CLINICAL OUTCOME ASSESSMENTS TRENDS IN BRAIN CANCER TRIALS

Abstract BACKGROUND Clinical outcome assessments (COAs) are a key component of patient-centered assessment of net clinical benefit in trials. In neuro-oncology, unique symptoms, treatment-related toxicities, and overall poor prognosis further necessitate a focus on symptom management and quality of life. We conducted a computational survey of trends of COA use in past and ongoing neuro-oncology trials. METHODS Neuro-oncology trials on ClinicalTrials.gov were identified using primary malignant CNS tumor terms. Instrument names from PROQOLID (n= 2695) were used to determine COA use. Regression and interrupted time-series analyses assessed chronological and design-related trends. RESULTS Among 3584 adult neuro-oncology studies, 20% reported using a specific COA instrument: 21% among (n= 3038) interventional and 16% among (n= 524) observational trials. Among interventional studies, most trials used one instrument (91%) as a secondary outcome (81%). 269 unique COAs were reported overall, most frequently patient-reported (72%) and clinician-reported outcomes (44%) indicated for general neoplasms (59%), all conditions (30%), and brain tumors (21%). Most commonly used instruments among treatment-focused trials (n= 523 reporting COAs) included Performance Status (KPS 18%, ECOG 9%), EORTC QLQ-C30 and QLQ-BN20 (9%), and MMSE (7%). Among supportive care studies (n= 47), HADS (13%), FACT-Br (11%), and KPS (11%) were most frequent. COAs use was more likely in phase 3 versus early phase 1 and phase 1 (OR= 0.12 [(95% CI:) 0.02-0.42]; OR= 0.22 [0.09-0.52]) but not versus phase 2 (OR= 0.60 [0.26-1.36]), and was more likely in supportive care trials (versus diagnostics and prevention: OR= 0.10 [0.01-0.65]; OR= 0.05 [0.00-0.79]). The rate of COA use increased linearly over time (1998-2020; β= 1.1 [0.8–1.4]), with no significant changes surrounding individual regulatory events. CONCLUSION A growing proportion of neuro-oncology trials specified COA use, reflecting positive changes toward patient-centered drug evaluation. Further investigation of COA use by phase and trial focus may inform future trial design.

NIMG-85. RADIOMIC FEATURES PREDICTIVE OF RESPONSE IN HGG-TARGETING CAR-T THERAPY

Abstract SIGNIFICANCE Radiomics may improve precision medicine in CAR-T (Chimeric Antigen Receptor T Cell) therapy patient selection. BACKGROUND High-Grade Glioma (HGG) is a heterogenous primary CNS neoplasm with a high recurrence rate and poor outcomes. Many studies are exploring CAR T cells to combat HGG. Radiomic models have shown value in identifying biomarkers predictive of tumor genetics, response, and patient prognosis. In this study, we explore radiomic features derived from four clinical sequences and volumes of edema and enhancing tumor to predict treatment response to the first three doses of CAR-T therapy. METHODS In this IRB-approved phase 1 clinical trial (IRB 13384), patients underwent surgical resection of the tumor and received CAR-T cell therapy. Of the 82 patients accrued, 59 (20 females, median age = 49) completed three cycles of therapy and had 3T field strength MRI scans with minimal imaging artifacts. T1 weighted pre-contrast, T1 weighted post-contrast, T2 weighted, and T2 FLuid Attenuated Inversion Recovery sequences were used to generate 3D and 2D radiomics features. In total 28,541 radiomic features were generated per patient using the images prior to CAR-T administration. Each patient’s response to treatment after three cycles was determined to be either stable disease (29 patients) or progression. The radiomic feature set dimensionality was reduced using Maximum Relevance Minimum Redundancy. 10-fold cross-validation XGBoost was used to determine radiomic features predictive of treatment response with a randomized grid search for hyperparameter tuning. RESULTS Six radiomic features (four shape-based), had high SHapley Additive exPlanations (SHAP)-based importance feature predictive of RANO response with an AUC >0.73. CONCLUSION Despite the limited study size, such imaging-based radiomic models can serve as a potential basis for optimizing clinical trial design through more precise patient screening and providing potential predictive imaging biomarkers of whether a patient will respond to CAR-T cell therapy in HGGs.

SURG-38. ASSESSING THE ROLE OF FRAILTY IN CRANIAL NEUROSURGERY FOR PRIMARY CNS NEOPLASMS IN THE GERIATRIC POPULATION: SEVEN YEAR RETROSPECTIVE ANALYSIS USING THE NATIONWIDE READMISSION DATABASE

Abstract Frailty is a clinical state of increased vulnerability due to age-associated decline and has been well established as a perioperative risk factor. Yet, literature describing the effects of frailty on short- and long-term complications in geriatric patients is limited. In this study, the authors evaluate the effects of frailty in geriatric patients receiving cranial neurosurgery for a primary CNS neoplasm. For this purpose, we conducted a retrospective cohort study between 2010 and 2017 by using the Nationwide Readmission Database. Demographics and frailty were queried at primary admission, and readmissions were analyzed at 30-, 90-, and 180-day intervals. Nearest-neighbor propensity score matching for demographics was implemented to identify nonfrail control patients with similar diagnoses and procedures. The analysis used Welch two-sample t-tests for continuous variables and chi-square test with odds ratios. A total of 6713 frail patients and 6629 nonfrail patients were identified at primary admission. At primary admission, frail geriatric patients undergoing cranial neurosurgery had increased odds of developing acute posthemorrhagic anemia (OR 1.56, 95% CI 1.23-1.98; p = 0.00020); acute infection (OR 3.16, 95% CI 1.70-6.36; p = 0.00022); acute kidney injury (OR 1.32, 95% CI 1.07-1.62; p = 0.0088); urinary tract infection prior to discharge (OR 1.97, 95% CI 1.71-2.29; p < 0.0001); acute postoperative cerebral infarction (OR 1.57, 95% CI 1.17-2.11; p = 0.0026); and mortality (OR 1.64, 95% CI 1.22-2.24; p = 0.0012) compared to nonfrail geriatric patients receiving the same procedure. In addition, frail patients had a significantly increased inpatient length of stay (p < 0.0001) and all-payer hospital cost (p < 0.0001) compared to nonfrail patients at primary admission. Frailty may significantly increase the risks of short-term acute complications in geriatric patients receiving cranial neurosurgery for a primary CNS neoplasm. Long-term analysis revealed no significant difference in complications between frail and nonfrail patients.

RADT-22. RISING UTILIZATION AND REDUCED MEDICARE SPENDING OF SHORT-COURSE RADIATION THERAPY FOR PRIMARY CNS TUMORS IN ELDERLY ADULTS

Abstract INTRODUCTION For elderly/frail glioma patients, shortening radiotherapy from 6 to 3 weeks (short-course RT [SC-RT]) is non-inferior to standard long course (LC-RT) though usage is estimated to be < 20%. We analyzed real-world utilization of SC-RT with/without systemic therapy in Medicare beneficiaries treated with RT for primary CNS tumors using CMS data on radiation episodes. METHODS Radiation modality, year, age (65-74, 75-84, ≥ 85), and site-of-care (freestanding vs hospital-affiliated) were evaluated. Utilization of SC-RT (11-20 fractions) vs LC-RT (21-30 fractions) and systemic therapy was evaluated by multivariable logistic regression. Medicare spending over the 90-day episode was analyzed using multivariable linear regression (adjusted β coefficients reported). RESULTS From 2015-2019, 9,572 episodes were included (2,966 [31%] SC-RT). SC-RT utilization increased (27% in 2015, 34% in 2019; OR 1.2 per year [95%CI:1.1-1.2]) and was associated with older age (age ≥ 85 vs 65-74, OR 7.0 [95%CI:5.7-8.7], hospital-affiliated sites (OR 1.2 [95%CI:1.1-1.4]), conventional RT (vs IMRT OR 2.8 [95%CI 2.4-3.3]), and lack of systemic therapy (OR 1.2 [95%CI:1.1-1.3]; p < 0.001 for all). Rise in SC-RT was concentrated in hospital-affiliated sites (interaction p = 0.005). Most (6,629, 69%) received systemic therapy with no differences by site-of-care (p = 0.34). Systemic therapy utilization increased over time (67% in 2015, 71% in 2019; OR 1.1 per year [95%CI:1.1-1.1]) and was less likely for older patients, conventional RT, and SC-RT (p-value < 0.001 for all). SC-RT significantly reduced spending vs LC-RT (β=$8,416, 95%CI:8,317-8,515), while spending modestly increased with systemic therapy usage (β=$316, 95%CI:220-409). CONCLUSIONS While most Medicare beneficiaries received LC-RT for primary brain tumors, SC-RT utilization increased in hospital-affiliated centers; despite high-level evidence, discrepancy in SC-RT implementation by site-of-care persists and necessitates further investigation. Given RT course length had a greater impact on Medicare spending than systemic therapy, increased use of SC-RT in appropriate populations reflects an opportunity to increase high value care.

INNV-32. COMPARING THE MONTREAL COGNITIVE ASSESSMENT (MOCA) FULL AND 5-MINUTE PROTOCOLS IN MILD COGNITIVE IMPAIRMENT SCREENING OF ADULT CNS TUMOR PATIENTS

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

CTNI-62. LONG-TERM EFFICACY AND SAFETY OF LAROTRECTINIB IN PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS

Abstract BACKGROUND Larotrectinib is a highly selective TRK inhibitor that demonstrated an objective response rate (ORR) of 30% and a 24-week disease control rate (DCR) of 73% across 33 evaluable adult and pediatric patients with TRK fusion primary CNS tumors, as of July 2020 (Doz et al, Neuro Oncol 2021). We report updated data on an expanded dataset. METHODS Patients with TRK fusion primary CNS tumors in two clinical trials (NCT02637687, NCT02576431) were included. Responses were investigator-assessed. RESULTS As of July 2021, 38 patients with TRK fusion primary CNS tumors (median age, 10.8 [range 1.3–79.0] years) were identified: high-grade glioma (HGG; n = 23), low-grade glioma (LGG; n = 9), and other (n = 6). Sixteen (42%) patients had ≥ 2 prior systemic therapies. ORR for 37 evaluable patients was 30% (95% confidence interval [CI] 16–47): three complete responses, eight partial responses, 21 stable disease (16 patients ≥ 24 weeks), and five progressive disease. For pediatric patients (n = 28), the ORR was 39% (95% CI 22–59). For pediatric patients with HGG and LGG, ORRs were 43% (95% CI 18–71) and 38% (95% CI 9–76), respectively. ORRs for patients with 0, 1, 2, and ≥ 3 prior therapies were 33%, 20%, 38%, and 38%, respectively. Median time to response was 1.9 months. The 24-week DCR was 73% (95% CI 56–86). Median duration of response (DoR) was not reached; 12-month DoR rate was 64%. Median progression-free survival was 16.5 months (95% CI 6.7–not estimable). Median overall survival (OS) was not reached; 24-month OS rate was 65%. Treatment duration ranged from 0.1+ to 38.7+ months. Treatment-related adverse events (TRAEs) were mostly Grade 1–2. No patients discontinued treatment due to TRAEs. CONCLUSION Larotrectinib demonstrated a high DCR, rapid and durable responses, and a manageable safety profile in patients with TRK fusion primary CNS tumors.

TMET-34. RADIATION METABOLOMICS IN PRIMARY HUMAN MENINGIOMA AND SCHWANNOMA: EARLY EXPERIENCE AND INITIAL RESULTS

Abstract Introduction Meningiomas and schwannomas account for 45% of primary CNS tumors. Yet when surgery and radiation fail, no further treatments exist. Metabolomics has been used to discover new cancer therapies; however, to date few have used metabolomics to study meningiomas and schwannomas. Here we present initial results and lessons learned from this novel endeavor. METHODS Primary tumors were obtained from patients during surgery and immediately taken for culturing or xenograft implantation. Upon reaching >90% confluence, cultures were treated with 0gy, 3gy, 10gy, or 20gy gamma radiation, then flash frozen 6 or 72 hours post-treatment. Xenograft tumors were implanted in nude mice. MRI 4 weeks post-implantation confirmed tumor viability. Mice were then given 10gy, 20gy, or sham radiation treatment. Xenografts were harvested 72 hours post-treatment. Metabolites were measured with a ThermoISQ gas chromatography-mass spectrometer. RESULTS Eleven meningiomas and nine schwannomas were successfully cultured. Unsupervised hierarchical clustering of cultures demonstrated greater influence from tumor of origin than from radiation. Univariate analysis of schwannoma xenografts demonstrated elevated ornithine following radiation (fold change 1.62; P = 0.008). However, principal component analysis did not show significant between-group differentiation. Orthotopic meningioma xenografts did not produce sufficient tissue for metabolomics; however, subsequent subcutaneous implants have been successful (data forthcoming). CONCLUSION Standard cell cultures did not reveal significant metabolic changes following radiation; it is unclear whether this was due to culture technique or inter-tumor heterogeneity. In radiated schwannoma xenografts, elevated ornithine may implicate related pathways such as ornithine decarboxylase-mediated polyamide synthesis for DNA double-strand break repair. Compared to other ‘-omics’ studies, metabolomics requires more tissue per sample ( >10mg) and is more sensitive to environmental conditions. Thus, large sample sizes are needed to detect significant changes, and xenografts are likely superior to cell culture. Future plans include increased xenograft sample size and stable isotope tracing for pathway analysis.

INNV-26. EMERGENCE OF VIRTUAL TUMOR BOARD [VTB] IN NEURO-ONCOLOGY: OPPORTUNITIES AND CHALLENGES

Abstract INTRODUCTION Virtual tumor board [VTB] platforms are an important aspect of cancer management. They enable easier access to a multidisciplinary team of experts. In order to deliver high-quality cancer care, it is necessary to coordinate numerous therapies and providers, and maintain open lines of communication among all professionals involved. Design/ METHODS We performed a systematic search of all VTBs incorporating a platform designed for this specific role. We reviewed the records of Genomet, Medical University of South Carolina[MUSC] and Xcures virtual tumor boards. Summary data examined include year of launch, demographics, characteristics of cases, average response time, advantages, and how they handle protected health information. RESULTS 30% of VTBs examined launched in 2017. All had a HIPAA compliant online environment. Xcures records reveals median age of female patients was 57yrs and the median age of male patients was 55 years. The data showed that 44% with a confirmed treatment preferred VTB integrated option. 76% of patients in Xcures registry consist of primary CNS tumors. There are at least 556 patients in the tumor registry which included 46% Glioblastoma cases [96% primary, 4% secondary]. MUSC VTB shows 112 thoracic tumor cases and 9 neuro-Oncology cases. Genomet VTB data shows age range from 6 months to 84 years [mean age 44.5 years] with 69.6% males and 30.4% females, 43.5% glioblastoma, 8.7% adenocarcinoma, 8.7% infratentorial tumor. Average response time observed in all cases was ≤ 24 hours. CONCLUSION VTBs allow for quicker expert analysis of cases. More studies are needed to gain additional insight into user engagement metrics.

Malignant Dural Solitary Fibrous Tumor; An Exceedingly Rare Entity

Abstract Introduction/Objective A solitary fibrous tumor (SFT) is an extremely rare mesenchymal neoplasm, accounting for <1% of all primary CNS tumors. Most SFT is dural-based and occurs predominantly in the fourth to sixth decade of life. Here, we present a case of a dural solitary fibrous tumor. Methods/Case Report A 28-year-old male presented with intermittent throbbing headache, nausea, and vomiting. Imaging revealed a large, well-circumscribed left parafalcine, dural-based multilobulated, solid, and cystic mass. The patient underwent craniotomy with mass resection. Preliminary intraoperative findings were of a spindle cell neoplasm. Histopathologic examination showed hypercellular neoplasm composed of the spindle to ovoid cells with a high nuclear to cytoplasmic ratio and limited intervening stroma arranged in a haphazard pattern with prominent branching staghorn vasculature. Focal areas of necrosis and mitotic counts of 8/10 high power field were also seen. The lesional cells showed focal cytoplasmic CD34 expression and strong STAT6 nuclear expression. Finally, a diagnosis of SFT, haemangiopericytoma phenotype classified as grade 3, was made. Results (if a Case Study enter NA) NA Conclusion Most SFTs are considered clinically benign (grade 1 tumors) with favorable outcomes after complete resection. However, haemangiopericytoma phenotype with hypercellularity, necrosis, and elevated mitotic count (> 4/10 HPF) is known to have an increased risk of local recurrence and rare metastasis, requiring patients to receive adjuvant radiotherapy after resection for longer progression-free survival. Therefore, it is vital to be aware of this entity for optimal management and more active systemic surveillance in patients with high-grade SFT tumors. Our patient is currently doing well post-adjuvant radiotherapy and is under active annual surveillance.

Identification of the miR-423-3p/VLDLR Regulatory Network for Glioma Using Transcriptome Analysis.

As the most prevalent primary CNS tumor, glioma is characterized by high mortality and morbidity. This research aims to investigate glioma-associated microRNAs (miRNAs) and their target mRNAs, as well as to explore their biological functions in gliomas. The Gene Expression Omnibus (GEO) database was applied to acquire the GSE112264 miRNA microarray dataset and the GSE15824 mRNA dataset. We selected samples from the GSE112264 dataset and the GSE15824 to identify differently expressed miRNAs (DE-miRNAs) as well as differentially expressed mRNAs (DEGs), respectively. Next, the intersections of mRNA and target mRNAs of miRNA were selected, and we constructed miRNA-mRNA regulation networks. These DEGs were selected for Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses by conducting the package clusterProfiler. After conducting Cytoscape software, a protein-protein interaction (PPI) network was created. Next, survival analysis of the miR-423-3p was confirmed by conducting TCGA database. Subsequently, Quantitative real-time PCR (qRT-PCR) was conducted to verify miR-423-3p's expression. Finally, miR-423-3p's biological functions of in effecting the cell proliferative, migratory, and invasive capabilities of glioma were investigated by performing Cell Counting Kit-8 (CCK-8) and Transwell assays. Our analysis elucidated a novel miRNA-mRNA regulatory network related to glioma carcinogenesis, which may be considered as future therapeutic biomarkers for glioma.

Risk of Secondary Malignant Neoplasms in Children Following Proton Therapy vs. Photon Therapy for Primary CNS Tumors

<h3>Purpose/Objective(s)</h3> Central nervous system tumors are the second most common primary neoplasms seen in children and radiation therapy is a key component in management of most of these tumors. Secondary malignant neoplasms (SMNs) are rare but dreaded complications, particularly in the pediatric population. Proton beam therapy (PBT) can potentially minimize the risk of SMNs compared to conventional photon radiation therapy (RT). Multiple recent studies with mature data have reported the risk of SMNs after PBT. We performed this systematic review and meta-analysis to characterize and compare the incidence of SMNs after proton and photon-based radiation for pediatric CNS tumors. <h3>Materials/Methods</h3> A systematic search of literature on electronic (PubMed, Cochrane Central, and Embase) databases was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. We included studies reporting incidence and nature of SMNs in pediatric patients with primary CNS tumors. The crude incidence of SMNs and all secondary neoplasms were separately extracted, the random-effects model was used for pooled analysis and subgroup comparison was performed between studies using photons vs protons. <h3>Results</h3> Twenty-four studies (21 with conventional RT and 4 with PBT) were included for meta-analysis after performing the systematic review. A total of 418 SMNs and 645 any secondary neoplasms were seen in 38163 patients overall. The most common secondary neoplasms seen were gliomas (40.6%) followed by meningiomas (38.7%), sarcomas (4.8%), thyroid cancers (4.2%), and basal cell carcinomas (1.3%). The overall median follow-up was 8.8 years (range: 3.3 to 23.2 years), while the median latency to a secondary cancer was 9.8 years (range: 5 to 23 years). The median latency to a secondary cancer for photons and protons was 11.9 years (range: 5 to 23 years) and 5.9 years (range: 5 to 6.7 years), respectively. The pooled incidence of SMNs was 1.8% (95% CI: 1.1% – 2.6%, I²=94%) with photons and 1.5% (95% CI: 0 - 4.5%, I²=81%) with protons. There was no significant difference among the two subgroups (p = 0.91). Similarly, the pooled incidence of all secondary neoplasms was not different among the two subgroups [photons: 3.6% (95% CI: 2.5% – 4.8%, I²=96%) vs protons: 1.5% (95% CI: 0 – 4.5%, I²=80%); p = 0.21]. <h3>Conclusion</h3> We observed a slightly lower rate of SMN with PBT at 1.5% compared to 1.8% with photon-based RT for pediatric CNS tumors, although the difference was not statistically significant. We observed a shorter latency to secondary cancers with proton therapy compared to photon-based radiation, which may be related to secondary neutron exposure. With increasing use of techniques that decrease the irradiated tissue volume outside the clinical target volume, like pencil beam scanning proton therapy and VMAT, further studies with longer follow-up are warranted to evaluate the risk of secondary cancers in patients treated with these newer modalities.

Radiosurgery for Primary and Metastatic CNS Malignancies in the Pediatric Population

<h3>Purpose/Objective(s)</h3> Safety and efficacy of stereotactic radiosurgery (SRS) are not well described for pediatric patients. This study presents disease control and toxicity outcomes after SRS for malignant CNS lesions in pediatric patients. <h3>Materials/Methods</h3> Retrospective chart review was performed for 31 pediatric patients treated at a single institution with a non-invasive stereotactic radiosurgery instrument for primary or metastatic CNS malignancies between 2000-2020. Analyses were performed with descriptive statistics, Kaplan-Meier, and proportional hazards modeling. <h3>Results</h3> Twenty-five patients were treated with SRS for focal recurrences of primary CNS malignancies, 1 patient was treated in the early adjuvant setting after initial resection, and 5 patients were treated for brain metastases. Primary CNS histologies included ependymoma (n=14), glioma (n=4), medulloblastoma (n=2), and meningioma (n=2). 65% were WHO grade 3 or 4 at the time of diagnosis. Brain metastases were from non-germinomatous germ cell tumors (n=3), papillary thyroid cancer (n=1), and neuroblastoma (n=1). 71% of patients had prior involved-field external beam radiation to the brain (median dose 59.4 Gy in 33 fractions). Median age at SRS was 14 years (range 4-21). SRS was predominantly performed in a single fraction (median dose 17 Gy, range 15-20) to a total of 42 targets among 29 patients, with a median total gross target volume (GTV) of 1.3 cc. Two patients underwent fractionated radiosurgery to 30 Gy in 5 fractions for larger brain metastases (GTVs 8.5 cc & 23.2 cc). Median follow up after SRS was 44 months (interquartile range 20-72). The 3-year actuarial rates of local control, intracranial progression-free survival, and overall survival after SRS were 77.6%, 33.3%, and 74.6%, respectively. 9 patients (29%) had no evidence of intracranial disease after SRS at a median follow up of 39 months. 6 patients (19%) developed local recurrence at a median of 13 months after SRS. 16 patients (52%) developed distant brain recurrence without local failure at a median of 9 months after SRS. Among primary CNS tumors, there was no significant association of histology, grade, or dose with disease control outcomes on univariate analysis. All patients with subsequent CNS recurrence after SRS underwent salvage therapy, including additional radiosurgery (36%), systemic therapy (23%), resection (9%), or combined modality treatment (32%). In total, 4 patients developed CTCAE grade 2-3 toxicity from SRS, all of which were related to radiation treatment effect and occurred within 1 year of SRS. 2 patients received steroids alone, and 2 underwent invasive procedures (1 shunt revision, 1 resection of nonviable tumor). <h3>Conclusion</h3> SRS for malignant CNS lesions in the pediatric population provides effective local control and is generally well-tolerated. Although there remains a substantial risk of distant CNS failures, all patients were able to receive additional salvage therapy after SRS.