Supratentorial High-grade Gliomas Research Articles

Management of high grade primary cerebellar tumours.

Cerebellar high-grade gliomas (cHGG) are uncommon in adults, making up only about 1% of all high-grade gliomas. These tumours differ from supratentorial high-grade gliomas (sHGG) in terms of epidemiology, molecular traits, and the age of the patients. cHGG patients are typically younger and show a higher frequency of neurofibromatosis 1 (NF1) mutations, atypical RAS mutations, and H3K27M mutations. Standard treatment includes surgical resection followed by chemotherapy and radiation. Recent studies emphasize the genetic differences between cerebellar and supratentorial tumours, with new treatments targetting specific molecular abnormalities. Immunotherapy has shown limited effectiveness due to the unique tumour environment in cHGG, and further research is required to improve treatment strategies for these rare tumours.

HGG-12. A PHASE IB/II STUDY ON ASIDNA™ IN ASSOCIATION WITH RE-IRRADIATION IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS WITH RELAPSING HIGH-GRADE GLIOMA

Abstract BACKGROUND AsiDNA is a synthetic cholesterol-oligodeoxyribonucleotide conjugate, inducing false DNA damage signaling, which prevents DNA repair in tumor cells. AsiDNA therefore increases the vulnerability of tumor cells to irradiation without increasing toxicity in healthy tissues. Preclinical data showed encouraging results of AsiDNA combined to irradiation in glioma and medulloblastoma models. We aimed to determine the safety and efficacy of AsiDNA, a DNA-repair inhibitor, in children, adolescents and young adults with recurrent High-grade Glioma (HGG) eligible for re-irradiation. METHODS AsiDNA was administered intravenously using a 3 consecutive days loading dose, followed by a weekly dose (350 mg/m2/dose or 600 mg for patients ≥ 50kg) for 11 weeks. Focal radiotherapy, using 1.8 Gy daily fraction, 5 days a week, was administered in combination during the first weeks: 18 Gy for brainstem diffuse midline glioma (DMG) and 36 Gy for supra-tentorial HGG (DMG or non-DMG). The first part of the study aimed to assess the safety and to confirm the recommended phase-II dose based on dose limiting toxicities (DLT) during the first 8 weeks. A second part was planned to assess activity/efficacy of the combination based on the progression-free survival (PFS) rate at 3 months. AsiDNA pharmacodynamics (PD) was studied in peripheral blood mononuclear cells (PMBC). RESULTS Eight (8) patients were enrolled: median age 14 y (6.2-24.5), 5 DMG. No DLT was observed. Median FU was 9.1 months, disease progression was observed in 8 patients; 6 died because of disease progression. Median PFS was 3.9 months. The PD results showed no significant target engagement in PBMCs. CONCLUSIONS Considering the low PFS as well as lack of efficacy on PD markers, the DSMB recommended stopping the study.

Brain and Brain Stem Necrosis After Reirradiation for Recurrent Childhood Primary Central Nervous System Tumors: A PENTEC Comprehensive Review

Reirradiation is increasingly used in children and adolescents/young adults (AYA) with recurrent primary central nervous system tumors. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) reirradiation task force aimed to quantify risks of brain and brain stem necrosis after reirradiation. A systematic literature search using the PubMed and Cochrane databases for peer-reviewed articles from 1975 to 2021 identified 92 studies on reirradiation for recurrent tumors in children/AYA. Seventeen studies representing 449 patients who reported brain and brain stem necrosis after reirradiation contained sufficient data for analysis. While all 17 studies described techniques and doses used for reirradiation, they lacked essential details on clinically significant dose-volume metrics necessary for dose-response modeling on late effects. We, therefore, estimated incidences of necrosis with an exact 95% CI and qualitatively described data. Results from multiple studies were pooled by taking the weighted average of the reported crude rates from individual studies. Treated cancers included ependymoma (n = 279 patients; 7 studies), medulloblastoma (n = 98 patients; 6 studies), any CNS tumors (n = 62 patients; 3 studies), and supratentorial high-grade gliomas (n = 10 patients; 1 study). The median interval between initial and reirradiation was 2.3 years (range, 1.2-4.75 years). The median cumulative prescription dose in equivalent dose in 2-Gy fractions (EQD22; assuming α/β value = 2 Gy) was 103.8 Gy (range, 55.8-141.3 Gy). Among 449 reirradiated children/AYA, 22 (4.9%; 95% CI, 3.1%-7.3%) developed brain necrosis and 14 (3.1%; 95% CI, 1.7%-5.2%) developed brain stem necrosis with a weighted median follow-up of 1.6 years (range, 0.5-7.4 years). The median cumulative prescription EQD22 was 111.4 Gy (range, 55.8-141.3 Gy) for development of any necrosis, 107.7 Gy (range, 55.8-141.3 Gy) for brain necrosis, and 112.1 Gy (range, 100.2-117 Gy) for brain stem necrosis. The median latent period between reirradiation and the development of necrosis was 5.7 months (range, 4.3-24 months). Though there were more events among children/AYA undergoing hypofractionated versus conventionally fractionated reirradiation, the differences were not statistically significant (P = .46). Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD22 of about 112 Gy is associated with an approximate 5% to 7% incidence of brain/brain stem necrosis after a median follow-up of 1.6 years (with the initial course of radiation therapy being given with conventional prescription doses of ≤2 Gy per fraction and the second course with variable fractionations). We recommend a uniform approach for reporting dosimetric endpoints to derive robust predictive models of late toxicities following reirradiation.

MODL-22. DEVELOPMENT OF A PATIENT-DERIVED MODEL BIOBANK TO PROVIDE AN ACCURATE TOOL DECIPHERING BRAIN TUMOR INITIATION, PROGRESSION, AND THERAPEUTIC RESISTANCE

Abstract Brain cancers are the most incident and deadliest tumor types in pediatric and young adult populations. Among them, several histotypes are characterized by their molecular drivers and co-alterations currently guiding our therapeutic strategies. Due to inter- and intra-tumoral heterogeneity, those tumors are becoming rapidly chemo- and radioresistant. To encompass all their intrinsic and extrinsic mechanisms of therapeutic resistances, there is an urgent need to generate accurate brain tumors’ modeling to predict therapeutic responses. Patient-derived cell lines (PDCL) remain for now the most reliable model to estimate and mimic evolutive situation. Main difficulties rely on the derivation methods themselves (2D vs. 3D, in vitro vs. in vivo), but also on the methods to validate their molecular similarities comparatively to the primary tumors. Here we collected, through the PEDIAMODECAN program, 104 fresh brain tumors (e.g., 23 pilocytic astrocytomas (PA), 3 low-grade gliomas (LGG), 13 supra-tentorial high-grade gliomas and 10 DIPG/DMGs, 19 ependymomas, 19 medulloblastomas, 17 other rare entities) to generate PDCL and patient-derived xenografts (PDX). Using Next-Generation Sequencing (NGS), methylome assay and RNA sequencing, we were in capacity to underline similarities with initiated samples. Looking to derivation itself, we successfully maintained 80% samples in 2D cultures and 54% were derived in PDX. As expected, the PA/LGG group shows the higher percentage of failure of PDX generation (90%) and all established PA/LGG PDCLs were limited to a low number of passages. Nevertheless, for high-grade subtypes, PDX generation rate increased to 85,7%. No correlation was observed between derivation success and time between surgical removal and dissociation process. Whereas PDX histology was reproducing the same microscopic features than the primary tumors, methylome assay proves to be a good method to confirm original histotype group. Furthermore, those primary models afford a large biobank reproducing the diversity of pediatric brain tumors and were easily drug screened.

HGG-10. A SAFETY AND EFFICACY STUDY OF NOVOTTF-100A FOR PEDIATRIC HIGH-GRADE GLIOMA: RESULTS OF THE PLANNED INTERIM ANALYSIS OF THE FIRST THREE CASES

Abstract BACKGROUND The safety and efficacy of Tumor-Treating Fields (TTFields) therapy for pediatric diffuse high-grade glioma (HGG) are uncertain. Despite differences between adult GBM and pediatric HGG in terms of genetic etiology, both have certain clinical behaviors in common, allowing TTFields therapy to be tested in pediatric HGG. METHODS The present study [jRCTs032200423] aims to evaluate the safety of NovoTTF-100A in pediatric HGG and conduct an exploratory analysis of its efficacy. The target population is ten children aged 5 to 17 years with newly diagnosed supratentorial HGG or its first-recurrence following frontline therapy. After completion of surgical resection of the tumor and radiation therapy, all the patients will receive TTFields therapy using NovoTTF-100A for 28 days per course for up to 26 courses until the end-of-therapy criteria (including disease progression) are met. The primary endpoint is the adverse event rate with causality. The secondary endpoints include various efficacy parameters and quality of life. In total, the ten patients will be enrolled by September 2023. RESULTS The planned interim analysis, which was done in October 2022, included 3 female patients aged 14, 17, and 9 years, respectively. All had a histological grade 4 tumor, two of which were radiation-induced secondary HGG. Although the first patient with recurrent disease had early progression after enrollment and experienced disease-related adverse events, no serious, treatment-related toxicities or device-related issues were observed. The second patient had a recurrence after six courses, and the third patient remained through the second course. All 3 patients were able to maintain device usage of 75% or more of the time, in alignment with use recommendations, suggesting treatment feasibility. DISCUSSION Based on the results presented above, the study was resumed as the current, multicentric study aimed at obtaining approval for the expanded use of NovoTTF-100A for pediatric HGG.

TREATMENT OUTCOME AND RECURRENCE RATE IN PATIENTS WITH SUPRATENTORIAL HIGH GRADE GLIOMA

Introduction: Glioma is a term used to describe any tumor that arises from the supportive tissue of the brain. This tissue, called glia, helps to keep neurons in place. High grade glioma are WHO grade III and IV tumors. Aims and objective: To estimate the treatment outcome and recurrence rate in patients with supratentorial high grade glioma. Materials and method: This prospective study was carried out at on all the patient with the provisional radiological diagnosis of supratentorial glioma admitted in Department of Neurosurgery, J. A. Group of Hospitals, G. R. Medical College Gwalior, over a period of 24 month (from December 2017 to November 2019). Results: Most common KPS score at admission was 70 (17 of 50 patients) and at discharge was 80 (13 of 50 patients). Recurrence was found only in glioblastoma and grade III astrocytoma. 30% recurrence was found in grade III astrocytoma (6 in 20) and 35.7% in glioblastoma (10 in 28) within 6 month of surgery. Conclusion: Despite multimodality treatment (surgery and adjuvant therapy) prognosis is poor and recurrence is common

56 Using machine learning to predict 30-day readmission and reoperation following resection of supratentorial high-grade gliomas: A national analysis of 9,418 patients.

OBJECTIVES/GOALS: High-grade gliomas (HGG) are among the rarest, most aggressive tumors in neurosurgical practice. We aimed to identify the clinical predictors for 30-day readmission and reoperation following HGGs surgery using the NSQIP database and seek to create web-based applications predicting each outcome. METHODS/STUDY POPULATION: We conducted a retrospective, multicenter cohort analysis of patients who underwent resection of supratentorial HGG between January 1, 2016, and December 31, 2020, using the NSQIP database. Demographics and comorbidities were extracted. The primary outcomes were 30-day unplanned readmission and reoperation. A stratified 80:20 split of the available data was carried out. Supervised machine learning algorithms were trained to predict 30-day outcomes. RESULTS/ANTICIPATED RESULTS: A total of 9,418 patients were included in our cohort. The rate of unplanned readmission within 30 days of surgery was 14.9%.Weight, chronic steroid use, pre-operative BUN, and WBC count were associated with a higher risk of readmission. The rate of early unplanned reoperation was 5.47%. Increased weight, higher operative time, and a longer period between hospital admission and the operation were linked to increased risk of early reoperation. Our Random Forest algorithm showed the highest predictive performance for early readmission (AUC = 0.967), while the XG Boost algorithm showed the highest predictive performance for early reoperation (AUC = 0.985).Web-based tools for both outcomes were deployed: https://glioma-readmission.herokuapp.com/, https://glioma-reoperation.herokuapp.com/. DISCUSSION/SIGNIFICANCE: A high fraction of documented early unplanned readmission and reoperation were considered preventable and related to surgery. Machine learning allows better prediction of resected HGG’s prognosis based on findings from baseline methods leading to more personalized patient care.

Cerebellar High-Grade Glioma: A Translationally Oriented Review of the Literature.

World Health Organization (WHO) grade 4 gliomas of the cerebellum are rare entities whose understanding trails that of their supratentorial counterparts. Like supratentorial high-grade gliomas (sHGG), cerebellar high-grade gliomas (cHGG) preferentially affect males and prognosis is bleak; however, they are more common in a younger population. While current therapy for cerebellar and supratentorial HGG is the same, recent molecular analyses have identified features and subclasses of cerebellar tumors that may merit individualized targeting. One recent series of cHGG included the subclasses of (1) high-grade astrocytoma with piloid features (HGAP, ~31% of tumors); (2) H3K27M diffuse midline glioma (~8%); and (3) isocitrate dehydrogenase (IDH) wildtype glioblastoma (~43%). The latter had an unusually low-frequency of epidermal growth factor receptor (EGFR) and high-frequency of platelet-derived growth factor receptor alpha (PDGFRA) amplification, reflecting a different composition of methylation classes compared to supratentorial IDH-wildtype tumors. These new classifications have begun to reveal insights into the pathogenesis of HGG in the cerebellum and lead toward individualized treatment targeted toward the appropriate subclass of cHGG. Emerging therapeutic strategies include targeting the mitogen-activated protein kinases (MAPK) pathway and PDGFRA, oncolytic virotherapy, and immunotherapy. HGGs of the cerebellum exhibit biological differences compared to sHGG, and improved understanding of their molecular subclasses has the potential to advance treatment.

Effect of intraoperative goal-directed fluid therapy on the postoperative brain edema in patients undergoing high-grade glioma resections: a study protocol of randomized control trial

IntroductionBrain edema is the most frequent postoperative complication after brain tumor resection, especially in patients with high-grade glioma. However, the effect of SVV-based goal-directed fluid therapy (GDFT) on postoperative brain edema and the prognosis remain unclear.Methods and analysisThis is a prospective, randomized, double-blinded, parallel-controlled trial aiming to observe whether stroke volume variation (SVV)-based GDFT could improve the postoperative brain edema in patients undergoing supratentorial high-grade gliomas compared with traditional fluid therapy. The patient will be given 3 ml/kg hydroxyethyl starch solution when the SVV is greater than 15% continuously for more than 5 min intraoperatively. The primary outcome will be postoperative cerebral edema volume on brain CT within 24 h.Ethics and disseminationThis trial has been registered at ClinicalTrials.gov (NCT03323580) and approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University (reference number: KY2017-067-02). The findings will be disseminated in peer-reviewed journals and presented at national or international conferences relevant to the subject fields.Trial registrationClinicalTrials.gov NCT03323580 (First posted: October 27, 2017; Last update posted: February 11, 2022).

Dural arteriovenous fistulas misdiagnosed as intracranial neoplasms: illustrative case.

Dural arteriovenous fistulas (dAVF) may induce imaging findings attributable to various disease entities including malignant neoplasms. In these cases, diagnosis and adequate treatment are often delayed and patients may be exposed to spurious treatments in addition to the risks inherent to an untreated dAVF with cortical venous drainage. The authors report a case of a patient referred for surgical treatment of a supratentorial high-grade glioma. Thorough review of imaging data challenged the initial radiological diagnosis and led to proper angiographic workup. As a result, a high-grade dAVF was confirmed and successfully embolized. In addition to this case, we provide an extensive literature review on dAVF initially diagnosed as cerebral neoplasms, including clinical, imaging and follow-up data. The literature provides diagnostic criteria for dAVF on magnetic resonance imaging; however, those criteria may be only partly applicable in many cases. Misdiagnosis of a neoplasm due to dAVF has been reported but remains rare, especially in supratentorial lesions. Digital subtraction angiography should be pursued to rule out an underlying vascular pathology if any doubt. This may prevent unnecessary interventions such as biopsies, pharmacological treatment and a delay in dAVF treatment, given its associated risk of hemorrhage and nonhemorrhagic neurological deficits.

MODL-28. DEVELOPING A STRATEGY FOR MODELING HIGH-GRADE GLIOMA IN GӦTTINGEN MINIPIGS

Abstract BACKGROUND The current literature does not describe a reproducible large animal model of intracranial high-grade glioma (HGG). Prior work has demonstrated the feasibility of inducing HGG de-novo in rodents by targeting specific oncogenic pathways. Here we report our approach to the production of supratentorial HGG in a series of minipigs through lentiviral gene transfer and subsequent initial characterization of a porcine glioma cell line. METHODS Four minipigs received injections into the subcortical white matter using a combination of lentiviral vectors expressing platelet-derived growth factor beta (PDGF-B), HRAS, and shRNA-p53. Animals underwent behavioral monitoring through porcine neurobehavioral scoring (PNS) and veterinary monitoring. Magnetic resonance imaging (MRI) was conducted at endpoint prior to necropsy. Post-mortem tissue biopsies underwent tissue culture and neuropathologic evaluation with hematoxylin and eosin (H&E) staining, immunohistochemistry, and immunofluorescent staining. Data are presented using appropriate statistical tests where relevant and descriptive statistics. RESULTS Two pigs received 50ul injections and reached endpoint by the end of post-operative week 1 and 2. Two pigs received 25 ul injections and were asymptomatic until a pre-determined endpoint of 4 weeks. MRI scans at endpoint demonstrated contrast enhancing, mass forming lesions at the site of injection with evidence of hemorrhage and perilesional edema, consistent with high-grade glioma. On H&E staining high-grade glioma growth was identified in 100% of animals. We observed immunopositivity for tumor markers GFAP, OLIG2, NG2, SOX2, and PDGFRA, as well as redox markers, and microenvironmental features consistent with high-grade glioma. Porcine glioma cell cultures were found to have significantly greater proliferative rate compared to control, and demonstrated GFAP, OLIG2, PDGFRA, and CD68 immunopositivity. CONCLUSIONS Lentiviral gene transfer represents a feasible strategy for glioma modeling in the Gӧttingen minipig. With our described methodology, we present a realistic strategy for reproducible modeling of intracranial glioma as a platform for preclinical neurosurgical development programs.

Brain and Brainstem Necrosis after Re-Irradiation for Recurrent Childhood Central Nervous System (CNS) Tumors: A Report from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) Task Force

<h3>Purpose/Objective(s)</h3> Re-irradiation is increasingly used in children, adolescents and young adults (AYA) with recurrent CNS tumors. The PENTEC re-irradiation task force reports the results on the risk of symptomatic necrosis following cranial re-irradiation, and its dependence on cumulative dose. <h3>Materials/Methods</h3> A systematic literature search for peer-reviewed articles 1975 to 2021 identified 1183 studies on re-irradiation and 92 studies on re-irradiation for recurrent CNS tumors. Studies on predominantly adult populations and re-irradiation for secondary neoplasms were excluded (n=49). Data from the remaining 43 studies were captured. 17 studies (n=449), reporting brain and brainstem necrosis were used for analysis. While all studies mentioned techniques and range of doses used for re-irradiation, they lacked details on significant dose-volume metrics (e.g., percentage of re-irradiation treatment volume overlapping with primary radiotherapy, mean and maximum cumulative equivalent dose in 2Gy fractions, with alpha-beta ratio=2 (EQD2/2) to organs at risk) necessary for a dose-response modelling. We, therefore, estimated the incidence of necrosis with an exact 95% confidence interval (CI) and provided a qualitative description of the data. <h3>Results</h3> Treated cancers included ependymoma (n=279;7 studies), medulloblastoma (n=98; 6 studies), any CNS tumors (n=62: 3 studies) and supratentorial high-grade gliomas (n=10: 1 study). The median interval between initial and re-irradiation was 2.3 years (range 1.2-4.75). The median cumulative EQD2/2 prescription dose was 103.8 Gy (range 79.7-141.3). Among 449 children/AYA treated with re-irradiation, 22 (4.9%, 95% CI 3.1-7.3%) developed brain necrosis and 14 (3.1%, 95% CI 1.7-5.2%) brainstem necrosis. The median cumulative prescription EQD2/2 was 111.4 Gy (range 79.7-141.3) for development of any necrosis, 107.7 Gy (range 79.7-141.3) for brain necrosis and 112.1 Gy (range 100.2-117) for brainstem necrosis. In 6 studies (n=176) of conventionally fractionated (≤2 Gy per fractions) re-irradiation, 7 patients developed brain necrosis (3.9%) and 4 brainstem necrosis (1.7). In the 5 studies (n=160) of hypofractionated (4-24 Gy per fraction) re-irradiation, 9 patients developed brain necrosis (5.6%) and 10 brainstem necrosis (6.9%). Though there were more necroses in the hypofractionated group, it was not statistically significant (Fisher's exact test 2-tailed p value=0.4664). The remaining six studies (n=113) used a range of fraction size (1.8-24 Gy). No studies reported cumulative dosing for individual organs at risk. <h3>Conclusion</h3> Existing literature suggests that in children and AYA with recurrent brain tumors, re-irradiation results in less than 5-7% incidence of brain/brainstem necrosis with conventional prescription doses after a median follow-up of 2.3 years. A uniform approach for reporting dosimetric endpoints is recommended to derive a robust predictive model of late toxicities following re-irradiation.

Supratentorial high-grade gliomas: maximal safe anatomical resection guided by augmented reality high-definition fiber tractography and fluorescein

The theoretical advantages of augmented reality (AR) with diffusion tensor imaging (DTI)-based high-definition fiber tractography (HDFT) and sodium fluorescein (F) in high-grade glioma (HGG) surgery have not been investigated in detail. In this study, the authors aimed to evaluate the safety and efficacy profiles of HDFT-F microscope-based AR cytoreductive surgery for newly diagnosed supratentorial HGGs. Data of patients with newly diagnosed supratentorial HGGs who underwent surgery using the AR HDFT-F technique were reviewed and compared with those of a cohort of patients who underwent conventional white-light surgery assisted by infrared neuronavigation. The safety and efficacy of the techniques were reported based on the postoperative Neurological Assessment in Neuro-Oncology (NANO) scores, extent of resection (EOR), and Kaplan-Meier curves, respectively. The chi-square test was conducted for categorical variables. A p value < 0.05 was considered statistically significant. A total of 54 patients underwent surgery using the AR HDFT-F technique, and 63 underwent conventional white-light surgery assisted by infrared neuronavigation. The mean postoperative NANO scores were 3.8 ± 2 and 5.2 ± 4 in the AR HDFT-F group and control group, respectively (p < 0.05). The EOR was higher in the AR HDFT-F group (p < 0.05) than in the control group. With a mean follow-up of 12.2 months, the rate of progression-free survival (PFS) was longer in the study group (log-rank test, p = 0.006) than in the control group. Moreover, the complication rates were 9.2% and 9.5% in the study and control groups, respectively. Overall, AR HDFT-F-assisted surgery is safe and effective in maximizing the EOR and PFS rate for patients with newly diagnosed supratentorial HGGs, and in optimizing patient functional outcomes.

Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors

The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18–69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.

IMG-20. RADIOMIC FEATURES IMPROVE PROGNOSTICATION OVER CONVENTIONAL MR DERIVED QUALITATIVE DESCRIPTORS IN PEDIATRIC SUPRATENTORIAL HIGH GRADE GLIOMA: COMPARISON OF MACHINE LEARNING TECHNIQUES

PURPOSE/OBJECTIVESPediatric supratentorial high-grade glioma (stHGG) is a biologically heterogeneous disease defined by unique mutations, natural history and prognosis. Prior work by our group outlined a role for qualitative imaging features in aiding prognostication. We build on that work by evaluating the prognostic utility of radiomic features (RM) when paired with clinical factors. MATERIALS/METHODSNinety-one patients age < 21 years with stHGG treated between 1980–2007 were retrospectively reviewed. Prognostic clinical, qualitative imaging (Visually AcceSAble Rembrandt Images, VASARI), and treatment characteristics were evaluated in concert with manual and automatically segmented (DeepMedic), tumor-derived semi-quantitative radiomic features (Pyradiomics) extracted from MR images. Prognostic RM were limited to stable imaging features which were subsequently selected using bootstrapped least absolute shrinkage and selection operator (LASSO). Nonparametric descriptive statistics and prognostication model evaluation, incorporating RM and clinical variables, were developed using random forest (RF), Cox proportional hazards (CPH), and deep learning (deepsurv) algorithms and assessed for goodness of fit using (c-index).RESULTSA subset (N=80) of 386 intensity, shape, and texture derived RM were stable between pre-treatment MR. 28 RM features were independently predictive of survival when compared to models utilizing combinations of clinical, VASARI and had comparable model fit statistics. CPH, RF and deepsurv showed comparable utility in modelling RM features. Combined modelling of clinical, VASARI and RM features using CPH, RF, and deepsurv resulted in c-indices of 0.68, 0.67, 0.68, respectively.CONCLUSIONRM features are stable and independently prognostic. Combined modelling of clinical, VASARI, and RM features improves prognostication in stHGG.

HGG-44. DEFECTS OF MISMATCH REPAIR PROTEINS IN PEDIATRIC HIGH GRADE GLIOMAS

Hetero- and homozygous germline mutations of the mismatch repair genes MLH1, PMS2, MSH2 and MSH6 cause Lynch and constitutional mismatch repair (CMMRD) cancer predisposition syndrome, respectively. Affected CMMRD individuals are at risk to develop a variety of neoplasms including CNS tumors, particularly high grade gliomas (HGG), during childhood. Currently, few data exist on the prevalence of CMMRD in children with pediatric HGG. We screened a consecutive series of 79 supratentorial HGGs. Tumor tissue was available in 42 patients, 5 were reclassified as non-HGGs. Immunohistochemistry with antibodies against MLH1, PMS2, MSH2 and MSH6 was performed in 37 tumors. Four patients (3 families) with known CMMRD were included. The evaluation of the slides was performed blinded to the CMMRD status. All four patients with known CMMRD (3 patients with PMS2, one with MSH6 mutation) were identified, showing loss of PMS2 and MSH2/MSH6, respectively. Additionally, we identified 6 patients with loss of MSH2/MSH6 staining in tumor cells, but retained staining in preexisting cells, indicating a pattern like in Lynch syndrome. NGS sequencing of these tumor tissues revealed in 2 patients MSH2 mutations and in one patient a hypermutator phenotype with MSH2 and MSH6 mutations. In 3/6 patients no mutations in the MMR genes were detectable. In summary, we found a low prevalence of CMMRD among HGGs, but identified also 2 patients with probable Lynch syndrome. Immunhistochemistry is an effective tool to screen for patients with MMR defects and should be performed in HGGs to optimize treatment and offer affected families genetic counseling.

QOLP-24. PATIENTS’/PARENTS’ EXPERIENCES OF RECEIVING OPTUNE DELIVERED TUMOR TREATMENT FIELDS: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY: PBTC-048

Abstract BACKGROUND Optune-delivered TTFields is a promising anti-mitotic FDA-approved cancer therapy in adult patients with high-grade gliomas (HGG), although effectiveness is not yet proven in pediatric patients. A multicenter trial [NCT03033992] evaluating the feasibility and device-related toxicity for children with recurrent or progressive supratentorial high-grade glioma (HGG) and ependymoma is being conducted. This presentation reports the interim health-related quality of life (HRQOL) and device-use experiences reported by patients and parents. METHODS Participating patients (aged 5–21 years) and one of their parents completed the following measures at baseline and prior to each intervention cycle: PROMIS Fatigue, Anger, Anxiety, Depressive Symptoms, Mobility, Upper Extremity Function, and Peer Relationships and Neuro-QOL Stigma. Participants completed an exit survey when they were off the study regarding their experiences wearing the device. RESULTS This planned interim analysis included 11 patients (7 males/4 females) with supratentorial tumors: ten HGG and one ependymoma. Median age was 14.2 (6.4–21.3) years. Patients reported worse HRQOL than the norms on all domains. Of these 11 patients, 6 completed the exit survey. No significant changes (p&lt; 0.05) between the baseline and the final assessment were found except for Stigma. Patients perceived less stigma at baseline than at the final assessment (t=2.82, p=0.0370). Of these 6 parents who completed the Exit Survey: most considered wearing the device to be easy (n=5).Patient reminders were unnecessary (n=5), patients rarely/didn’t complain (n=4) or refuse (n=5) to wear the device, there was rare/no (n=4) difficulty with daily activities because of the device, and patients were not (n=4) or sometimes (n=2) embarrassed to wear the device. CONCLUSION Preliminary results indicate Optune-delivered TTFields therapy is feasible and accepted by children and parent with no evidence of negatively impacting patients’ QOL. Accrual has been expanded beyond the interim analysis.

101 Re-Irradiation for Children with Recurrent Supratentorial High-Grade Glioma

101 Re-Irradiation for Children with Recurrent Supratentorial High-Grade Glioma

Repeat Irradiation for Children with Supratentorial High-Grade Glioma

Repeat Irradiation for Children with Supratentorial High-Grade Glioma

Tenascin-C expression contributes to pediatric brainstem glioma tumor phenotype and represents a novel biomarker of disease

Diffuse intrinsic pontine glioma (DIPG), an infiltrative, high grade glioma (HGG) affecting young children, has the highest mortality rate of all pediatric cancers. Despite treatment, average survival is less than twelve months, and five-year survival under 5%. We previously detected increased expression of Tenascin-C (TNC) protein in DIPG cerebrospinal fluid and tumor tissue relative to normal specimens. TNC is an extracellular matrix (ECM) glycoprotein that mediates cell-matrix interactions, guides migrating neurons during normal brain development and is thought to maintain the periventricular stem cell niche in the developing brain. Tumor TNC expression is reported in adult glioma and other cancers. However, the pattern and effects of TNC expression in DIPG has not been previously explored. Here, we characterize TNC expression in patient derived pediatric supratentorial HGG (n = 3) and DIPG (n = 6) cell lines, as well as pediatric glioma tumor (n = 50) and normal brain tissue specimens (n = 3). We found tumor specific TNC gene and protein overexpression that directly correlated with higher tumor grade (WHO III and IV, p = 0.05), H3K27 M mutation (p = 0.012), shorter progression free survival (p = 0.034), and poorer overall survival (0.041) in association with these factors. TNC knockdown via lentiviral shRNA transfection of HGG (n = 1) and DIPG (n = 3) cell lines resulted in decreased cell proliferation, migration, and invasion in vitro (p < 0.01), while TNC cDNA transfection resulted in increased cell migration, invasion and proliferation (p < 0.01) as well as altered cell morphology in H3K27 M mutant DIPG lines. Whole transcriptome sequencing analysis (RNA-Seq) on DIPG (n = 3) and HGG (n = 2) cell lines after TNC cDNA, shRNA, and empty vector control transfection revealed the effects of TNC expression level on global gene expression profiles. Together, our findings reveal TNC expression in DIPG in association with H3K27 M mutation and VEGF signaling, and suggest that TNC may contribute to DIPG tumor phenotype, and serve as a clinically detectable biomarker for DIPG.