Anaplastic Oligodendroglioma Research Articles

Large tumour volume reduction of IDH-mutated anaplastic glioma involving the insular region\xa0following radiotherapy

BackgroundThe impact of near-total resection of IDH-mutated anaplastic glioma (IDHmutAG) is well-established but there remains uncertainty of benefit in tumours of the insular cortex where the extent of safe resection may be limited. This study aimed to assess tumour volume reduction in patients following IMRT and impact of residual post-surgical volume.Methods and materialsPatients with IDHmutAG involving insular cortex managed with IMRT from 2008 to 2019 had baseline patient, tumour and treatment factors recorded. Volumetric assessment of residual disease on MRI was performed at baseline, month+ 3 and month+ 12 post-IMRT. Potential prognostic factors were analysed for tumour reduction and relapse-free survival, and assessed by log-rank and Cox regression analyses.ResultsThirty two patients with IDHmutAG of the insular cortex were managed with median follow-up post-IMRT of 67.2 months. Pathology was anaplastic astrocytoma (AAmut) in 20, and anaplastic oligodendroglioma (AOD) in 12 patients. Median pre-IMRT volume on T1 and T2Flair was 24.3cm3 and 52.2cm3. Twenty-seven patients were alive with 5-year relapse-free survival of 80%. There was a median 67 and 64% reduction from baseline occurring at 3 months post-IMRT for T1 and T2Flair respectively; and subsequent median 78 and 73% at 12 months. At 12 months AOD patients had median 83% T1 volume reduction compared to 63% in AAmut (p < 0.01). There was no difference on T2Flair volume (p = 0.64). No other pathological factors influenced volume reduction at 12 months. No factors were associated with relapse-free survival including baseline T1 (p = 0.52) and T2Flair (p = 0.93) volume.ConclusionIMRT provides large tumour volume reduction in IDHmutAG of the insular cortex. While maximal safe debulking remains standard of care when feasible, this patient cohort reported no significant negative impact of residual disease volume on relapse-free survival.

A patient with two gliomas with independent oligodendroglioma and glioblastoma biology proved by DNA-methylation profiling: a case report and review of the literature

Here, we report on a patient presenting with two histopathologically distinct gliomas. At the age of 42, the patient underwent initial resection of a right temporal oligodendroglioma IDH mutated 1p/19q co-deleted WHO Grade II followed by adjuvant radiochemotherapy with temozolomide. 15 months after initial diagnosis, the patient showed right hemispheric tumor progression and an additional new left frontal contrast enhancement in the subsequent imaging. A re-resection of the right-sided tumor and resection of the left frontal tumor were conducted. Neuropathological work-up showed recurrence of the right-sided oligodendroglioma with features of an anaplastic oligodendroglioma WHO Grade III, but a glioblastoma WHO grade IV for the left frontal lesion. In depth molecular profiling revealed two independent brain tumors with distinct molecular profiles of anaplastic oligodendroglioma IDH mutated 1p/19q co-deleted WHO Grade III and glioblastoma IDH wildtype WHO grade IV. This unique and rare case of a patient with two independent brain tumors revealed by in-depth molecular work-up and epigenomic profiling emphasizes the importance of integrated work-up of brain tumors including methylome profiling for advanced patient care.

Analysis of the prognosis of high-grade gliomas in the view of new immunohistochemistry markers and 2016 who classification

To evaluate isocitrate dehydrogenase (IDH) mutation status and Ki67 percentages of tumors that were treated in our institution to determine whether these markers affected the initial diagnosis and survival rates. High-grade glioma patients, who were operated in our department between 2013 and 2018, were enrolled in the study and retrospectively reviewed. New immunohistochemistry staining studies were conducted and survival analyses were performed. Of 135 patients and 136 tumors, 117 were glioblastoma multiforme (GBM), 8 were grade III-IV glioma, 4 were anaplastic astrocytoma and 7 were anaplastic oligodendroglioma. One patient had two different lesions, which were GBM and anaplastic astrocytoma respectively. Mean age was 55 (7-85) years, and 88 (65%) were male and 47 (35%) were female. The most common complaint was motor deficit (56%). Fourteen patients underwent reoperation due to recurrent disease. Tumors were most commonly found in the frontal lobe (53, 39%). Magnetic resonance imaging (MRI) features showed that existence of necrosis is strongly related to GBM (p < 0.01). Approximately 126 patients were found to be IDH-wildtype, which changed 6 patients? diagnosis to GBM, IDH wildtype from grade III-IV glioma. Five patients, who were diagnosed with anaplastic astrocytoma and anaplastic oligodendroglioma initially were found to be IDH wildtype. IDH mutation status, extend of resection, and age were found to affect survival. IDH mutation status is important in classifying high-grade gliomas, as well as its effects on prognosis. This mutation is related to several radiological features of tumors. Extent of resection and patient age are also profoundly affect survival. Detailing the diagnosis with molecular features will help physicians to shape targeted adjuvant therapies, which would better outcomes.

Prognostic value of O 6-methylguanine-DNA methyltransferase methylation in isocitrate dehydrogenase mutant gliomas.

BackgroundPatients with isocitrate dehydrogenase (IDH) mutant gliomas have been associated with longer survival time than those that are IDH wild-type. Previous studies have shown the prognostic value of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for glioblastoma multiforme (GBM), which are predominantly IDH wild-type. Little is known of the prognostic value of MGMT methylation status for IDH mutant gliomas.MethodsWe retrospectively identified IDH mutant gliomas patients between 2011 and 2020 that were tested for MGMT promoter methylation. We generated Kaplan–Meier estimator curves and performed Cox proportional hazard models for overall survival (OS) and progression-free survival (PFS) to compare the outcomes of MGMT promoter methylated versus MGMT unmethylated patients.ResultsOf 419 IDH mutant gliomas with MGMT promoter methylation testing, we identified 54 GBMs, 223 astrocytomas, and 142 oligodendrogliomas. 62.3% patients had MGMT methylated tumors while 37.7% were MGMT unmethylated. On Kaplan–Meier analysis, median OS for all MGMT methylated patients was 17.7 years and 14.6 years for unmethylated patients. Median PFS for all MGMT methylated patients was 7.0 years and for unmethylated patients 5.2 years. After univariate subgroup analysis, MGMT methylation is only prognostic for OS and PFS in GBM, and for OS in anaplastic oligodendroglioma and anaplastic oligodendroglioma for OS. In multivariate analysis, MGMT unmethylated GBM patients carry a higher risk of death (HR 7.72, 95% CI 2.10–28.33) and recurrence (HR 3.85, 95% CI 1.35–10.96).Conclusions MGMT promoter methylation is associated with better OS and PFS for IDH mutant GBM. MGMT promoter methylation testing for other IDH mutant glioma subtypes may not provide additional information on prognostication.

Malignant glioma subset from actuate 1801: Phase I/II study of 9-ING-41, GSK-3β inhibitor, monotherapy or combined with chemotherapy for refractory malignancies.

BackgroundGSK3β serine/threonine kinase regulates metabolism and glycogen biosynthesis. GSK3β overexpression promotes progression and resistance through NF-κB and p53 apoptotic pathways. GSK3β inhibits immunomodulation by downregulating PD-L1 and LAG-3 checkpoints and increasing NK and T-cell tumor killing. 9-ING-41, a small-molecule, selective GSK3β inhibitor, showed preclinical activity in chemo-resistant PDX glioblastoma models, including enhanced lomustine antitumor effect.MethodsRefractory malignancies (n = 162) were treated with 9-ING-41 monotherapy (n = 65) or combined with 8 cytotoxic regimens after prior exposure (NCT03678883). Recurrent gliomas (n = 18) were treated with 9-ING-41 IV TIW q21day cycles at 3.3, 5, 9.3, 15 mg/kg, as monotherapy or combined with lomustine 30 mg/m² PO weekly q84day cycles. Primary objective was safety.ResultsRP2D of 15 mg/kg IV TIW was confirmed across all 9 regimens, no accentuated chemotherapy toxicity noted. Glioma subtypes included: 13 glioblastoma, 2 anaplastic astrocytomas, 1 anaplastic oligodendroglioma, 1 astrocytoma. Median age 52 (30–69) years; 6 female, 12 male; median ECOG 1 (0–2); median recurrences 3 (1–6). All received upfront radiation/temozolomide (18/18), plus salvage nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), or immunotherapy (4/18). IDH/mutation(3/18); 1p19q/codeletion(1/18); MGMT/methylated(1/18). Four received 9-ING-41 monotherapy, 14 concurrent with lomustine. No severe toxicities were attributed to 9-ING-41, only mild vision changes (9/18, 50%), or infusion reactions (4/18, 22%). Lomustine-related toxicities: G3/4 thrombocytopenia (3/14, 21%), G1/2 fatigue (4/14, 28%). Median days on therapy was 55 (4–305); 1 partial response (>50%) was noted. Median OS was 5.5 (95% CI: 2.8–11.4) months and PFS-6 was 16.7%.Conclusion9-ING-41 plus/minus lomustine is safe and warrants further study in glioma patients.

ACT-8 Current status and prospects for the treatment of malignant glioma using cancer gene panel tests

Introduction: The cancer gene panel test was covered by insurance in June 2019. Our institution started the test in May 2020 and has experienced 10 cases, so we will report on the current status and future prospects. Methods: The subjects were 10 patients who underwent the cancer gene panel test using FoundationOne CDx. Results:The cases included 8 glioblastomas, an anaplastic astrocytoma, and an anaplastic oligodendroglioma. The total number of tumor mutational burden (TMB) was judged to be low in all cases, and the microsatellite instability test (MSI) showed no instability in all cases (MSI-Stable). The total number of genetic changes detected was 11 ± 5.0, oncogene mutations were 5.3 ± 2.4, and gene mutations of unknown relevance to cancer were 5.7 ± 2.8. Major oncogene mutations were IDH1 mutation in 4 cases, ATRX mutation in 2 cases, TP53 mutation in 6 cases, and BRAF V600E mutation in 1 case. Based on the test results, a 25-year-old man with BRAF V600E mutation was initiated into the NCCH1901 study (Patient-Proposed Healthcare Services). A case with IDH1 mutation (47-year-old male) entered a phase I clinical trial of a mutant IDH1 inhibitor. It is estimated that the chance of finding an appropriate drug by cancer gene panel test is about 10–20%. However, in cases that are resistant to standard treatment, the benefits can be expected if the drugs associated with the cancer gene panel test can be used. Conclusions: Although Malignant gliomas are often TMB-low and MSI-stable and the response rate to molecular-targeted drugs and other therapies is not high, there are some cases that can be salvaged by performing the cancer gene panel test. It is suggested that the active use of cancer gene panel test may contribute to the development of new drugs with high response rates and the improvement of prognosis.

STMO-17 Treatment outcome of photodynamic therapy using talaporfin sodium for recurrent high-grade glioma

Objective: Photodynamic therapy (PDT) using Talaporfin Sodium (TS) is a novel therapeutic strategy to improve local tumor control in high-grade glioma. TS is a photosensitizer that accumulates in tumor cells and produces highly toxic free radicals by intraoperative irradiation of laser with a 664nm wavelength. However, little is known about the treatment outcomes of PDT in recurrent high-grade gliomas (rHGG). In this study, we investigated the treatment outcome of PDT in rHGG and evaluated the correlation between intratumoral TS accumulation and outcomes. Methods: We included 21 patients with rHGG and 22 tumors, who were treated by PDT between June 2016 and March 2021. TS was transvenously administered 22–26 hours before PDT. Intratumoral TS concentrations were measured by liquid chromatography using frozen tissue. Results: The rHGGs included 10 glioblastoma, IDH1/2-wildtype (GBM, IDH1/2-WT: 45.5%), 3 GBM, IDH1/2-mutant (GBM, IDH1/2-Mut: 13.6%), 7 anaplastic oligodendroglioma, IDH1/2-Mut/codel (AO, IDH1/2-Mut/codel: 31.8%), 1 anaplastic astrocytoma, IDH1/2-WT (AA, IDH1/2-WT: 4.5%), 1 high-grade astrocytoma, IDH1/2-WT (4.5%). The median local progression free survival (PFS) time after PDT was 3.6 months and the median survival time from PDT was 19.4 months. The intratumoral TS concentrations of 7 tumors (TS(-): 31.8%) were below the limit of quantification, and the intratumoral TS concentrations of the remaining 15 tumors (TS(+)) were 43.5 ng/mg-protein (14.7–132 ng/mg-protein). The intratumoral TS concentrations were not significantly associated with IDH1/2 mutation status, cellularity, tumor grade, and pattern of enhancement. The median PFS from PDT tended to be longer in TS(+) than in TS(-) (TS(+): 6.3 vs TS(-): 1.4 months, p = 0.054). Conclusions: We found that the intratumoral TS concentrations were heterogeneous and 31.8% were below the limit of quantification. TS(+) tended to have better local tumor control than TS(-), suggesting the intratumoral TS accumulation have an impact of treatment outcomes of PDT.

NI-10 Reclassification of diffuse gliomas based on molecular diagnosis -evaluation of methionine uptake and treatment outcome-

Object: The revised 2016 WHO Classification of Tumours of the Central Nervous System incorporates genetic alterations into the classification system, with the goal of creating more homogenous disease categories with greater prognostic value. In this study, we reclassified diffuse gliomas with molecular diagnosis and examined for 11C-methionine uptake and prognosis. Methods. 182 diffuse glioma patients (Grade II in 42 patients, Grade III in 61 patients, Grade IV in 77 patients) treated at Tokyo Medical and Dental University Hospital from 2000 to 2018 were included in this study. The IDH1/2, ATRX and 1p19q status were analyzed using tumor samples. The tumor-to-normal ratio (T/N) of 11 C-methionine uptake was calculated by dividing the mean standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. Result. By molecular diagnosis, 11 diffuse astrocytomas and 17 anaplastic astrocytomas were diagnosed as “IDH-mutant”, while 14 diffuse astrocytomas and 29 anaplastic astrocytomas were diagnosed as “IDH-wild”. 5 out of 77 grade IV tumors had IDH mutation. 4 tumors were diagnosed as “Diffuse midline glioma, H3 K27M-mutant”. In the 32 oligodendroglial tumors, 12 oligodendrogliomas and 9 anaplastic oligodendrogliomas were diagnosed as “IDH-mutant and 1p/19q-codeleted”. The median T/N ratios in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” were significantly higher than those in astrocytic tumors with “IDH-mutant”. On the other hand, in tumors with the same genetic background, higher grade tumor has significant higher T/N ratio. Kaplan-Meier survival analysis revealed that oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” had significantly better outcomes regardless of WHO grade. Overall survival was 90.9% at 5 years and 77.9% at 10 years in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted”. IDH wild tumors had significantly worse outcomes.Conclusions. The results indicated that diffuse glioma categories reclassified with molecular classification correlate with the T/N ratio of methionine and the prognosis.

PEDT-1 Integrated diagnoses of pediatric gliomas in our institute by cIMPACT-NOW recommendations

Purpose:Since many genetic abnormalities in glioma have been revealed in recent years, Integrated diagnoses are necessary in the updated fourth edition of the WHO Classification of Tumors of the Central Nervous System(CNS) published in 2016. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) was established to provide a forum to evaluate and recommend proposed changes to future CNS tumor classification. We retrospectively classified pediatric gliomas in our hospital in accordance with cIMPACT-NOW recommendations. Methods: This study includes 13 consecutive glioma patients under the age of 18 who underwent surgical resection at our hospital from 2000 to 2021. Histopathological diagnoses and molecular status such as IDH, H3F3A and BRAF were analyzed. Results: There were four females and nine males, ranging in age from 0 to 17 years, median 9.0 years. Three pilocytic astrocytomas (PA) and a polymorphous low-grade neuroepithelial tumor of the young (PLNTY) had BRAF fusion. Four cases were classified as Diffuse midline glioma, H3K27M-altered. Two cases were classified as Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype. No genetic alteration was observed in two diffuse astrocytoma cases. An anaplastic oligodendroglioma case with PDGFRA amplification could not be classified as any new entity. All three PA cases with BRAF fusion occurred in cerebellum and all four H3K27M altered cases occurred in midline location such as thalamus, brainstem and cervical spinal cord. Six cases which were classified as pediatric-type diffuse high grade gliomas had poor prognosis. Conclusion:Genetic status is associated to tumor location and patients prognosis. Integrated diagnoses are important in pediatric glioma patients.

TB-9 An attempt to establish a patient-derived brain tumor culture model by organoid culture method

Background: Molecular heterogeneity among and within tumors are one of the reasons for the poor survival rate of brain tumors even with the current standard therapy. However, monolayer culture and neuro-sphere culture (NS) use exogenous growth factors, so may not show the true nature of the tumor. And the culture establishment rate is low, especially low-grade tumors. Therefore, we used the glioblastoma organoid (GBO) culture method showed by Fadi to create culture models of various brain tumors and investigated their characteristics. Methods: We examined the establishment rate in pathological and genotypic types of 56 patients who underwent brain tumor resection at our hospital between January 2020 and June 2021 and were cultured with GBO or NS. If tumor cells are increased visually at 1 month after culture, we defined establishment. Results: There were 15 cases of glioblastoma, 7 cases of anaplastic astrocytoma, 7 cases of diffuse astrocytoma, 3 cases of diffuse midline glioma, 2 cases of anaplastic oligodendroglioma, 5 cases of oligodendroglioma, and 16 cases of others. The establishment rate was 76.5% by the GBO method and 40% by the N S method. By histological type, GBO: 80% in glioblastoma, NS: 58.3% in glioblastoma, GBO: 83.3% in AA, NS: 40% in AA, and GBO: 100% in DA. The IDH mutation and pTERT mutation were investigated in GBO: IDHwt/TERT+ 87.5%, IDHwt/TERT- 64.3%, IDHmt/TERT- 100%, and in NS: IDHwt/TERT+ 75%, IDHwt/TERT- 33.3%, IDHmt/ TERT- 20% in NS. In addition, establishment was observed in GBO 2 case in medulloblastoma, 1 case in ependymoma. Discussion and Conclusion: This suggest that GBO can be used to establish culture models for low-grade tumors. In addition, GBO can establish culture earlier, so it is expected to be applicable to personalized therapies such as preclinical drug efficacy studies tailored to individual patients.

CTNI-13. MALIGNANT GLIOMA SUBSET FROM ACTUATE 1801 PHASE 1/2 STUDY OF 9-ING-41, A GLYCOGEN SYNTHASE KINASE 3 BETA (GSK-3β) INHIBITOR, AS A SINGLE AGENT AND COMBINED WITH CHEMOTHERAPY REFRACTORY

Abstract BACKGROUND GSK3β serine/threonine kinase regulates metabolism and glycogen biosynthesis. GSK3β overexpression promotes tumor progression and resistance through NF-κB and p53 apoptotic pathways. GSK3β inhibits immunomodulation by downregulating checkpoints, e.g. PD-L1 and LAG-3, and increasing NK and T-cell mediated tumor killing. 9-ING-41 is a small-molecule, potent, selective GSK3β inhibitor with preclinical activity. In chemoresistant PDX glioblastoma models, 9-ING-41 enhanced lomustine antitumor effect. METHODS Patients with refractory malignancies were treated with 9-ING-41 monotherapy (n=65) or combined with 8 cytotoxic regimens after prior exposure (n=162) in the first-in-human study (NCT03678883). The recurrent gliomas subset was treated with 9-ING-41 monotherapy IV TIW q21day cycles at 3.3, 5, 9.3, 15mg/kg, or combined with lomustine 30 mg/m² PO weekly q84day cycles. Primary objective was safety and tolerability. RESULTS An RP2D of 15mg/kg IV TIW was confirmed across all 9 regimens, no accentuation of chemotherapy toxicity noted. Of 18 glioma patients enrolled, 13 were glioblastoma, 2 anaplastic astrocytomas, 1 anaplastic oligodendroglioma, and 1 diffuse astrocytoma; 6 female, 12 male; median age 52 (30-69) years; median ECOG was 1 (0-2). All received initial radiation and temozolomide (18/18), prior salvage therapies included nitrosoureas (15/18), bevacizumab (8/18), TTFields (6/18), checkpoint inhibitor (4/18). Median recurrences 3 (1-6). NGS alterations included: IDH/wildtype (11), IDH/mutation(3); 1p19q/codeletion(10); MGMT/unmethylated(11), MGMT/methylated(1); EGFR/amplification(6), EGFR/v3mutation(3), TERT/mutation(6), PTEN/loss(3), NF1/rearrangement(2), ATRX/loss (2), TP53/mutation(4), CDKN2A/deletion(2), RB1/loss(1), PALB2/mutation(10). Four patients received 9-ING-41 monotherapy, 14 concurrently treated with lomustine. No SAEs or grade 3/4 AEs attributed to 9-ING-41 noted, only G1/2 vision changes (9/18, 50%), infusion reactions (4/18, 22%). Lomustine-related toxicities included G3/4 thrombocytopenia (3/14, 21%), and G1/2 fatigue (4/14, 28%). Median therapy duration was 55 (4-305); 1 partial response ( &amp;gt;50%) noted with 9-ING-41/lomustine. Median PFS and OS were 1.9 (0.3-11.1) and 6.0 (1.6-16.6) months, respectively. CONCLUSIONS 9-ING-41 plus/minus lomustine is safe and warrants further study in glioma patients.

PATH-17. POSSIBLE ASSOCIATION BETWEEN OLIGODENDROGLIAL HISTOLOGICAL FEATURES OF IDHMUT/CODEL LOWER GRADE GLIOMAS AND PATIENT'S FAVORABLE PROGNOSIS, BUT NOT IN IDHMUT/NONCODEL AND IDH-WILDTYPE TUMORS

Abstract Comprehensive diagnostic using histological and molecular characteristics began to be implemented in WHO 2016 but the relevance of oligodendroglial histological features to patients’ prognoses is still controversial. To elucidate the connection between oligodroglial histology and patient’s prognoses we analyzed 93 LrGGs resected for about 2 decades were reassessed for histological features based on WHO2007 with special interest to pure oligodendroglial diagnosis (namely, oligodendroglioma or anaplastic oligodendroglioma) and presence of classic for oligodendroglioma (CFO) features. Those histological features, patients’ OS, and tumor chromosomal/genetic characteristics were correlated each other in each of the 3 IDH-1p/19q based molecular groups. The reassessed morphology-based diagnosis was shown to be most strict for astrocytic, but loosened for oligodendroglial tumors as compared with the original institutional diagnoses and WHO2016. The pure oligodendroglial diagnosis by reassessment was associated with longer OS in IDHmut/codel group, but not in IDHmut/noncodel and IDH-wildtype groups. The presence of CFO was not associated with patients’ OS in any molecular groups. Gain of 8q was associated with the oligodendroglial diagnosis in IDHmut/noncodel group. Neither the oligodendroglial diagnosis nor CFO was predictive for the methylation status of the MGMT gene in any of the 3 molecular groups. NGS of the IDHmut/codel tumors suggested that mutations in the FUBP1 and CIC genes might be associated with poor prognosis. The oligodendroglial histological feature is not independently predictive for either patients’ prognosis or chemotherapeutic response in LrGGs, except the oligodendroglial diagnosis in IDHmut/codel tumors.

QOLP-15. FEASIBILITY OF AN ELECTRONIC PATIENT REPORTED STEROID TOXICITY MONITORING PROGRAM IN PATIENTS WITH MALIGNANT GLIOMAS

Abstract OBJECTIVE To determine the feasibility of a longitudinal, electronic, patient-reported survey of steroid toxicity in patients with malignant glioma (MG). BACKGROUND Corticosteroids are frequently used for management of cerebral edema in MG, with side effects resulting from prolonged use or high dosage. Corticosteroid use is common and may negatively impact quality of life (QOL) and survival in MG. DESIGN/METHODS We prospectively enrolled patients with MG receiving neuro-oncologic care at the University of Rochester with or without their caregivers on an IRB-approved study. Subjects received 12 weekly electronic questionnaires through a secure health portal focused on symptoms of corticosteroid toxicities, dosing and functional status. Weekly toxicity scores were calculated based on the number of reported toxicities (0-17). Completed questionnaires were reviewed by a care team member to inform clinical management. Corticosteroid dosing adjustments were documented in the medical record. Feasibility was defined as an overall questionnaire completion rate of 70%. RESULTS 11 patient/caregiver pairs were enrolled (11 patients, including 9 with caregivers). Median patient age was 58. Patient tumors were glioblastoma (82%), anaplastic astrocytoma (9%) and anaplastic oligodendroglioma (9%). Phase of treatment was concurrent (55%), adjuvant (36%) and recurrence (9%). Median dexamethasone does at study start and conclusion were 4mg/day and 3mg/day. Median weekly toxicity score was 5/17 (range: 0-14). The most common toxicities were muscle weakness, sleep disturbance and weight gain and were reported by 82% of participants. Overall questionnaire completion rate was 81%. Ten percent of questionnaires resulted in clinically significant symptoms requiring follow-up from a provider. CONCLUSION Patients with MG experience frequent corticosteroid toxicities. Electronic corticosteroid toxicity monitoring is feasible in patients with MG and may lead to changes in management. Future studies are needed to assess utility of this tool and impact on QOL and survival.

BIOM-22. RELEVANCE OF TUMOR MUTATION BURDEN (TMB) IN HIGH-GRADE GLIOMAS

Abstract BACKGROUND Efforts have been directed toward searching for molecular biomarkers predicting response to immunotherapy in glial tumors. Recently, FDA granted accelerated approval of pembrolizumab for treatment patients with solid tumors with high mutational burden (TMB-H; ≥ 10 mut/Mb). There are conflicting results regarding the use of this parameter in glial tumors. OBJECTIVE to review NGS examinations of patients with glial tumors and high TMB and to analyze their response to immunotherapy. METHODS we retrospectively reviewed NGS examinations from patients with glial tumors treated in Tel-Aviv Medical Center from 2016-2021. Cases with TMB-H were retrieved and analyzed. RESULTS We identified nine high-grade glioma patients with TMB-H. The median age was 38 (19-65). There were 4 patients with glioblastoma; three with anaplastic oligodendroglioma; and two with anaplastic astrocytoma. All but one received radiation prior to the biopsy used for NGS examination, and all were treated with temozolomide. The median TMB was 54 (19-252). Only one glioblastoma patient with a family history of Lynch syndrome had microsatellite instability (MSI)-high; all other patients were MSI stable (MSS). Nevertheless, in all cases, mutated mismatch repair (MMR) genes were detected (MSH6 in 3 patients, MSH2 in one patient, MLH1 in one patient, PMS 2 in one patient, and both MSH2 and 6 in one patient). Six patients received immunotherapy. Only one patient with recurrent glioblastoma and the highest TMB in the group (252) demonstrated a near complete response to pembrolizumab and remains on treatment more than three years. All other patients did not respond to immunotherapy. CONCLUSION TMB-H in primary glioma is associated with mutations of MMR genes. It is typically associated with MSS in these patients (MSI-high was seen in only one syndromic patient). In contrast to systemic neoplasms with TMB-H, the majority of our patients did not respond to immunotherapy.

INNV-07. TTFIELDS TREATMENT OF GLIOSARCOMA AND RECURRENT ANAPLASTIC OLIGODENDROGLIOMA

Abstract INTRODUCTION The Optune device delivers tumor treating fields (TTFields) and is considered as a standard of care for newly diagnosed and recurrent glioblastoma patients. The efficacy of Optune in other glioma subtypes, such as gliosarcoma and anaplastic oligodendroglioma, is still unclear. In this small case series, we present the clinical, pathologic and radiographic findings of two patients who utilized Optune and had improved outcomes compared to historical controls. CASE 1 A 49 year old woman underwent resection of a right temporal lobe gliosarcoma in November 2017. She received conventional radiation therapy with concurrent temozolomide, which was complicated by significant thrombocytopenia and leukopenia. She initiated Optune as monotherapy six weeks after completing radiation, and used the device for 24 months. She still has not had a recurrence, now 3.5 years since her initial diagnosis. CASE 2 A 46 year old woman underwent resection of a right frontal lobe oligodendroglioma, WHO Grade 2, in September 2011. She received one cycle of temozolomide in April 2014, complicated by thrombocytopenia, and no further chemotherapy was administered. In November 2017, she underwent resection of a new focus of enhancement at the margin of the resection cavity, which was confirmed to have transformed to WHO Grade 3. In August 2019, a radiographic progression of an enhancing nodule was observed. She initiated Optune as monotherapy in September 2019, and since that time, has had stable disease for 18 months. Optune treatment is still ongoing. CONCLUSIONS In a case of newly diagnosed gliosarcoma, Optune monotherapy has contributed to progression-free and overall survival of 3.5 years to date. In a case of recurrent anaplastic oligodendroglioma, Optune monotherapy has achieved stable disease for at least 18 months. These cases demonstrate that Optune can be safely utilized in these glioma subtypes and contributed to improved survival outcomes in these two patients.

CTNI-18. PHASE I AND PRELIMINARY PHASE 0 RESULTS OF ABTC 1801: A MULTI-ARM CLINICAL TRIAL OF THE PARP INHIBITOR PAMIPARIB (BGB290) WITH VERY LOW DOSE METRONOMIC TEMOZOLOMIDE IN RECURRENT IDH MUTANT GLIOMAS

Abstract BACKGROUND Preclinical studies have demonstrated that IDH1-mutant (IDHmt) gliomas harbor a BRCAness phenotype with a defect in homologous recombination that confers PARP inhibitor sensitivity. Pamiparib (BeiGene BGB-290) is an effective PARP-trapping PARP inhibitor with demonstrated favorable brain penetration in animal models. METHODS ABTC 1801 is a study examining the safety, pharmacokinetics, and efficacy of the combination of pamiparib with low dose metronomic temozolomide in recurrent IDHmt gliomas. The Phase I component utilized a 3 + 3 design with a target DLT rate ≤ 33%. Pamiparib dose was 60 mg BID and temozolomide dose 20 mg daily, with dose de-escalation levels for anticipated hematological toxicity. RESULTS Seven patients were enrolled on the Phase I portion at dose level 1; one patient was replaced for inadequate dosing secondary to non-compliance. All patients had prior radiotherapy and temozolomide; 4/7 had received multiple lines of alkylator therapy including nitrosoureas. Median age was 45, KPS 90, and number of prior relapses 3. Four patients had anaplastic astrocytoma, 2 anaplastic oligodendroglioma, and 1 glioblastoma. One of 6 patients (16.7%) experienced DLT during the first cycle (grade 3 neutropenia and thrombocytopenia). Two additional patients had grade 2 neutropenia. Two patients remain on study treatment at 12+ and 10+ months, while a third progressed at 10.1 months (PFS-6 43%). Tumor tissue was collected from two patients in the surgical arm. In enhancing and non-enhancing tumors, the mean unbound pamiparib concentrations were 198 and 160 nmol/L (or nmol/kg), respectively, which were &amp;gt; 20-fold the in vitro IC50 for PARP inhibition; mean unbound tumor-to-plasma ratios were 0.65 and 0.38. CONCLUSIONS Phase I results support pamiparib 60 mg BID with temozolomide 20 mg daily as the dosages for the Phase II study. Preliminary Phase 0 data suggest that pamiparib likely achieves sufficient pharmacologically active concentrations in both enhancing and non-enhancing brain tumors.

IMMU-27. LONG TERM STABILIZATION OF RECURRENT HIGH-GRADE GLIOMA WITH PD-1 INHIBITOR PEMBROLIZUMAB IN TWO CASES

Abstract INTRODUCTION Despite PD-1 inhibition having success in many cancers, it has uncertain effects in brain tumors. We report two cases of recurrent high-grade gliomas that have remained stable for over one year since starting pembrolizumab. CASE REPORTS Case 1: A 59-year-old male was diagnosed with glioblastoma (GBM) without MGMT methylation or IDH mutation in late 2018 after surgery. He received radiation and temozolomide (TMZ) followed by adjuvant TMZ before tumor progression. He underwent second tumor debulking with recurrent GBM on pathology with negative PD-L1 expression. He started carboplatin. Progression was noticed after 7 to 8 cycles. Pembrolizumab was added. Tumor was stabilized. Carboplatin was completed after total 12 cycles and the patient has continued single agent of pembrolizumab for more than one year with stable brain MRIs. The patient has survived for 24 months since recurrence and 30 months since diagnosis. Case 2: A 53-year-old male had a brain tumor discovered on MRI in 2012 and received no treatment until resection in 2014. In 2016, he underwent second tumor debulking and was diagnosed with anaplastic oligodendroglioma with negative PD-L1 expression. He received radiation followed by PCV regimen. 17 months since diagnosis, he had first tumor progression on PCV. TMZ was started. 22 months since diagnosis, bevacizumab was initiated due to further growth. 33 months since diagnosis, pembrolizumab was added due to new lesions after 12-months of bevacizumab therapy. His tumor was stabilized. Bevacizumab was eventually discontinued. He has continued single agent pembrolizumab for 6 months so far. His tumor has been stable for 22 months since starting pembrolizumab. Survival has been 38 months from first recurrence and 7 years since tissue diagnosis. DISCUSSION These cases demonstrate the potential effects of anti-PD-1 immunotherapy in stabilizing recurrent high-grade glioma with combination of other treatment agents followed by single agent as maintenance therapy.

PATH-07. INFRATENTORIAL HIGH-GRADE GLIOMAS: NEUROSURGICAL CASE SERIES WITH MOLECULAR ANALYSIS

Abstract INTRODUCTION Most high grade gliomas (HGG) are located supratentorially, while less than 1% arise infratentorially. Growing evidence suggests that infratentorial HGGs (iHGG) represent a collection of distinct molecular entities and that further elucidation of their molecular features can help guide management. We perform here a clinical and molecular analysis of our institutional iHGG case series. METHODS We retrospectively reviewed iHGG patients treated surgically at Brigham and Women’s Hospital (1992-2020), and evaluated their history of prior malignancies, tumor location, treatment, molecular profile, tumor recurrence, and survival. iHGG were identified by review of pathology records, using WHO Histologic Grading Criteria as grade III-IV gliomas located infratentorially. Molecular analysis data was obtained from pathology records. RESULTS Among 37 iHGGs, 16 (43%) were glioblastomas, 11 (30%) were anaplastic astrocytomas, 2 (5%) were diffuse midline gliomas, 2 (5%) were infiltrating gliomas, 2 (5%) were anaplastic ependymomas, 1 (3%) was an anaplastic oligodendroglioma, and 3 (8%) were HGG not otherwise specific. Sixteen (43%) patients were female, median age was 49 years. Fifteen patients had history prior malignancy, 11 of which received radiation and 8 chemotherapy. Surgical resection of iHGG included gross total resection in 4 (11%) and subtotal in 33 (89%). Twenty-one patients (57%) received adjuvant radiation and 19 (51%) chemotherapy. At follow-up, 13 (35%) patients demonstrated symptomatic deterioration, 15 (41%) were stable, and 7 (19%) were improved. Seven patients (19%) experienced recurrence at a mean time of 19 months, and one-year survival was 35%. Molecular analysis revealed 7/15 (47%) tumors were MGMT promoter methylated, IDH was mutated in 3/24 (13%), EGFR was amplified in 3/10 (30%), CDKN2A/B homozygous deletion in 4/7 (57%), TP53 was mutated in 14/15 (93%), and H3K27M was present in 4/10 (40%). CONCLUSIONS iHGGs demonstrate substantial distinction from their supratentorial counterparts. Herein we examined their clinical course, molecular features, management, and outcomes.

EPID-09. VARIATION IN GLIOMA INCIDENCE AMONG US HISPANICS BY GEOGRAPHIC REGION OF ORIGIN

Abstract BACKGROUND Glioma incidence is 25% lower in U.S. Hispanics than in White non-Hispanics. The US Hispanic population is diverse and registry-based analyses may mask incidence differences associated with geographic/ancestral origins. METHODS County-level glioma incidence data in U.S. Hispanics were retrieved from the Central Brain Tumor Registry of the United States (CBTRUS), which includes data from the Centers for Disease Control’s National Program of Cancer Registries and the National Cancer Institute’s Surveillance, Epidemiology, and End Results program and covers ~100% of the U.S. population. American Community Survey (ACS) data were used to determine county-level proportion of the Hispanic population of Mexican/Central American origin, Caribbean origin (Puerto Rican, Cuban, Dominican), or other origin. Incidence rate ratios (IRRs) were generated to assess the association of glioma incidence in Hispanics with predominant origin group. RESULTS Compared to Hispanics living in predominantly Caribbean-origin counties, Hispanics in predominantly Mexican/Central American-origin counties were at lower age-adjusted risk of glioma (IRR=0.83; P&amp;lt; 0.0001), glioblastoma (IRR=0.86; P&amp;lt; 0.0001), diffuse and anaplastic astrocytoma (IRR=0.78; P&amp;lt; 0.0001), oligodendroglioma (IRR=0.82; P&amp;lt; 0.0001), ependymoma (IRR=0.88; P=0.0121), and pilocytic astrocytoma (IRR=0.76; P&amp;lt; 0.0001). Associations were consistent in children and adults, and when using more granular regions of origin. However, Central American origin was associated with modestly increased incidence of several lower-grade glioma histologies. Associations were only partially attenuated after adjusting for state-level estimated of European admixture in Hispanics using 23andMe data. CONCLUSIONS Glioma incidence in U.S. Hispanics differs significantly in association with the geographic origins of the Hispanic community, with those of Mexican/Central American origin at significantly reduced risk relative to those of Caribbean origin. U.S. Hispanics are culturally, socioeconomically, and genetically diverse. Although classified as a single ethnic group in most registry data, more granular analytic approaches could advance cancer epidemiology and disparities research.

CTIM-24. RANDOMIZED TRIAL OF NEOADJUVANT VACCINATION WITH TUMOR-CELL LYSATE INDUCES T CELL RESPONSE IN LOW-GRADE GLIOMAS

Abstract BACKGROUND The prognosis of WHO grade II low-grade gliomas (LGG) is varied with potential for long survival.Given their relatively intact immune system and slow growth rate, vaccines are an attractive treatment strategy for LGG in an attempt to defer more toxic treatments. The goals of this pilot study were to evaluate safety and immunological effects of vaccination with GBM6-AD, an allogeneic glioblastoma stem cell line lysate, with poly-ICLC in LGG. METHODS Eligible patients were ≥ 18 years old, ≥ 70 KPS, with recurrent LGG or imaging consistent with LGG, and amenable to resection. Patients were randomized to vaccine prior to surgery (Arm 1) or not (Arm 2) and all received adjuvant vaccine. Co-primary outcomes were safety and immune response in the tumor, with exploratory outcomes of survival and immunologic effects in peripheral blood. RESULTS A total of 17 eligible patients were evaluable – nine into Arm 1 and eight into Arm 2. Median age was 33 years, with median time from initial diagnosis of 4.7 years (0 – 20). Two patients (11.8%) previously received radiotherapy and seven (41.2%) prior systemic therapy. No dose limiting toxicities or grade 3 AEs were observed. Neoadjuvant vaccination induced up regulation of type-1 cytokines and chemokines in peripheral blood, and CD8+ T cell clones that reacted to the vaccine were also detected in the tumor. Median follow-up time from first post-operative vaccine was 20.8 months with median PFS of 11.0 months and time to change in therapy of 23.7 months. Of the six patients to receive additional treatment, three had second surgery only one confirming malignant progression to anaplastic oligodendroglioma. CONCLUSION Treatment was well-tolerated with no regimen-limiting toxicity. GBM6-AD plus poly-ICLC induced effector CD8+ T cell response in peripheral blood and enables some vaccine-reactive CD8+ T cells to migrate into the TME. Further investigation is warranted.