Diffuse Astrocytoma Research Articles

Abstract 895: Tumor-wide neoantigen-specific T-cells infiltrating mutant IDH1 low-grade gliomas and persisting in peripheral blood allow for personalized TCR-based immunotherapies

Abstract BACKGROUND: The low mutational burden and immunologically “cold” microenvironment of mutant IDH1 low-grade gliomas (LGG) are considerable challenges facing immunotherapy against these tumor types. However, we hypothesize that LGG-targeting T-cells may exist at low frequency and with limited regional infiltration within the tumor. Multi-region tumor sampling coupled with high-throughput T-cell receptor (TCR) profiling across the LGG landscape detected neoantigen-specific T-cells that persisted in peripheral blood. TCR-engineered T-cells transduced with these TCRs demonstrated neoantigen-specific immunogenicity. METHODS: Maximal-anatomical sampling of at least 10 distinct tumor regions were collected at the initial resection for three WHO Grade II diffuse astrocytoma patients for exome-based prediction of clonally and subclonally expressed neoantigens, RNAseq analysis of regional immune cell composition, and TCR beta deep sequencing. We used these predictions to generate a barcoded library of patient-specific peptide-HLA multimers loaded with predicted neoepitopes. With this library, neoantigen-specific CD8+ T-cells were captured and isolated from patient peripheral blood. Single cell TCR sequencing allowed us to identify the neoantigen-reactive TCR clonotypes which were transduced subsequently into Jurkat76 cell lines for functional validation. RESULTS: We screened patient-derived peripheral blood drawn two years after initial resection in 3 mutant IDH1 LGG patients and detected a total of 20 TCR clonotypes recognizing neoepitopes derived from truncal, tumor-wide mutations in CNTNAP1 (n=8), TP53 (n=3), and MRPL46 (n=2) as well as subclonal mutations in PRMT5 (n=1) and ZDHHC5 (n=6). Multi-sampling RNAseq analysis indicated varying degrees of interpatient and intratumoral immune infiltration as well as distally located populations of neoantigen-reactive T-cells within the tumor, suggesting widespread migration of neoantigen-specific T-cells across the glioma landscape. We proceeded with TCR functional analysis for one patient (P375) with 5 detected TCR clonotypes recognizing neoantigens derived from mutations in PRMT5, MRPL46, and TP53. Jurkat76 cells transduced with the mutant-PRMT5-specific TCR demonstrated a neoantigen-specific immune response when co-cultured with mutant-PRMT5 pulsed-antigen presenting cells expressing HLA-A*0201 (T2 cells). CONCLUSION: Our study demonstrates the existence and persistence of neoantigen-targeting T-cells within the blood and tumor of mutant IDH1 LGG patients. We identified a TCR clonotype that successfully recognizes and induces an immune response against mutant-PRMT5. These findings suggest a feasible methodology to develop personalized T-cell-based immunotherapies for patients with mutant IDH1 LGGs. Citation Format: Darwin W. Kwok, Michael Y. Zhang, Cliff Wang, Nicholas Stevers, Tyler Borrman, Zheng Pan, Benjamin Yuen, Songming Peng, Diana Nguyen, Michael Martin, Chibo Hong, Stephanie Hilz, Joanna Phillips, Anny Shai, Nancy Ann Oberheim Bush, Shawn Hervey-Jumper, Michael McDermott, Stefanie Mandl, Hideho Okada, Joseph Costello. Tumor-wide neoantigen-specific T-cells infiltrating mutant IDH1 low-grade gliomas and persisting in peripheral blood allow for personalized TCR-based immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 895.

874 Direct Visualization of Planned Resection Volumes with Microbubble-Enhanced MR-Guided Focused Ultrasound Blood-Brain Barrier Opening and Sodium Fluorescein in Infiltrating Gliomas

INTRODUCTION: Surgical resection of infiltrating gliomas (IG,Grade II-IV) can be challenging, as many do not consistently enhance on gadolinium-enhanced MRI. Evidence of survival benefit of supratotal resection is mounting. No method exists to preoperatively demarcate a planned surgical resection volume. Such physical demarcation could significantly improve the resection of IGs. METHODS: Four patients were treated (3M:1F), with a mean age of 32.5 (29-36). All were suspected of having or were previously diagnosed with a supratentorial IG. Patients underwent awake transcranial MB-FUS BBBO of the lesion bed and perilesional areas planned for resection at the discretion of the operating neurosurgeon (GFW). Subsequently, patients were transported directly to the operating room. For each patient, sodium fluorescein was administered, and then tumors were resected with standard craniotomies under general anesthesia, using neuronavigation and fluorescent microscopy. RESULTS: Patients tolerated the procedure well without adverse events with a median follow-up of 15.7 months. The mean tumor volume was 18.2 cm3 (6.8-32.9). The demarcated planned resection volume was visualized with fluorescent microscopy. Fluorescing tissue was completely resected. Gross-total or supratotal resection was achieved in all patients. Pathologies included diffuse astrocytoma, oligodendroglioma, and anaplastic oligodendroglioma. CONCLUSIONS: MB-FUS BBBO and sodium fluorescein present a safe and novel method of demarcating a preoperatively planned surgical resection volume with resultant intraoperative visualization in IGs. This method is resilient to brain shift, and is an addition to the current repertoire for visualizing non-contrast-enhancing gliomas. The same method can be investigated for use in epilepsy surgery.

868 Analysis of the Surgical Edge of Adult-Type Diffuse Astrocytomas and its Correlation With Prognosis

INTRODUCTION: Glioma cells extend beyond the macroscopic margins of the tumor, making it impossible to pursue a cure based only on surgical treatment in patients with the diagnosis of Adult-Type Diffuse Glioma (ATDG). The tumor volume left behind in the surgical bed is a significant predictor of recurrence and survival. In the present study, we analyzed the grade of malignancy in the surgical edge (SE) after tumor removal and correlated it with progression-free survival (PFS) in patients diagnosed with ATDG. METHODS: Surgical edge biopsy samples were obtained after tumor removal in 15 patients (3 A2; 2 A3; 2 A4; and 8 GBM, WHO CNS 5); the samples were analyzed by three neuropathologists and were classified in a GOM (2, 3, or 4). An MRI was performed within 48 hours after surgery in all patients to assess the extent of resection. PFS was obtained from clinical and MRI follow-up. Data analysis was conducted using a nonparametric Spearman rank coefficient correlation test. RESULTS: Correlation analysis between the highest grade of malignancy found in the SE and PFS was -0.8080 (95% CI = -0.9359 to -0.4920, p < 0.0001). See Image 1. CONCLUSIONS: A strong correlation between the GOM in the SE and PFS was found in ATDG Astrocytomas. See Image 2 and 3.

Characterization of an IDH1 R132H Rabbit Monoclonal Antibody, MRQ-67, and Its Applications in the Identification of Diffuse Gliomas.

The current diagnosis of diffuse glioma involves isocitrate dehydrogenase (IDH) mutation testing. Most IDH mutant gliomas carry a G-to-A mutation at IDH1 position 395, resulting in the R132H mutant. R132H immunohistochemistry (IHC), therefore, is used to screen for the IDH1 mutation. In this study, the performance of MRQ-67, a recently generated IDH1 R132H antibody, was characterized in comparison with H09, a frequently used clone. Selective binding was demonstrated by an enzyme-linked immunosorbent assay for MRQ-67 to the R132H mutant, with an affinity higher than that for H09. By Western and dot immunoassays, MRQ-67 was found to bind specifically to the IDH1 R1322H, with a higher capacity than H09. IHC testing with MRQ-67 demonstrated a positive signal in most diffuse astrocytomas (16/22), oligodendrogliomas (9/15), and secondary glioblastomas tested (3/3), but not in primary glioblastomas (0/24). While both clones demonstrated a positive signal with similar patterns and equivalent intensities, H09 exhibited a background stain more frequently. DNA sequencing on 18 samples showed the R132H mutation in all IHC positive cases (5/5), but not in negative cases (0/13). These results demonstrate that MRQ-67 is a high-affinity antibody suitable for specific detection of the IDH1 R132H mutant by IHC and with less background as compared with H09.

Imaging features of localized IDH wild-type histologically diffuse astrocytomas: a single-institution case series

Isocitrate dehydrogenase wild-type (IDHwt) diffuse astrocytomas feature highly infiltrative patterns, such as a gliomatosis cerebri growth pattern with widespread involvement. Among these tumors, localized IDHwt histologically diffuse astrocytomas are rarer than the infiltrative type. The aim of this study was to assess and describe the clinical, radiographic, histopathological, and molecular characteristics of this rare type of IDHwt histologically diffuse astrocytomas and thereby provide more information on how its features affect clinical prognoses and outcomes. We retrospectively analyzed the records of five patients with localized IDHwt histologically diffuse astrocytomas between July 2017 and January 2020. All patients were female, and their mean age at the time of the initial treatment was 55.0 years. All patients had focal disease that did not include gliomatosis cerebri or multifocal disease. All patients received a histopathological diagnosis of diffuse astrocytomas at the time of the initial treatment. For recurrent tumors, second surgeries were performed at a mean of 12.4 months after the initial surgery. A histopathological diagnosis of glioblastoma was made in four patients and one of gliosarcoma in one patient. The initial status of IDH1, IDH2, H3F3A, HIST1H3B, and BRAF was “wild-type” in all patients. TERT promoter mutations (C250T or C228T) were detected in four patients. No tumors harbored a 1p/19q codeletion, EGFR amplification, or chromosome 7 gain/10 loss (+ 7/ − 10). We assessed clinical cases of localized IDHwt histologically diffuse astrocytomas that resulted in malignant recurrence and a poor clinical prognosis similar to that of glioblastomas. Our case series suggests that even in patients with histologically diffuse astrocytomas and those who present with radiographic imaging findings suggestive of a localized tumor mass, physicians should consider the possibility of IDHwt histologically diffuse astrocytomas.

Expression of IDH1, ATRX, p53 in Diagnosis of Gliomas as Per 2016 WHO Classification

Introduction: The 2016 World Health Organisation (WHO) classification of tumours of the Central Nervous System (WHO CNS 2016 classification) is used to classify diffuse gliomas as astrocytoma, Oligodendroglioma (ODG), glioblastoma which are three prognostically distinct groups based on Isocitrate Dehydrogenase (IDH1), alpha thalassaemia/mental retardation, x-linked (ATRX) mutations, p53 and 1p/19q co-deletion status. Although WHO CNS 2022 classification has been brought in use, it is based on molecular studies. In a resource limited setting like in many Indian diagnostic centres it’s difficult to apply the WHO CNS 2022 classification. It is felt that WHO CNS 2016 classification has not lost its utility. Aim: To investigate the Immunohistochemistry (IHC) status of IDH1, ATRX, p53 in diagnosis of diffuse glial tumours and to classify them according to WHO 2016. Materials and Methods: This cross-sectional study was conducted at Bharati Vidyapeeth Medical College, Hospital and Research Centre, Pune, Maharashtra, India for two years and six months (July 2020 to December 2022). Thirty-two diffuse glioma cases and IHC markers IDH1, ATRX, p53 were evaluated. Ki-67 index was additionally done. Results: Total 32 cases were studied, 19 cases were male. Mean age of the patients was 40.13 years. Fourteen patients belonged to WHO Grade-II, 6 to Grade-III, and 12 to GradeIV. As per the IHC findings and histopathological features, there were 16 (50%) patients with diffuse astrocytoma, while 12 (37.5%) and 4 (12.5%) patients were diagnosed as glioblastoma and ODG respectively. Reclassification of these cases was done depending on IHC results where IDH1 was positive in 71.9% cases, ATRX was positive in 40.6% cases and p53 was positive in 15.6% cases. This result includes all the cases where these IHC markers showed reactivity. The diagnosis of four patients was modified based on findings of IHC markers. Conclusion: The study demonstrates subgrouping of gliomas based on IDH1, ATRX, p53. There was no significant association between grade of tumour and Ki-67 expression.

The role of surgery in IDH wildtype diffuse astrocytomas

The role of surgery in IDH wildtype diffuse astrocytomas

Paediatric-type diffuse low-grade gliomas: a clinically and biologically distinct group of tumours with a favourable outcome.

The WHO 2021 classification of central nervous system cancers distinguishes diffuse gliomas that arise in adults (referred to as the "adult type") and those that arise in children (defined as "paediatric") based on clinical and molecular characteristics."). However, paediatric-type gliomas may occasionally be present in younger adults and occasionally adult-type gliomas may occur in children. Diffuse low-grade paediatric glioma includes diffuse astrocytoma altered by MYB or MYBL1, low-grade polymorphic juvenile neuroepithelial tumour, angiocentric glioma, and diffuse low-grade glioma with an altered MAPK pathway. Here, we examine these newly recognised entities according to WHO diagnostic criteria and propose an integrated diagnostic approach that can be used to separate these clinically and biologically distinct tumor groups.

Role of CDKN2A deletion in grade 2/3 IDH-mutant astrocytomas: need for selective approach in resource-constrained settings.

The authors aimed to assess the frequency of homozygous CDKN2A deletion in isocitrate dehydrogenase (IDH)-mutant diffuse astrocytomas (grade 2/3) and to narrow down the clinicopathological indications in which the CDKN2A fluorescence in situ hybridization (FISH) assay is cost-effective in resource-constrained settings. IDH-mutant astrocytomas were analyzed for ATRX, p53, MIB1-LI, and p16 expression using immunohistochemistry. The FISH assay was used to evaluate CDKN2A deletion and 1p/19q codeletion. Survival outcomes were assessed according to the different molecular markers. A total of 150 adult patients with IDH-mutant grade 2 (n = 95) and grade 3 (n = 55) astrocytomas (145 primary and 5 recurrent) were analyzed. Using a cutoff value of 30% for defining significant homozygous CDKN2A deletion, none of the grade 2 and 10.9% (6/55) of grade 3 astrocytomas showed this deletion (4 primary and 2 recurrent grade 3 tumors) and were reclassified as grade 4. This mutation was more frequent in recurrent (40%, 2/5) than primary (2.76%, 4/145) gliomas. Half (3/6, 50%) of the CDKN2A-deleted cases demonstrated poor outcomes; 2 of these cases experienced recurrence at 12 and 36 months after surgery, and 1 died at 5 months. The majority of CDKN2A-deleted cases showed marked cellularity (100%), pleomorphism (100%), brisk mitosis (83.3%), and tumor giant cell formation (83.4%). None of the cases with retained p16 expression harbored this deletion. Both overall survival (p = 0.039) and progression-free survival (p = 0.0045) were found to be worse in cases with p16 loss. Selectively performing CDKN2A FISH only in high-risk cases with histomorphological features of anaplasia, p16 loss, or recurrent tumors achieved a sensitivity and negative predictive value of 100%. This approach would have resulted in saving 41.1% of the original expenditure ($6900 US per 150 samples) and 27.6 person-minutes per sample without compromising the identification of deleted cases. Homozygous CDKN2A deletion is conspicuously absent in grade 2 and rare in primary grade 3 IDH-mutant astrocytomas. The authors propose that restricting use of the FISH assay to cases showing histomorphological features of anaplasia, p16 loss, or recurrent tumors will help this platform to be utilized in the most cost-effective manner in resource-constrained settings.

TMET-31. CHOLESTEROL ESTERIFICATION IN A PATIENT WITH DIFFUSE ASTROCYTOMA PROGRESSING TO GLIOBLASTOMA

Abstract Metabolic profiles of diffuse astrocytoma and recurrent tumor tissues were compared in a patient with diffuse astrocytoma who showed tumor recurrence and progressed to glioblastoma (GBM). The patient presented with a diffuse infiltrating tumor and was operated in April 2018. The pathology report showed that the tumor was a diffusely infiltrating astrocytoma with Ki-67 of 5% (WHO Grade II). In addition, the molecular testing results indicated that the tumor was IDH1wt with TERTp mutation and showed an indeterminate MGMT promoter status. Given diffuse brain involvement and IDH1wt status, an aggressive behavior was suggested for this tumor. After ~3.5 years (January 2022), the MRI examination showed tumor recurrence and the patient underwent craniotomy for the resection of the recurrent tumor. The pathology report showed a high-grade glial neoplasm composed of ovoid tumor cells with nuclear pleomorphism (GBM, WHO Grade IV). We collected the tumor specimens from both surgeries and compared the metabolic profiles using 1H NMR spectroscopy. The tumor specimens were extracted using methanol-chloroform (2:1 ratio) extraction-method. The methanol-layer of the recurrent tumor showed decreased levels of N-acetylaspartate (NAA) and myo-inositol, and the elevated levels of phosphocholine (PC) and glycine, compared to the diffuse astrocytoma. Decreased NAA and elevated PC and glycine are metabolic features of high-grade gliomas, suggesting progression of the low-grade astrocytoma to GBM. The chloroform-layers of both tumors showed the presence of cholesterol; however, cholesteryl ester (CE) was detected only in the recurrent tumor (GBM). The ratio of CE to cholesterol was 0.44, suggesting that 44% of cholesterol pool was esterified in GBM. Cholesterol esterification is dysregulated in GBM and targeting this metabolic pathway using AcylCoA:cholesterol acyltransferase (ACAT) inhibitors would be promising in the treatment of GBM and astrocytomas with TERTp mutation which transform to GBM.

SURG-22. STAGED LASER INTERSTITIAL THERAPY (LITT) FOR THE SURGICAL TREATMENT OF INSULAR GLIOMA: A CASE SERIES WITH A NOVEL TREATMENT PARADIGM

Abstract BACKGROUND Insular gliomas pose a significant surgical challenge due to the insula’s delicate surrounding functional and vascular anatomy. Insular gliomas are conventionally treated with open surgical resection augmented by several surgical adjuvants. Despite advancements in technology and surgical techniques, surgical resection of insular gliomas has been associated with frequent and potentially severe morbidity. Laser interstitial thermal therapy (LITT) is a novel, cytoreductive, and less-invasive treatment option for glioma. OBJECTIVE We describe the first-ever series of patients with insular glioma treated with staged LITT with or without subsequent craniotomy. METHODS A retrospective institutional database identified patients with insular glioma who underwent staged LITT treatments. Clinical, histopathological, and volumetric lesional characteristics were obtained. Procedural characteristics, morbidity, overall survival (OS), and progression-free survival (PFS) were determined. RESULTS Between 2019-2022, 11 patients with insular glioma were treated in stages with a total of 21 LITT procedures with or without subsequent craniotomy. Four patients had Diffuse Astrocytoma (IDHmt/TP53+), one Gemistocytic Astrocytoma (IDHmt/TP53+), three Anaplastic Astrocytoma (IDHmt/TP53+), one Anaplastic Oligodendroglioma (IDHmt/1p19q codel), one secondary GBM (IDHmt/TP53+), and one GBM (IDHwt/TP53-). Six patients were treated with LITT alone, while five patients were treated with LITT followed by a craniotomy for complete resection. Patients had a median tumor volume of 31.5 cm3 (9.58, 97) and a mean extent of ablation±resection of 97.68% (S.D. 5.4). At a median follow-up of 12.59 months, patients had a median PFS of 12.88 months and an OS of 14.46 months. No patients had a change in KPS following LITT. Two patients had a decrease in KPS following surgery. CONCLUSION We present the first-ever reported series of insular glioma treated with staged LITT with/without subsequent resection. We found that staged treatment of insular gliomas with LITT is safe, effective, and a minimally invasive option that avoids the potentially significant morbidity associated with conventional surgery.

QOL-21. REAL-WORLD QUALITY-OF-LIFE AND HEALTH UTILITIES FOR PATIENTS WITH CNS CANCERS ON THE XCELSIOR PLATFORM

Abstract OBJECTIVE xCures operates a direct-to-patient, real-world evidence platform according to the nationwide observational research protocol XCELSIOR (NCT03793088), which aggregates medical data in an FDA-compliant electronic database. There is a relative scarcity of published results on real-world Quality-of-Life (QoL) outcomes and resulting health state utilities for patients with Central Nervous System (CNS) cancers. We sought to use the xCures platform to help address this issue. METHODS XCELSIOR participants were invited weekly to complete the EuroQol 5-Dimension (EQ-5D-5L) QoL survey. A EuroQol-endorsed model was used to estimate health state utilities from patient surveys. Survey results, utility estimates, and clinical information were analyzed to understand the influence of common mutations in glioma on patient reported outcomes. RESULTS 30 patients (21 glioblastoma, 4 oligodendroglioma, 2 diffuse midline glioma, 2 diffuse astrocytoma, 1 Schwannoma) completed at least one EQ-5D-5L survey over the course of 9 weeks. Health state utilities were positively correlated (p< .03) with Karnofsky Performance Score (KPS). The average utility for EGFR-mutated patients (N=6) was .578 (SD=.334) while for EGFR-wildtype patients (N=7) it was .747 (SD=.227). The average utility for MGMT-methylated patients (N=13) was .816 (SD=.139) while for non-methylated patients (N=10) it was .583 (SD=.379). The average utility for IDH-mutated patients (N=9) was .789 (SD=.153) while for non-mutated patients (N=17) it was .685 (SD=.324). The average utility for patients with a 1p/19q co-deletion (N=4) was .837 (SD=.126) while for those without a co-deletion (N=8) it was .744 (SD=.244). CONCLUSION The xCures platform has enabled the study of real-world QoL outcomes for patients with CNS cancers. This is the first report studying the influence of genetic mutations on QoL collected through patient reported outcomes. Future research aims to perform similar studies with larger number of patients.

MODL-38. DEVELOPMENTAL EFFECTS OF MYBL1 ACTIVATION ON MURINE BRAIN AND GLIAL DEVELOPMENT

Abstract Low-grade gliomas (LGG) represent 30% of pediatric brain tumors. Their cellular origins are unknown but are presumed to arise from subtle alterations of progenitor cell cycle regulation during brain development. Rearrangements activating MYB and MYBL1 have been identified as drivers of LGG in angiocentric glioma and diffuse astrocytomas, respectively, but the roles of these genes in the normal brain and the development of LGG are poorly understood. We first performed a developmental analysis of human and mouse Mybl1 expression from bulk and single-cell RNA-sequencing and identified exclusive expression of MYBL1 in neural stem and progenitor cells in the ganglionic eminence. We also found that MYBL1high cell transcriptomes are enriched in genes functionally involved in centromere and mitotic processes, strongly suggesting an association between MYBL1 expression and cellular proliferation states. We next hypothesized that C-terminal truncation may drive tumorigenesis through a direct increase in MYBL1 expression and cell proliferation. We developed a novel Cre-dependent knock-in mouse-model for human truncated MYBL1 expression and tested effects in oligodendroglial(Olig2-cre), astrocytic hGFAP-cre), and somatic(Ubiquitin-cre) cell types. In Ubq-cre:R26-MYBL1-tr mice there was expression and dysplasia in the salivary gland but no significant effects on brain development. In Olig2-Cre+/tg:R26-MYBL1-tr+/fl mice we observed higher susceptibility to motor seizures, early postnatal death without gross or microscopic abnormalities of brain morphology. In contrast, expression in stem cells and astrocytes of hGFAP-Cre+/tg:R26-MYBL1-tr+/flmice drove dramatic abnormalities in brain development and altered proliferation of progenitor and stem cells, but not glioma formation. Single-cell RNA sequencing of MYBL1-tr cells from mNSCs and brains of mice were also used to determine patterns of altered expression driven by MYBL1-tr. These results indicate that aberrant MYBL1 activation affects neural stem/progenitor cell and brain development through altered cell proliferation. Future targeting of the pathways identified may be therapeutically beneficial for patients with LGG driven by MYB-family oncogenes.

INNV-31. PROTECT: PROCARBAZINE, LOMUSTINE, AND VINCRISTINE VERSUS TEMOZOLAMIDE IN HIGH-RISK, LOW-GRADE GLIOMAS: A RETROSPECTIVE COHORT STUDY

Abstract INTRODUCTION Low-grade gliomas (LGG), specifically WHO grade 2 diffuse astrocytoma and oligodendroglioma, are increasingly considered for adjuvant chemotherapy with high-risk features (age ≥ 40y or subtotal resection). This is based on prospective studies showing improvement in survival with adjuvant procarbazine, CCNU, vincristine (PCV) or temozolomide (TMZ) in this cohort. Use of PCV or TMZ is variable without published head-to-head comparison. PROTECT is a Canadian multicentre retrospective study aiming to compare overall survival (OS) in high-risk LGGs receiving PCV or TMZ. We are presenting results from The Ottawa Hospital Cancer Centre (TOHCC). METHODS Patients age ≥ 18y with LGG that received PCV or TMZ within 6 months of primary brain tumor resection at TOHCC from 2005 to 2019 were included. The primary outcome is OS. Secondary outcomes include 1)time to progression (TTP), 2)rate of completion of 6 cycles of PCV or TMZ, and 3)rate of hospitalization or death due to chemotherapy-related complications. RESULTS Of 250 cases, 20 patients (11 diffuse astrocytoma, 9 oligodendroglioma) were eligible. IDH status was mutated in 11, wild-type in 1, and unknown in 5 cases. 1p/19q co-deletion was present in 6, non-co-deleted in 1, and unknown in 13 cases. Six patients received PCV, and 14 received TMZ. Hematologic toxicity (CTCAE Grade 1-2) occurred in 3 PCV patients and 0 of 11 of assessable TMZ patients; no severe toxicity was observed. Median follow-up was 64.5 (IQR 42.5–88) months. The median OS and TTP for PCV and TMZ groups were not reached. The 5-year OS and TTP were 75% vs. 100 % (p=0.08) and 83.3% vs 81.3% (p=0.7) respectively. CONCLUSIONS There are insufficient cases and follow-up time to determine OS and TTP amongst patients treated with PCV or TMZ. Hematologic toxicity appears to be more common with PCV. Patient screening and data collection is ongoing at 8 other cancer centres.

INNV-05. CO-OCCURRENCES OF A HIGH-GRADE GLIOMA WITH CAVERNOUS MALFORMATIONS AND PATHOGENIC VARIANTS IN PDCD10 AND SMARCA4

Abstract INTRODUCTION The co-occurrence of multiple disease processes can make for more challenging diagnoses. Here we report an unusual case of a patient found to have an IDH1-mutant high-grade glioma along with multiple cerebral cavernous malformations and pathogenic germline variants in PDCD10 and SMARCA4. Case Description: A 17-year-old female presented with left arm paresthesia and weakness along with persistent headaches within the frontal and occipital regions that progressed in intensity to include nausea and emesis. A fast sequence magnetic resonance imaging (MRI) of her head was obtained that revealed the presence of multiple bilateral cystic lesions suspicious for cavernomas with the most notable lesion in the right parietal lobe. Ophthalmology consultation revealed grade III papilledema bilaterally. A full brain MRI with and without contrast was obtained and demonstrated a right anterior parietal lobe lesion with associated mass effect, as well as multiple bilateral supratentorial and left cerebellar cavernous malformations. The patient underwent tumor debulking of her dominant lesion. Pathology revealed an IDH1 mutant diffuse astrocytoma, WHO grade 3. Germline genetic testing was pursued which revealed a PDCD10 pathogenic variant consistent with familial cerebral cavernous malformation syndrome and a likely pathogenic variant in SMARCA4. Treatment of her high-grade-glioma included radiation therapy followed by maintenance oral temozolomide. DISCUSSION This case illustrates the unusual co-occurrences of a high-grade glioma with familial cavernous malformation syndrome and germline pathogenic variants in PDCD10 and SMARCA4. Our patient continues to do well clinically, but because of her now significant risk of developing ovarian cancer she has elected to undergo a prophylactic bilateral salpingo-oophorectomy. Recognition of abnormal genetic results is critical in the setting of multiple disease processes and can play a crucial role in the on-going care for a patient.

EPCO-11. GATEKEEPER INACTIVATION DRIVES TUMOR PROGRESSION TO GRADE IV ASTROCYTOMA

Abstract IDH-mutant low-grade diffuse astrocytomas frequently progress to grade IV astrocytomas with implications for patient prognosis. To better understand this process, we applied whole-genome and transcriptome sequencing to matched tumor samples collected before and after progression to grade IV astrocytomas from five patients. All tumors carried an IDH1 mutation. The number of chromosomal rearrangements was increased between 1.3 and 3.5-fold in the tumors upon progression, with the exception of one case, in which the increase was only 1.03-fold. This case exhibited a hypermutation signature caused by homozygous deletion of the MSH2 gene, which encodes a member of the DNA mismatch repair complex. The most common genomic alterations acquired at progression were homozygous deletions in the CDKN2A/ RB1 -pathway or hemizygous deletion of PTEN. Additionally, PDGFRA was amplified in two grade IV tumors, with concordantly increased expression. For one of these cases, a PDGFRA-amplified subclone is likely to be present already in the low-grade astrocytoma. We further detected intrachromosomal rearrangements closeby the genes NRG3 in the progressed tumors as well as in the The Cancer Genome Atlas (TCGA) cohort. The expression of NRG3 decreased with increasing grade in the TCGA cohort and the gene was frequently deleted. Lower NRG3 expression was associated with shorter survival in the TCGA cohort. Several miRNAs showed differential expression upon progression. For two miRNAs the predicted targets were associated with cell cycle regulation and we detected inverse correlation between miRNA and target mRNA expression. While progression seems to occur via different pathways, the predicted outcome for many of the alterations was the inactivation of tumor suppressor genes and further dysregulation of cell proliferation.

Global survival trends for brain tumors, by histology: analysis of individual records for 556,237 adults diagnosed in 59 countries during 2000-2014 (CONCORD-3).

Survival is a key metric of the effectiveness of a health system in managing cancer. We set out to provide a comprehensive examination of worldwide variation and trends in survival from brain tumors in adults, by histology. We analyzed individual data for adults (15-99 years) diagnosed with a brain tumor (ICD-O-3 topography code C71) during 2000-2014, regardless of tumor behavior. Data underwent a 3-phase quality control as part of CONCORD-3. We estimated net survival for 11 histology groups, using the unbiased nonparametric Pohar Perme estimator. The study included 556,237 adults. In 2010-2014, the global range in age-standardized 5-year net survival for the most common sub-types was broad: in the range 20%-38% for diffuse and anaplastic astrocytoma, from 4% to 17% for glioblastoma, and between 32% and 69% for oligodendroglioma. For patients with glioblastoma, the largest gains in survival occurred between 2000-2004 and 2005-2009. These improvements were more noticeable among adults diagnosed aged 40-70 years than among younger adults. To the best of our knowledge, this study provides the largest account to date of global trends in population-based survival for brain tumors by histology in adults. We have highlighted remarkable gains in 5-year survival from glioblastoma since 2005, providing large-scale empirical evidence on the uptake of chemoradiation at population level. Worldwide, survival improvements have been extensive, but some countries still lag behind. Our findings may help clinicians involved in national and international tumor pathway boards to promote initiatives aimed at more extensive implementation of clinical guidelines.

An MRI-based joint model of radiomics and spatial distribution differentiates autoimmune encephalitis from low-grade diffuse astrocytoma

The differential diagnosis between autoimmune encephalitis and low-grade diffuse astrocytoma remains challenging. We aim to develop a quantitative model integrating radiomics and spatial distribution features derived from MRI for discriminating these two conditions. In our study, we included 188 patients with confirmed autoimmune encephalitis (n = 81) and WHO grade II diffuse astrocytoma (n = 107). Patients with autoimmune encephalitis (AE, n = 59) and WHO grade II diffuse astrocytoma (AS, n = 79) were divided into training and test sets, using stratified sampling according to MRI scanners. We further included an independent validation set (22 patients with AE and 28 patients with AS). Hyperintensity fluid-attenuated inversion recovery (FLAIR) lesions were segmented for each subject. Ten radiomics and eight spatial distribution features were selected via the least absolute shrinkage and selection operator (LASSO), and joint models were constructed by logistic regression for disease classification. Model performance was measured in the test set using the area under the receiver operating characteristic (ROC) curve (AUC). The discrimination performance of the joint model was compared with neuroradiologists. The joint model achieved better performance (AUC 0.957/0.908, accuracy 0.914/0.840 for test and independent validation sets, respectively) than the radiomics and spatial distribution models. The joint model achieved lower performance than a senior neuroradiologist (AUC 0.917/0.875) but higher performance than a junior neuroradiologist (AUC 0.692/0.745) in the test and independent validation sets. The joint model of radiomics and spatial distribution from a single FLAIR could effectively classify AE and AS, providing clinical decision support for the differential diagnosis between the two conditions.

57. Identification of key molecular mechanisms in IDH-mutant brain tumors to enable precise risk stratification

Isocitrate dehydrogenase 1 and 2 (IDH) mutations are the most prevalent genetic alterations in adult low-to intermediate grade diffuse astrocytomas, anaplastic astrocytomas, and oligodendrogliomas. Previous studies of adult IDH-mutant tumors have revealed unique tumor-specific signatures, allowing for stratification based on molecular phenotype and clinical presentation. However, very little is known about pediatric IDH-mutant tumors, resulting in fragmented clinical care. To perform precise molecular profiling of IDH-mutant brain tumors to predict patient outcomes and guide potential future therapeutic developments. First, we will harmonize data from nine pediatric and adult brain tumor datasets, along with our pediatric IDH-mutant tumor samples, to determine the genetic and epigenetic profiles of the brain tumors. We will then perform a comprehensive and integrated analysis of genetic, epigenetic, transcriptomic and demographic data from IDH-mutant tumors to identify co-occurring somatic/germline and epigenetic changes within the tumors. Finally, we will determine the impact of genomic, epigenomic and demographic parameters on patient outcomes. Using exome sequencing we identified mutations of tumor suppressors like TP53, ATRX and NF1, co-occurring with IDH mutations. Additionally, we also identified genes like MUC3A and MUC16, which has not been previously found to co-occur with IDH mutations. Combining the genomic, with the transcriptomic and epigenetic data, we would enable precise risk stratification that can be used to optimize treatments for all patients with IDH-mutant tumors.

Clinical Case of Lymphomatoid Papulosis

Lymphomatoid papulosis is a rare skin disease. The incidence averages 1.5 cases per 1 million population. It is the most common in adults around the age of 40. It was previously considered as paraneoplastic dermatosis, but recent studies have confirmed that lymphomatoid papulosis is a primary CD30 + T-lymphoma of the skin. Despite the aggressive morphological features, it is benign. The disease is characterized by a tendency to spontaneous regression. Typically, skin lesions last 3-12 weeks, although in some severe cases they may last longer. Skin lesions may disappear or recur over decades. Patients require observation because a second lymphoproliferative disease develops in 10-40% of patients.
 A case of lymphomatoid papulosis in a patient with diffuse astrocytoma is presented. The patient was treated with systemic retinoids. The results of differential diagnosis and additional research methods, including dermoscopy, are given. Although the use of dermoscopy was not crucial, the results of the research showed microscopic visual differences between the elements of the rash, depending on the stage of the disease. The picture was mostly typical, however, spots formed by the areas of central erythema on the background of light brown areas, with a predominance of the reticular vessels pattern were also noted in addition to the rash elements on the hairy skull. Clarification of this feature requires further study.
 The purpose of our report is to draw the attention of dermatologists and family doctors to cases of rare dermatoses. The rareness of the disease, lack of knowledge on the clinical findings lead to diagnostic errors, “inadequate treatment”.