bluuebunny/crossref_metadata_2025 huggingface dataset:
PATH-08. LONGITUDINAL MOLECULAR EVOLUTION OF IDH-WILDTYPE GLIOBLASTOMA IN ADULTS
Authors: Lucas Calixto-Hope , Al-Adli Nadeem , Young Jacob , Morshed Ramin , Gupta Rohit , Wu Jasper , Ravindranathan Ajay , Lee Julieann , Shai Anny , Bush Nancy Ann Oberheim , Taylor Jennie , de Groot John , Butowski Nicholas , Pekmezci Melike , Perry Arie , Bollen Andrew , Theodosopoulos Philip , Aghi Manish , Chang Edward , Hervey-Jumper Shawn , Costello Joseph , Clarke Jennifer , Diaz Aaron , Phillips Joanna , Berger Mitchel , Chang Susan , Solomon David
Published: November 2023

Glioblastoma, IDH-wildtype is a clinically and molecularly heterogeneous disease. To investigate how longitudinal molecular evolution drives tumor progression and treatment resistance, we performed comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent IDH-wildtype glioblastomas from 106 patients. The vast majority (96/106, 91%) demonstrated clonal genetic evolution and/or epigenetic subclass shifting between primary and recurrent tumors. This included oncogenic alterations initially present in a minute subclone that expanded to predominate at time of recurrence. 11% (12/106) developed hypermutation with a predominance of C > T transitions at time of recurrence secondary to the alkylating effects of temozolomide. In contrast, the remaining 9% (10/106) demonstrated nearly identical molecular signatures between the primary and recurrent tumors without additional acquired genetic drivers. We found that TERT promoter mutation and CDKN2A homozygous deletion were uniformly shared between initial and recurrent tumors, indicating that these are fundamental early events in gliomagenesis, whereas alterations involving EGFR, PDGFRA, PTEN, NF1, and TP53 were commonly among the events private to initial or recurrent tumors, indicating acquisition later during clonal evolution. Furthermore, we identified that 17% (18/106) of glioblastomas underwent sarcomatous transformation (i.e. “gliosarcoma”) at recurrence, which were highly enriched for NF1 inactivation and mesenchymal epigenetic subclass. Cell type deconvolution revealed an increased abundance of T-lymphocytes, tumor-associated macrophages, and neutrophils in NF1 inactivated glioblastomas. Together, our analyses demonstrate that most glioblastomas undergo longitudinal genomic and/or epigenomic evolution. While there is no predominant genetic event enriched in recurrent tumors, personalized genomic analysis at time of recurrence can reveal acquired treatment resistance mechanisms (e.g. EGFR variant switching, temozolomide-induced hypermutation, novel MGMT gene amplification) that may impact therapeutic decision making. As such, we believe that precision medicine treatment regimens for glioblastoma should be based on molecular studies performed on the most recent surgical specimen.
PATH-10. SURGICALLY RESECTED RECURRENT DIFFUSE GLIOMAS: HISTOMOLECULAR SPECTRUM
Authors: Sahay Ayushi , Ranade Manali , Dasgupta Archya , Shah Aekta , Chatterji Abhishek , Sahau Arpita , Puranik Amey , Dev Indraja , Moiyadi Aliasgar , Shetty Prakash , Singh Vikas , Menon Nandini , Gupta Tejpal , Epari Sridhar
Published: November 2023

Histological treatment-related changes (TRC) may mimic radiological progression in diffuse-gliomas on follow-up after complete therapy. If scans suggest recurrence, patients undergo re-surgery& re-RT, if recurrence is histologically confirmed. We evaluated 1) baseline characteristics of surgically-resected gliomas re-operated for clinicoradiological suspected recurrence; 2) compared histological changes from initial surgery. All adult-type diffuse-gliomas (n=122) re-operated following complete therapy, with available initial& subsequent slides reviewed, classified as per current WHO classification. Clinico-pathological features noted. RESULTS: Baseline median age:36years (IQR:29-44years), M:F=2.21, tumor-bed recurrence in majority (116/122). Of 92 astrocytomas, 47 were IDH-mutant (grade-2:18, grade-3:14, grade-4:15); 31 were IDH-WT (histological grade-2:4, grade-3:5, grade-4:22), IDH not-available (NA) in 14. Among IDH-mutant, 26 were MGMT-methylated (MGMT-M), 11 unmethylated (MGMT-UM). In IDH-WT 4 were MGMT-M, 23 MGMT-UM. Of 30 oligodendrogliomas, 21 were grade-2, 9 grade-3. All grade-2 gliomas (25astrocytoma, 21oligodendroglioma) showed high-grade transformation at re-surgery, with 40% astrocytoma upgrading to grade-3; 60% to grade-4. Six grade-3 astrocytoma recurred at same grade, while 18 as grade-4. Of 43 grade-4, on re-surgery 11 showed predominantly TRC ( >30%) with quiescent residual tumor (4 IDH-mutant, 5 IDH-WT, 2NA), while 32 showed recurrence (10 IDH-mutant, 18 IDH-WT, 4NA), of which 11 had scant (<5%) to focal (6-30%) TRC along-with actively proliferating tumor. Only 2 oligodendrogliomas showed TRC. Median disease-free interval (DFI) between both surgeries was significantly higher for oligodendroglioma (6.76years) than astrocytoma (3.59years, p-value< 0.001); for grade-2 (5.37years)& grade-3 astrocytoma (5.19years) than grade-4 (2.85years, p-value< 0.001); grade-2 versus grade-3 oligodendroglioma (7.02years versus 4.91years, p-value 0.041), &for MGMT-M versus MGMT-UM (5.17 versus 3.02years, p-value< 0.01). Significantly, median DFI was lower for grade-4 astrocytoma with TRC than without (2.34 versus 3.27years, p-value 0.015). CONCLUSIONS: Pseudo-progression gets confused with progression more commonly in high-grade gliomas than low-grade gliomas, and is associated with surgery closer to therapy completion. Careful histological assessment thus may help guide management.
PATH-12. CONTEMPORARY MOLECULAR LANDSCAPE, SURVIVAL, AND PROGNOSTIC FACTORS IN OVER 4,000 GLIOMAS
Authors: Ghosh Hia , Patel Ruchit , Woodward Eleanor , Greenwald Noah , Bhave Varun , Maury Eduardo , Hoffman Samantha , Li Yvonne , Gupta Hersh , Spurr Liam , Touat Mehdi , Dubois Frank , Cherniack Andrew , Cioffi Gino , Antonio Chiocca E , Reardon David , Wen Patrick , Meredith David , Santagata Sandro , Barnholtz-Sloan Jill , Ligon Keith , Beroukhim Rameen , Bi Wenya Linda
Published: November 2023

INTRODUCTION

Molecular glioma classification and advances in treatment modalities have expanded therapeutic options for patients. We sought to capture the genomic landscape, prognostic features, and contemporary outcomes of gliomas.

METHODS

We assembled patients from TCGA (n=770) and multi-institutional datasets (n=3,546) with somatic mutations and copy number/structural variants. All gliomas were classified using molecular definitions (WHO 2021/cIMPACT-NOW). We identified correlations between genes through permutations testing and prognostic features through multivariate cox models with backwards elimination.

RESULTS

We analyzed 4,316 patients (median age 52yrs, 41% female), including 2,155 glioblastoma, 1,199 IDH1/2-mutant astrocytoma, 531 oligodendroglioma, and 343 other IDH1/2-wiltype gliomas. Molecular classification shifted 27.2% of gliomas from their original histopathologic designation. Canonical alterations categorized glioma subtypes, showing unique correlations with clinical features and mutual exclusivity of alterations in tumorigenic pathways. 2,433 patients had clinical outcomes: 1,296 glioblastomas, 584 IDH1/2-mutant astrocytoma, and 327 oligodendrogliomas. Patients from contemporary institutional cohorts had improved overall survival compared to TCGA patients: glioblastoma (non-TCGA:17.9mo,TCGA:15.0mo,p< 0.0001), IDH1/2-mutant astrocytoma (non-TCGA:180mo,TCGA: 87.9mo,p=0.0002), and oligodendroglioma (non-TCGA: not reached,TCGA:135mo,p< 0.0001). In contemporary cohorts, median survival in grade 2-3 IDH1/2-mutant astrocytoma (180.3mo) was double that of grade 4 (75.4mo, p< 0.0001). In GBM and oligodendrogliomas, patients >65yrs had worse outcomes than patients 20-64yrs (p< 0.001). In glioblastoma, age (HR:1.03), CDKN2A/B homozygous deletion (HR:1.22), and NF1 alterations (HR:1.31) were negatively prognostic. Chemotherapy (HR:0.64), MGMT-methylation (HR:0.44), 19q-gain (HR:0.70), and non-TCGA cohort (HR:0.54,HR:0.34) were positively prognostic. In IDH1/2-mutant astrocytoma, CDKN2A/B homozygous deletion (HR:2.75), CCND2 alteration (HR:2.89), EGFR amplification (HR:2.93), PDGFRA alteration (HR:2.87), 9p-loss (HR:3.09), and 10q-loss (HR:1.99) were negatively prognostic; white race was the only prognostically positive feature (HR:0.35).

CONCLUSIONS

Overall survival in gliomas has improved over time. We corroborated canonical features and identified new prognostic features that are subtype-specific. The unique molecular profiles across glioma subtypes provide insight into biological drivers that influence heterogenous clinical outcomes.
PATH-13. APPLICATIONS OF SPATIAL TRANSCRIPTOMICS FOR THE DIAGNOSTICS OF GLIOMAS
Authors: Ritter Michael , Blume Christina , Tang Yiheng , Patel Bhuvic , Patel Areeba , Sievers Philipp , Seferbekova Zaira , Berghaus Natalie , Herold-Mende Christel , Wick Wolfgang , Gerstung Moritz , von Deimling Andreas , Heiland Dieter Henrik , Sahm Felix
Published: November 2023

Due to their infiltrative growth, diffuse gliomas can pose a major challenge for neuropathologists. Lack of specific immunohistochemistry markers for some gliomas like IDH-wildtype glioblastoma can make it hard to identify the tumour cell content or distinguish between tumour and reactive gliosis. Other hurdles are high fractions of DNA from healthy cells in molecular diagnostic analysis, or scarce tissue, which can result in a failed DNA extraction. To overcome these limitations, we evaluated the application of spatial transcriptomics on 14 glioblastoma bulk resections and 18 stereotactic biopsies of 7 glioblastoma, IDH wildtype, 4 oligodendroglioma IDH-mutant and 7 astrocytoma IDH-mutant samples with the aim to generate a diagnostic report containing all information needed by the neuropathologist and clinician. Using the SPATA2 R package, we were able to infer the copy number variation (CNV) profiles for each spot. When comparing the inferred CNVs to the CNVs calculated by the 850K methylome analysis, a correlation between CNVs identified from the 850K data and the inferred CNVs could be seen. For diagnostic relevant CNVs of chr. 7, 10, 1p and 19q, the inferred CNVs were concordant with the 850K data in 100% of the cases with confirmed tumour tissue. CNVs from spatial transcriptomics were able to reveal sub-clones, which could not be detected by the 850K array data. The CNVs could then be used in combination with a deconvolution approach to determine the tumour burden of the tissue. Using RNA expression, the immunohistochemistry staining of important diagnostic markers like NeuN, GFAP and Ki67 was predicted. In addition, the spatial gene expression could be used to identify the glioblastoma subtype based on the gene expression of different methylation subtypes. All the above-mentioned analysis also generated meaningful results for tissue fragments smaller than 1mm in diameter, which are too small for molecular diagnostic analysis.
PATH-22. CLINICAL AND MOLECULAR NEUROPATHOLOGICAL FEATURES OF EPITHELIOID GLIOBLASTOMA
Authors: Adachi Jun-ichi , Shirahata Mitsuaki , Suzuki Tomonari , Mishima Kazuhiko , Nishikawa Ryo
Published: November 2023

BACKGROUND

Epithelioid Glioblastoma (E-GBM) has been identified as a pathological subtype of Glioblastoma. It is a rare glioblastoma and is mainly known in case reports, and the details of its clinical features and genetic characteristics are not clear. Here, we retrospecivly studied the results of clinical course and genetic features of E-GBM.

METHODS

Four patients who underwent surgery at our institution and were diagnosed with E-GBM were included in this study. Histological diagnosis was obtained by surgical excision in all cases. We extracted DNA from the resected tissues and analyzed glioma-related genes using various methods such as high resolution melting (HRM), MGMT methylation-specific HRM, digital PCR, and Multiple ligation-dependent probe amplification (MLPA) analysis.

RESULTS

E-GBM tended to develop at a slightly younger age than other general glioblastoma. All patients underwent surgical resection followed by radiation therapy and concurrent temozolomide therapy. However, none of the patients were able to transition to temozolomide maintenance therapy due to disease progression, and the overall survival period was 8 to 19 weeks, indicating an extremely poor prognosis. Genetic analysis revealed both TERT promoter mutations and BRAFV600E mutation in all cases. In addition, IDH mutation was not found, and MGMT promoter methylation was unmethylated in all cases. EGFR amplification, CDKN2A/2B homozygous deletion and 1p/19q co-deletion were not found in any cases.

CONCLUSION

The simultaneous mutations of TERT promoter with BRAFV600E could serve as diagnostic molecular markers for the diagnosis of E-GBM. Standard therapy for glioblastoma was not expected to be effective in treating this tumor. It was considered necessary to introduce new therapeutic strategies such as early administration of BRAF and MEK inhibitors.
PATH-23. CLINICOPATHOLOGIC ANALYSIS OF NOVEL METHYLATION CLUSTERS OF IDH-WILDTYPE DIFFUSE GLIOMAS
Authors: Singh Omkar , Aldape Kenneth , Abdullaev Zied , Turakulov Rust , Andreiuolo Felipe , Costa Felipe D'Almeida , Camelo-Piragua Sandra , Pytel Peter , Zhang Daniel , Borys Ewa , Nix Stephen , Fernandes Igor , Sloan Emily , Phillips Kester , Serafini Luciano Neder , Trejo-Lopez Jorge , Mendez Joe , Eberhart Charles , Smith-Cohn Matthew , Neill Stewart , Christensen Brock , Macaulay Robert , Colman Howard , Nguyen Aivi , Giannini Caterina , Li Rong , Mandell James , Kessler Tobias , Wick Wolfgang , Jones Chris , Clarke Matthew , MacKay Alan , Helgager Jeffrey , Lee Han , Lopez Giselle , Perry Arie , Ahmadian Saman , Haeri Mohammad , Wang Shih-Hsiu , Dahiya Sonika , Souza Andrea , Marques Gregorio Joao Vitor Antunes , Sterman Hugo , Nasrallah MacLean P , Aboud Orwa
Published: November 2023

Methylation profiling of brain tumors has revealed novel clusters whose biological and clinical significance is unknown. These include three entities termed by the 12.5 version of the Heidelberg methylation classifier as adult-type diffuse high grade glioma, IDH-wildtype, subtype B (HGG_B), subtype E (HGG_E), and subtype F (HGG_F). We have identified 75 cases belonging to these groups: HGG_B (25 cases, 32% female), HGG_E (40 cases, 42% female), and HGG_F (18 cases, 33% female). Although originally characterized as “adult-type,” we find that 70% of HGG_E cases are pediatric, with a median age at diagnosis of 11 years. HGG_B cases are predominantly seen in young adults, and HGG_F in older adults. The histology varies among methylation classes, with HGG_B cases demonstrating high-grade, predominantly astrocytic, morphology, while HGG_E cases demonstrate high-grade glial histology with distinct nuclear features, and HGG_F cases show highly infiltrative but lower grade glial morphology. Patient outcome data obtained to date shows a collective median survival exceeding 5 years, suggesting re-consideration of the proposed grading for these tumors. MGMT promoter methylation differs across the HGG_B (0%), HGG_E (12%), and HGG_F (0%) subtypes. Mutational analyses show enrichment of TERT promoter mutations in the HGG_F group, while HGG_E samples are enriched for tumors with POLE mutations and elevated tumor mutation burden. HGG_E tumors show epigenetic similarity to pediatric high-grade diffuse gliomas (pedHGG_RTK1A); we therefore propose that HGG_E be considered a pediatric-type HGG. HGG_B tumors show demographic and genomic similarities to high-grade astrocytomas with piloid features, including a subset of cases with CDKN2A/2B loss and ATRX mutation. HGG_F separate into two groups dictated by brain location, and despite the presence of TERT promoter mutations, appear distinct from GBMs. Overall, our work represents an initial effort to understand the morphologic, genomic and clinical characteristics of these previously uncharacterized subtypes of gliomas.
PATH-25. EXPLORING THE PROGNOSTIC IMPLICATIONS OF MOLECULAR ALTERATIONS IN ASTROCYTOMAS USING COMPREHENSIVE GENOMIC PROFILING (CGP)
Authors: McNamee Nicholas , Lin Frank , Sim Hao-Wen , Napier Chrstine , Thomas David , Simes John , Thavaneswaran Subotheni
Published: November 2023

BACKGROUND

Astrocytomas display molecular heterogeneity with prognostic implications for genomic alterations, including IDH, EGFR, TERT promoter and CDKN2A/B. Increasing access to comprehensive genomic profiling (CGP) provides an opportunity to characterize the genomic landscape of these tumors and their clinical implications.

METHODS

Patients with astrocytomas undergoing CGP through the Australian Molecular Screening and Therapeutics (MoST) precision oncology program between March 2017 and January 2022 were identified; the frequencies of genomic alterations were assessed. Associations between overall survival (OS) and alterations in EGFR, TERT promoter and/or CDKN2A/B were estimated using Kaplan-Meier methods.

RESULTS

214 patients with astrocytomas were included. Median age was 49 years; majority were ECOG performance status 0-1 at screening (N=200/214, 93%) and histologically grade 4 (N=184/214, 86%). The median OS (mOS) for the cohort was 26.2mo (95%CI 24.0-31.5). For histologically grade 2/3 IDH-mutant tumors, mOS was 31.3mo (N=1) and 122.6mo (N=11, 95%CI 110-NA) for those with or without alterations in EGFR, TERT promoter and/or CDKN2A/B, respectively. For histologically grade 2/3 IDH-wildtype tumors, mOS was 19.9mo (N=7, 95%CI 15.8-NA) and 118.5mo (N=10, 95%CI 77.3-NA), respectively. For histologically grade 4 IDH-mutant tumors, mOS was 81.3mo (N=4, 95%CI 32.7-NA) and 82.8mo (N=15, 95%CI 71.0-NA), respectively. For histologically grade 4 IDH-wildtype tumors, mOS was 19.6mo (N=120 [56% TERT promoter, 42% EGFR, 14% CDKN2A/B], 95%CI 18.0-24.8) compared to 32.1mo (N=45, 95%CI 22.0-58.6; logrank P=0.0015), respectively. In grade 4 IDH-wildtype tumors additional co-occurring alterations involved PTEN (39%), TP53 (33%), NF1 (21%), RB1 (13%), CDK4 (13%) and PIK3CA (5%) genes. For the overall cohort, potentially actionable variants were seen in BRAF (5%), KIT (5%), MSH2 (2%), FGFR1 (1%) and FGFR3 (4%). Tumor mutational burden was ≥5 mutations/ megabase in 14%, without significant OS impact.

CONCLUSION

CGP provides additional prognostic information that complements histological grading. This demonstrates an emerging role in understanding the molecular heterogeneity of astrocytomas.
PATH-28. OUTCOME IMPACT OF THE CDKN2A/B HEMI-ZYGOUS DELETION IN IDH-MUTANT ASTROCYTOMA
Authors: Otsuji Ryosuke , Hata Nobuhiro , Yamamoto Hidataka , Kuga Daisuke , Hatae Ryusuke , Sangatsuda Yuhei , Fujioka Yutaka , Noguchi Naoki , Nakamizo Akira , Mizoguchi Masahiro , Yoshimoto Koji
Published: November 2023

Homozygous deletion of CDKN2A/B is a strong adverse prognostic factor in IDH-mutant astrocytomas. However, the impact of hemizygous deletions is unknown. We investigated the impact of CDKN2A/B hemizygous deletions on prognosis. We enrolled 52 adult patients with IDH-mutant astrocytomas between December 2002 and November 2021. CDKN2A/B deletion was evaluated with multiplex ligation-dependent probe amplification (MLPA) with threshold correction using a digital PCR-based IDH-mutant allele frequency. Immunohistochemical analysis of p16/MTAP was performed in CDKN2A/B deletion cases. Of the 52 cases, nine and three were classified as hemizygous and homozygous deletions, respectively. The OS was shorter in the order of homozygous deletion, hemizygous deletion, and copy-neutral groups (median OS:38.5, 59.5, and 93.1 months, respectively). Multivariate analysis revealed hazard ratios of 9.30 (p = 0.0191) and 2.44 (p = 0.0943) for homozygous and hemizygous deletions, respectively. Regarding PFS, in astrocytoma, the time to recurrence tended to be shorter in the order of homozygous deletion, hemizygous deletion, and copy-neutral, with a median PFS of 20.9, 38.9, and 53.0 months, respectively. There was no significant difference in PFS between the hemizygous deletion and copy-neutral groups (p = 0.4030). Malignant transformation was confirmed in 1 of 1 homozygous deletion, 2 of 3 hemizygous deletions, and 5 of 16 copy-neutrals. No significant difference was observed between the hemizygous deletion and copy-neutral groups; however, hemizygous deletion tended to require less time for malignant transformation than copy-neutral group (p = 0.1112). Immunohistochemistry revealed p16-negative and MTAP retention in cases with a hemizygous deletion, whereas homozygous deletions had p16-negative and MTAP loss. In conclusion, CDKN2A/B hemizygous deletions exerted a negative impact on OS in astrocytomas. Immunohistochemistry of p16/MTAP can be utilized to validate hemizygous or homozygous deletions in combination with conventional molecular diagnosis.
PATH-29. CLINICAL OUTCOMES FOR YOUNG ADULTS WITH H3 G34-MUTANT GLIOMAS
Authors: Mankuzhy Nikhil , Pike Luke , Miller Alexandra , Imber Brandon
Published: November 2023

Diffuse hemispheric gliomas are rare brain tumors with mutations in H3F3A codon 34 which have recently been molecularly classified as their own entity. They are primarily diagnosed in adolescents and young adults and are generally associated with a poor prognosis. Given the limited published clinical data on young adults with H3 G34-mutant diffuse hemispheric glioma, we reviewed our institutional experience to evaluate clinical outcomes. We reviewed pathology reports and targeted sequencing results from patients at our institution for alterations in G34. All cases of patients 18 years or older were reviewed for baseline characteristics and clinical outcomes. Eleven patients were identified that followed at our institution since 2013. Median age at diagnosis was 24 (range 19-32) and nine were male. Three had multifocal intracranial disease at diagnosis, while 8 had localized disease. All but one underwent surgery, and all were treated with radiotherapy and temozolomide. Four received an additional investigative systemic agent for initial treatment. At time of review, 9 patients had recurred and median time to first recurrence was 6.4 months. Site of first failure was intracranial in all patients, of which three developed multifocal intracranial recurrence. Overall, 6 patients eventually developed multifocal intracranial disease and 1 patient developed leptomeningeal disease involving the spinal cord. Four patients received subsequent radiation to the brain and one received radiation to the spine. After progression, one patient received one subsequent line of systemic therapy, 7 patients received two lines, and one received three lines before they died of disease. Median overall survival from diagnosis was 20 months, and median survival from first failure was 11 months. For H3 G34-mutant glioma, survival is comparable to IDH WT Glioblastoma patients. These findings augment the existing literature on histone altered gliomas. Further investigation of patterns of failure is needed to guide optimal therapy.
PATH-33. MORPHOLOGY, MOLECULAR FEATURES, AND CLINICAL BEHAVIOR OF METHYLATION CLASS PLEOMORPHIC XANTHOASTROCYTOMA
Authors: Dampier Chris , Shah Niharika , Galbraith Kirstyn , Rajan Sharika , Vaubel Rachael , Ketchum Courtney , Costa Felipe D'Almeida , Ferman Sima , Neto Osorio Lopes Abath , Wadhwani Nitin , Lee Han , Mao Qinwen , Robinson Lorraina , Marshall Michael , Baker Tiffany , Cathcart Sahara , Alexandrescu Sanda , Fernandes Igor , Cotter Jennifer , Gilani Ahmed , McCord Matthew , Thomas Diana , Thomas-Ogunniyi Jaiyeola , Pytel Peter , Lopes Beatriz , Conway Kyle , Gregory Jason , Andreiuolo Felipe , Nirschl Jeffrey , Abdullaev Zied , Quezado Martha , Giannini Caterina , Snuderl Matija , Aldape Kenneth
Published: November 2023

Methylation profiling has revealed unexpected relationships between traditional histopathology-based versus biologically-based classifications of brain tumors. Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the same methylation signature as classical PXA but with additional morphologic patterns, including overlap with glioblastoma (GBM). To characterize mcPXA, we examined epidemiologic, histologic, and molecular features as well as clinical behavior of a cohort (n=313) of tumors matching to mcPXA by the DKFZ classifier (v12 score >= 0.85). Patient median age was 19 (range 1-73) with a female predominance (178 female/135 male). CDKN2A/B homozygous deletion was observed in 273 (87%) cases. In the subset of cases tested for BRAF p.V600E (n=120), 111 (93%) harbored the mutation. Concomitant chr7+/chr10- was observed in 66 (21%) cases. In the subset of cases tested for TERT promoter mutations (n=50), 11 (22%) harbored the mutation, always with co-occurrence of BRAF p.V600E (11/11) and infrequently with chr7+/chr10- (3/11). MGMT promoter methylation was observed in 40 (13%) cases. Overall and progression-free survival (OS, PFS) in mcPXA were similar to grade 2-3 IDH-mutant astrocytoma (A-IDH). Prognostic factors in mcPXA included GBM-like histopathology (defined as cases diagnosed as GBM prior to methylation profiling), concomitant chr7+/chr10-, and MGMT promoter methylation. GBM-like histopathology was associated with shorter OS (p=0.02) and PFS (p< 0.01) compared to cases without GBM-like histopathology. Concomitant chr7+/chr10- was associated with shorter PFS (p=0.02), and MGMT promoter methylation was associated with shorter OS (p=0.03). Our findings demonstrate that mcPXA tumors affect adolescents and young adults, share molecular features of classical PXA, and manifest clinical behavior similar to classical PXA, but subsets of tumors with atypical features (chr7+/chr10-, MGMT promoter methylation, and/or GBM-like histopathology) are more aggressive. The use of a molecular definition of PXA reveals that this tumor type is more common than previously appreciated and warrants in-depth study for therapeutic options.
PATH-34. CLINICOPATHOLOGIC CHARACTERIZATION OF DIFFUSE PEDIATRIC-TYPE HIGH-GRADE GLIOMA, H3-WILDTYPE AND IDH-WILDTYPE: AN AGGRESSIVE AND GENOMICALLY COMPLEX GROUP OF TUMORS AFFECTING CHILDREN AND ADULTS
Authors: Wu Zhichao , Turakulov Rust , Chung Hye-Jung , Dazelle Karen , Abdullaev Zied , Costa Felipe D'Almeida , Neto Osorio Lopes Abath , Wadhwani Nitin , Mao Qinwen , Robinson Lorraina , Marshall Michael , Frosch Matthew , Cathcart Sahara , Alexandrescu Sanda , Fernandes Igor , McCord Matthew , Horbinski Craig , Thomas Diana , Pytel Peter , Conway Kyle , Gregory Jason , Nirschl Jeffrey , Vogel Hannes , Chandra Krishnan , Gokden Murat , Lucas Calixto-Hope , Wilson Yelena , Han Peng , Goodman Abigail , Dahiya Sonika , Vortmeyer Alexander , Quezado Martha , Aldape Kenneth , Cimino Patrick
Published: November 2023

Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (pHGG) was newly introduced in the 2021 WHO CNS5. pHGG is further divided into distinct methylation subtypes (MYCN, A/B, RTK1, RTK2). Compared to adult-type diffuse gliomas, relatively little is known about pHGG, especially in the adult population and we therefore aimed to more fully understand the clinicopathological spectrum of pHGG. Our cohort of methylation-profiling-confirmed pHGGs (n=299) included pediatric (n=211) and adult (n=88) populations (age range=0-79 years). The mean age was highest in the A/B subtypes (27.7 years) and lowest in the MYCN subtype (13.5 years). Median survival (18 months for the entire cohort), MGMT promoter methylation status, and history of prior radiation did not differ between the pediatric and adult populations. MGMT promoter methylation was highest in RTK1C (51%) and lowest in subtype A (0%). All those with history of prior radiation (n=37) were classified as RTK1, with subclass distribution differing between patients with history of prior radiation (RTK1A=7.3%, RTK1B=41.8%, RTK1C=50.9%) versus those without (RTK1A=41.8%, RTK1B=21.5%, RTK1C=36.7%). Interestingly, the genomic somatic copy number alteration (SCNA) load did not differ for RTK1 based on prior radiation history status. However, adult pHGG did harbor a higher SCNA load than pediatric pHGG (p< 0.01). The higher SCNA load was driven by genomic copy number losses rather than amplifications, including adult pHGG harboring more CDKN2A/B and RB1 deletions. Amplifications of MET, CDK4, PDGFRA, MYC, and KIT were present across all subtypes, but were enriched in RTK1. MYCN amplification was enriched in the MYCN subtype. EGFR, MDM4, and CDK6 amplifications did not have subtype predilection. Overall, while the pediatric and adult pHGG have similar outcomes, there are differences in their genomic structures, most notably in adult pHGG harboring a higher SCNA load. Overall, pHGG represent a biologically diverse set of clinically aggressive tumors that warrant further intensive study.
PATH-36. CLASSIFICATION OF DIFFUSE GLIOMA SUBTYPES USING A NEXT-GENERATION SEQUENCING PANEL IN ACCORDANCE WITH THE 2021 WORLD HEALTH ORGANIZATION CRITERIA
Authors: Kim Yongjae , Park Dohoon , Park Hwan , Park Kang-Seo , Sung Chang Ohk , Park Ji Eun , Yoon Shinkyo , Lee Ho-Su
Published: November 2023

Diffuse gliomas, which are the most common primary brain tumors, exhibit significant variations in their characteristics such as morphology, location, genetic alterations, and response to treatment. In 2021, the World Health Organization (WHO) introduced updated guidelines for glioma classification based on molecular alterations. This study aimed to classify 476 primary diffuse glioma samples utilizing a next-generation sequencing OncoPanel AMC, targeted DNA sequencing, in accordance with the 2021 WHO criteria. The samples were divided into 3 subtypes: oligodendroglioma (ODG; n=70), diffuse astrocytoma (DA; n=65), and glioblastoma (GBM; n=341). The median age of patients diagnosed with GBM (62 years) was significantly higher compared to those with ODG (50 years) and DA (42 years) (Page=0.056 [ODG vs.DA], 3.06×10-11 [ODG vs.GBM], and 3.06×10-11 [DA vs.GBM]). Gender and tumor mutational burden did not exhibit significant associations with the subtypes. Consistent with the 2021 WHO criteria, ODG samples exhibited frequent mutations in IDH1 (91%), NOTCH1 (27%), FUBP1 (23%), CIC (20%), and IDH2 (9%). DA samples had a high prevalence of mutations in IDH1 (98%), TP53 (91%), ATRX (78%), and IDH2 (2%). In contrast, GBM samples showed mutations in IDH-wildtype and EGFR (18%). Cox multivariate regression analysis of 341 GBM patients (median survival=15.9 months) revealed that older age, lack of MGMT promoter methylation, and impaired performance status (Karnofsky performance scale< 80) were significantly associated with survival outcome (HRage=1.40, Page=7.64×10-3, HRMGMT=1.43, PMGMT=6.98×10-3, and HRKPS=1.79, PKPS=3.05×10-6). In summary, by utilizing the AMC OncoPanel and the 2021 WHO criteria, we successfully classified diffuse glioma into three distinct.
PATH-37. PROGNOSTIC IMPACT OF TUMOR MUTATIONAL BURDEN AT BASELINE IN IDH-WILDTYPE GLIOBLASTOMA
Authors: Park Dohoon , Park Hwan , Kim Yongjae , Park Kang-Seo , Park Ji Eun , Sung Chang Ohk , Yoon Shinkyo , Lee Ho-Su
Published: November 2023

Tumor mutational burden (TMB) has emerged as a potential biomarker for survival and response to immune checkpoint therapy. However, limited data are available regarding the prognostic impact of TMB at baseline in glioblastoma (GBM). This study aimed to evaluate the somatic mutation status and survival outcomes of isocitrate dehydrogenase (IDH) wildtype GBM using a dataset of GBM samples from cBioPortal and single tertiary hospital. A total of 840 samples were extracted from cBioPortal, including 410 samples from Memorial Sloan Kettering Cancer Center (MSKCC), 234 samples from The Cancer Genome Atlas (TCGA), 106 samples from Glioma Longitudinal Analysis Consortium (GLASS), and 90 samples from Clinical Proteomic Tumor Analysis Consortium (CPTAC). Additionally, we enrolled 341 GBM patients with targeted sequencing data (OncoPanel AMC) from Asan Medical Center. The TMBHigh group was defined as the top 10% value of TMB within each cohort. Among the total of 1,081 IDH-wt GBM samples, 104 samples were classified as TMBHigh. No significance difference in overall survival (OS) was observed between the TMBHigh group and the non-TMBHigh group across the 5 cohorts. The mutations of DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and POLE) was significantly higher in the TMBHigh group compared with the non-TMBHigh group in 3 of 5 cohorts (pASAN=1.02x10-4, pMSKCC=1.5x10-2, and pCPTAC=1.26x10-2). However, when we calculated the indel to total mutation ratio (I-index) to dedect microsatellite Instability, only the MSKCC cohort showed a higher I-index in the TMBHigh group compared to the non-TMBHigh group (16.7% vs 13.7%, p=2.67x10-3). In summary, there is no significant association between TMB at baseline and poor survival outcomes in IDH-wildtype GBM. Further research is needed to explore the potential implications of TMB as a prognostic marker and its relevance for personalized treatment strategies in GBM patients.
PATH-43. INFRATENTORIAL IDH-MUTANT ASTROCYTOMAS REQUIRE HIGH INDEX OF SUSPICION FOR ACCURATE DIAGNOSIS
Authors: Ormond David , Guzman Samuel , Ney Douglas , DeMasters B K
Published: November 2023

BACKGROUND

Banan et al (PMID 2776277) recently identified infratentorial IDH-mutant astrocytomas (Inf-IDHmt) as a distinct subtype in which 80% have non-canonical mutations, precluding the use of IDH1 R132H immunohistochemistry (IHC) for diagnosis. They note “molecular testing is critical for detection of these tumors”. Only 47% have ATRX loss by IHC and only 56% have MGMT promotor methylation. Thus, it is critical that neurosurgeons take this into account during surgical planning due to the requirement for adequate tissue sample volume necessary for diagnosis. We review these diagnostic challenges in our recent single institution experience with these tumors.

METHODS

Database text word searches were conducted for the years 2007-2023 to generate cases, coupled with chart review.

RESULTS

7 cases were identified: 3 male and 4 female, ages 27-44. All cases were small stereotactic biopsies. The histological diagnosis was made exceptionally challenging by paucity of tumor cells (especially in grade 2), coupled with the fact that 5 of 7 had non-canonical IDH-mutation and 5 of 7 showed ATRX retention by IHC, necessitating a very high index of suspicion on the part of the pathologist to send for next-generation sequencing (NGS). Due to the rare co-expression of IDH and histone mutations in this subtype, 6 of 7 had H3 K27M IHC conducted; all were negative. Due to small tissue volumes, MGMT promotor methylation testing could only be conducted on 3 of 7 cases; testing was uninformative on these 3.

CONCLUSION

Preoperative high index of suspicion is required to obtain maximal safe biopsy volumes of tissue for molecular and MGMT methylation testing, which should be conducted on virtually all brainstem and cerebellar biopsies.
PATH-48. KI-67 INDEX AS A PREDICTIVE MARKER OF MENINGIOMA CLINICO-PATHOLOGIC COURSE AND RECURRENCE FOLLOWING SURGICAL RESECTION: A RETROSPECTIVE STUDY
Authors: Mizrachi Mark , Hartley Benjamin , Saleem Shahzaib , Hintz Eric , Ziemba Yonah , Li Jinyu , Schulder Michael
Published: November 2023

BACKGROUND/OBJECTIVE

Meningiomas are the most common primary intracranial tumor in adults. Although usually benign, they have a variable clinical course. Ki-67, a nuclear protein involved in cell cycle regulation, has been widely studied as a marker of cellular proliferation in various cancers. However, the prognostic significance of Ki-67 in meningiomas remains controversial. Here, we investigate the Ki-67 index, as a predictive marker of meningioma recurrence following surgical resection and compare it to established prognostic markers such as WHO grade and degree of resection.

METHODS

The medical records of 451 consecutive patients with previously untreated cranial meningiomas who underwent resections from January 2011 to January 2021 at North Shore University Hospital (NSUH) were reviewed. Collected data included WHO grade, Ki-67 proliferative index, degree of resection, and meningioma recurrence.

RESULTS

There were 290 patients with grade I, 154 with grade II, and 7 with grade III meningiomas. The average post-resection follow-up period was 4 years, and 82 tumors (18%) recurred. Recurrence occurred significantly more frequently in tumors with a Ki67 index of 5 or more (31%) compared to those with a Ki67 index less than 5 (10.4%). Likewise, higher WHO grades were associated with a higher rates of recurrence, with rates of 11.3%, 27.9%, and 71.4% for grades 1, 2, and 3, respectively. Higher WHO grades also correlated with higher Ki67 scores (2.59, 10.01, and 20.71) for grades 1, 2, and 3, respectively. Additionally, a multivariate logistic regression model identified ki67, WHO grade and degree of resection as independent predictive variables for meningioma recurrence.

CONCLUSION

Our 10-year retrospective study suggests that the Ki67 index is a promising predictive marker for recurrence of intracranial meningioma following surgical resection. Our findings add to a growing body of data which supports inclusion of ki67 index in the WHO grading criteria.
PATH-51. GENETIC CHARACTERIZATION AND MUTATIONAL PROFILING OF FORAMEN MAGNUM MENINGIOMAS: A MULTI-INSTITUTIONAL STUDY
Authors: Hua Lingyang , Fujio Shingo , Alkhatib Majd , Herold Sylvia , Eyuepoglu Ilker , Clark Victoria , Wakimoto Hiroaki , Shankar Ganesh M , Cahill Daniel , Brastianos Priscilla , Schackert Gabriele , Juratli Tareq
Published: November 2023

OBJECTIVE

Foramen magnum (FM) meningiomas pose significant surgical challenges and have high morbidity and mortality rates. This study aims to investigate the distribution of clinically actionable mutations in FM meningiomas and identify clinical characteristics associated with specific mutational profiles.

METHODS

We conducted targeted next-generation sequencing of 62 FM meningiomas from three international institutions, covering all relevant meningioma genes (AKT1, KLF4, NF2, POLR2A, PIK3CA, SMO, and TRAF7). Additionally, we retrospectively collected and evaluated patient and tumor characteristics, including age, sex, radiological features, and tumor location.

RESULTS

Our cohort consisted of 46 female and 16 male patients. Clinically significant driver mutations were detected in 58 patients (93.5%). The most commonly observed alteration was TRAF7 mutations (n=26, 41.9%), followed by AKT1(E17K) mutations (n=19, 30.6%). Both mutations were significantly associated with an anterolateral tumor location relative to the brainstem (p=0.0078). Tumors harboring these mutations predominantly (89.3%) displayed meningiothelial histology. NF2 mutations were present in 11 cases (17.7%) and were associated with posterior tumor location, in contrast to tumors with TRAF7 and AKT1(E17K) mutations. Other common mutations in FM meningiomas included POLR2A mutations (n=8, 12.9%), KLF4 mutations (n=7, 11.6%), and PIK3CA mutations (n=3, 4.8%). These mutations exclusively occurred in female patients and showed no significant correlation with specific tumor locations. Eight tumors exhibited intratumoral calcification which was significantly more frequent in NF2-mutant compared with AKT1-mutant FM meningiomas (p=0.047).

CONCLUSIONS

Our findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future.
PATH-59. SYSTEMATIC CHARACTERIZATION OF ANTIBODY-DRUG CONJUGATE TARGETS IN CENTRAL NERVOUS SYSTEM TUMORS
Authors: Coy Shannon , Lee Jong Suk , Chan Sabrina J , Woo Terri , Jones Jacquelyn , Alexandrescu Sanda , Wen Patrick , Sorger Peter K , Ligon Keith , Santagata Sandro
Published: November 2023

BACKGROUND

Antibody-drug conjugates (ADCs) enhance the specificity of cytotoxic drugs by directing them to cells expressing target antigens. Multiple ADCs are FDA-approved for solid cancers, including those expressing ERBB2/HER2, TACSTD2/TROP2, NECTIN4, folate receptor 1 (FOLR1), and tissue factor (CD142/TF). Recently, a next-generation ADC targeting HER2 (Trastuzumab-Deruxtecan) increased survival and reduced growth of brain metastases in treatment-refractory metastatic breast cancer, even in tumors with low HER2 expression. Thus, low-level ADC target expression may be sufficient for treatment responsiveness, and CNS tumors may be responsive to next-generation ADC. However, ADC target expression is poorly characterized in most CNS tumors.

METHODS

To systematically characterize ADC target expression in CNS tumors, we analyzed publicly available RNA-sequencing and proteomic data from the Children’s Brain Tumor Network (n=188 tumors) and GEO RNA-expression datasets (n=356 tumors) to evaluate expression of 14 potential ADC targets that are FDA-approved or under clinical investigation in solid cancers. We also used immunohistochemistry to score the levels of HER2, HER3, NECTIN4, TROP2, CLDN6, CLDN18.2, and CD276/B7-H3 protein in glioblastoma (GBM), oligodendroglioma, meningioma, ependymoma, pilocytic astrocytoma, medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), adamantinomatous craniopharyngioma (ACP), papillary craniopharyngioma (PCP), and primary CNS lymphoma (n=575 total tumors).

RESULTS

Multi-modal pan-CNS analysis showed consistent subtype-specific expression of ADC target proteins. Most tumors expressed HER3, B7-H3, and NECTIN4. Ependymomas (n=44) strongly expressed HER2 (36/44; 81% of cases by IHC), while meningiomas weakly-moderately expressed HER2 in most tumors (201/234; 86%). ACP (n=15) and PCP (n=3) strongly expressed B7-H3 (100% of cases), with TROP2 and HER2 expression in whorled ACP epithelium (100% of cases). AT/RT strongly expressed CLDN6 (8/9; 89%). GBM showed little subtype-specific marker expression, suggesting a need for further target development.

CONCLUSIONS

CNS tumors exhibit subtype-specific expression of ADC targets including several FDA-approved for other indications. Clinical trials of ADCs in CNS tumors may therefore be fruitful.
PATH-60. BRAIN TUMORS: FROM ONCOSTREAMS TO LIQUID CRYSTALS
Authors: Lowenstein Pedro , Faisal Syed M , Argento Anna , Comba Andrea , Motsch Sebastien , Blanch-Mercader Carles , Castro Maria
Published: November 2023

High grade gliomas (HGG) are the most common, destructive, and varied of all malignant brain tumors. HGG are heterogeneous at the histological, cellular, and molecular level, which makes them hard to study and treat. One particular tumor pathological differentiation is mesenchymal differentiation, containing oblong, motile cells. We recently noted distinct fascicles of elongated, aligned, mesenchymal-like cells in mouse and human gliomas, which we denote as oncostreams. Time-lapse confocal microscopy in ex vivo slices, and in in vivo two photon imaging, indicated that cells in oncostreams are motile. Oncostream motility was classified based on cellular orientation. The molecular characteristics of oncostreams were determined by laser capture microdissection, RNA-sequencing, and bioinformatics. 43 genes were differentially expressed; COL1A1 was overexpressed in oncostreams. Inhibition of COL1A1 in mouse gliomas, using the Sleeping Beauty transposon model, reduced oncostreams, tumor aggressiveness, proliferation, tumor vasculature, and collective glioma invasion. More recently, we elucidated that glioma cell growth in vitro, and potentially in vivo displays domains of nematic orientation (oncostreams) and topological defects, suggesting that gliomas are organized as liquid crystals. Topological defects are singularities of local orientation, and characteristic of liquid crystals. Further, studies of gliomas in vivo, suggest the presence of ±1/2 topological defects. Thus, nematic orientation and topological defects are present in brain tumors in vitro and in vivo. This provides support for our hypothesis that brain tumors are organized as active liquid crystals. As topological defects have been exploited to alter liquid crystal behavior, we hypothesize that manipulating brain tumor liquid crystalline behavior will be of therapeutic importance. Comba et al. (2022) Spatiotemporal analysis of glioma heterogeneity reveals COL1A1 as an actionable target to disrupt tumor progression. Nature Communications: Wood et al. (2023) Scale-free correlations and potential criticality in weakly ordered populations of brain cancer cells. Science Advances (in press).
PATH-61. NGS DATA INFLUENCE ON CLINICIAN DECISION-MAKING ACROSS PRIMARY BRAIN TUMORS AT NORTHWESTERN UNIVERSITY
Authors: Eckburg Adam , John Jordan , Kumthekar Priya
Published: November 2023

BACKGROUND

Next-generation sequencing (NGS) is routinely completed for systemic solid tumors; however, its utility is unclear in brain tumors. Our study sought to investigate and compare the impact of NGS on treatment decision-making for glioblastoma and other primary brain tumors.

METHODS

An IRB-approved retrospective chart review was conducted with patients at Northwestern University who were diagnosed with a primary brain tumor receiving NGS sequencing between October 2013 and February 2020. Tempus reports for each in-house sequencing event along with pertinent medical information from the electronic medical record (EMR) was extracted. Primary brain tumor types assessed included glioblastoma, astrocytoma, oligodendroglioma, and other rare subtypes (including meningioma, ependymoma, ganglioma, pleomorphic xanthoastrocytoma, atypical teratoid rhabdoid tumors, glioneuronal tumors, and CNS lymphomas). NGS-impacted decision-making was defined as a physician prescribing a targeted treatment that corresponded with an actionable mutation in the Tempus report.

RESULTS

NGS was completed in 261 patients with glioblastoma and 121 patients with other primary brain tumors. NGS impacted decision-making in 12.6% (33) of glioblastoma patients and 9.1% (11) of other brain tumor patients. These figures in grades 1-3 astrocytoma and oligodendroglioma were 9.1% (4 of 44) and 8.1% (3 of 37), respectively. NGS impacted treatment in 10.0% (4 of 40) of all remaining subtypes analyzed. Overall, NGS sequencing data influenced clinical decision-making 11.5% of the time across all brain tumor types. Across the 382 patients assessed, EGFR copy number gain or GOF mutations were targeted most often (52.3% of all mutations targeted), followed by BRAF (11.4%) and IDH1 (11.4%).

CONCLUSIONS

NGS influences treatment decisions less often in primary brain tumors compared to other systemic cancers; however, NGS should still be considered in primary brain tumor patients, as it impacts treatment decision-making across subtypes. As more targeted therapies become available for CNS tumors, the utility of NGS will only increase.