bluuebunny/crossref_metadata_2025_split 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

Abstract
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 &gt; 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

Abstract
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 ( &gt;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 (&lt;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&lt; 0.001); for grade-2 (5.37years)& grade-3 astrocytoma (5.19years) than grade-4 (2.85years, p-value&lt; 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&lt; 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

Abstract

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&lt; 0.0001), IDH1/2-mutant astrocytoma (non-TCGA:180mo,TCGA: 87.9mo,p=0.0002), and oligodendroglioma (non-TCGA: not reached,TCGA:135mo,p&lt; 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&lt; 0.0001). In GBM and oligodendrogliomas, patients &gt;65yrs had worse outcomes than patients 20-64yrs (p&lt; 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

Abstract
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

Abstract

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

Abstract
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

Abstract

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

Abstract
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

Abstract
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.