bluuebunny/crossref_metadata_2025_split huggingface dataset:
PATH-02. MESENCHYMAL-TYPE GENETIC MUTATIONS ARE LIKELY PRE-REQUISITE FOR GLIOBLASTOMA TO METASTASIZE OUTSIDE THE CENTRAL NERVOUS SYSTEM: AN ORIGINAL CASE SERIES AND SYSTEMATIC REVIEW OF THE LITERATURE
Authors: Laurin Bryce , Treffy Randall , Connelly Jennifer , Straza Michael , Mueller Wade , Krucoff Max 
Published: November 2024

Abstract
Glioblastoma multiforme (GBM) is locally aggressive, yet it metastasizes outside the central nervous system (CNS) in only 0.4% of cases. Little is known about what enables this subset of GBMs to survive outside the CNS, so we conducted a PRISMA-compliant systematic review of metastatic GBM wherein we reviewed 3579 search results and 1080 abstracts, ultimately analyzing data from 139 studies and 211 unique patients. Additionally, we analyzed four modern-day cases treated at our institution. In our patients, primary GBM lesions revealed consistent mutations in NF1, TERT, TP53, CDK4, and RB1/PTEN genes. Unique to the metastatic lesions were amplifications in integral cell-cycle regulating genes such as p53 and PDGFRA/KIT, as well as increased vimentin and Ki-67 expression. These data support the hypothesis that glial cells likely underwent mesenchymal-like mutations prior to extra-CNS involvement. How these cells reach the extra-axial environment is still under debate. In our systematic review, we found that metastases were discovered near previous surgical sites in at least 36.9% of cases, suggesting tumor seeding into the scalp during surgery may facilitate mesenchymal-type mutation in some cases. However, this is unlikely to be sole mechanism of spread as there are several reports of spread without surgery, and other hypothesized mechanisms include spontaneously circulating cells and glymphatics. Other sites of GBM metastasis included bone (47.9%), lung (25.6%), lymph nodes (25.1%), and liver (14.2%). On average, metastases were diagnosed 12.1 months after the most recent resection, and the mean survival from discovery was 5.7 months. In sum, there is strong evidence that GBMs acquire novel mutations to survive outside the CNS, are spread spontaneously or iatrogenically, and portend a poor prognosis once disseminated. Routine genetic and molecular characterization of both primary and metastatic GBMs and widespread reporting will help further characterize mechanisms of spread for this rare but deadly pathology.
PATH-05. CLINICAL, PATHOLOGICAL AND MOLECULAR DISEASE CHARACTERISTICS OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: Le Rhun Emilie , Bink Andrea , Felsberg Joerg , Gramatzki Dorothee , Brandner Sebastian , Benhamida Jamal K , Wick Antje , Tonn Joerg C , Mohme Malte , Tabatabai Ghazaleh , Capper David , Snuderl Matija , Razis Evangelia , Ronellenfitsch Michael , Neidert Nicolas , Ng Ho-Keung , Pohl Ute , Bale Tejus , Quach Stefanie , Rieger David , Schüller Ulrich , Onken Julia , Drueschler Katharina , Maurage Claude Alain , Regli Luca , Healy Estelle , Graham Maya , Hortobagyi Tibor , Paine Simon , Ansorge Olaf , Bridges Leslie , Lausova Tereza , Medici Valentina , Sievers Philipp , Schrimpf Daniel , Wick Wolfgang , Sahm Felix , Reifenberger Guido , von Deimling Andreas , Weller Michael 
Published: November 2024

Abstract

BACKGROUND
Diffuse hemispheric glioma, histone 3 (H3) G34-mutant, is a pediatric-type diffuse high-grade glioma newly defined in the World Health Organization (WHO) classification of central nervous system tumors 2021. Here we sought to define the prognostic roles of clinical, neuroimaging, pathological, and molecular features of these tumors.

METHODS
We retrospectively assembled a cohort of 114 patients with diffuse hemispheric glioma, H3 G34-mutant and profiled the imaging presentation and the molecular landscape of their tumors.

RESULTS
Compared with glioblastoma, H3 G34-mutant tumors exhibited less avid contrast enhancement, less necrosis and less edema on MRI. Comprehensive analyses of mutational and DNA copy number profiles revealed recurrent mutations in TP53 and ATRX, homozygous deletions of CDKN2A/B, and amplifications of PDGFRA, EGFR, CCND2, and MYCN. MGMT promoter methylation was detected in 79 tumors (75%); 11 tumors (13%) showed DNA copy number profiles suggestive of circumscribed deletions on 10q26.3 involving the MGMT locus. Median survival was 21.5 months (95% CI 15.3-27.7) and eight patients (7.0%) survived for ≥ five years. Female sex, gross total resection, and MGMT promoter methylation were positive prognostic factors on univariate analysis. Among radiological, pathological and molecular features, absence of pial invasion, and presence of microvascular proliferation and CDK6 amplification were positive prognostic factors on univariate analyses.

CONCLUSION
This study refines the clinical and molecular landscape of H3 G34-mutant diffuse hemispheric gliomas. Dedicated trials for this novel tumor type are urgently needed.
PATH-09. CLINICAL CHARACTERISTICS AND MOLECULAR CHARACTERISTICS OF 244 MEDULLOBLASTOMAS IN JAPAN
Authors: Go Kohichi , Katsuma Asako , Makino Yasuhide , Yamamoto Etsuko , Yoshioka Ema , Shofuda Tomoko , Kanematsu Daisuke , Takada Shigeki , Sano Noritaka , Tanji Masahiro , Mineharu Yohei , Fukuoka Kohei , Kodama Yoshinori , Mano Masayuki , Ichimura Koichi , Sasaki Atsushi , Hirato Junko , Inoue Takeshi , Nishikawa Ryo , Date Isao , Nonaka Masahiro , Nagane Motoo , Arakawa Yoshiki , Kanemura Yonehiro 
Published: November 2024

Abstract

BACKGROUND
Medulloblastomas are at least classified into four core subgroups, including WNT-activated, SHH-activated, group 3 and group 4. These molecular subgroups have been introduced in the WHO classification, which has become fundamental and indispensable. The JPMNG is co-organized by the Japan Society for Neuro-Oncology and the Japanese Society for Pediatric Neurosurgery, and we have summarized clinical and molecular characteristics of Japanese MBs.

METHODS
We enrolled 267 cases of medulloblastoma from 44 centers participating in the JPMNG study. Central histopathological diagnosis was performed by three neuropathologists, and molecular genetic diagnosis was performed by NanoString nCounter system or DNA methylation array, and their single nucleotide mutations and copy number aberrations have been also examined.

RESULTS
A total of 244 cases were finally analyzed, and the 4-subgroup classification was WNT: 39 (16%), SHH: 61 (25%), group3: 42 (17%), and group4: 102 (41.8%), respectively. In cases of less than 3 years old, no WNT have been found and 62.2% cases were SHH. In cases of WNT-MB, the majority being children (6-18 years) (31/39: 79.5%), and 8 cases (8/39: 20.5%) in adults older than 18 years. In cases between 3 to 17 years old, Group 4 is the most (48.6%), and these trends is almost consistent with published. references. Metastatic or MYC gain Group 3 MBs were poor prognosis, while Group 4 MBs with loss of chromosome 11 or whole chromosomal aberration were good prognosis.

CONCLUSIONS
Clinical and molecular characteristics of Japanese WBT-MB were almost consistent with those reported in other countries, and the relationship between molecular properties and prognosis of group3/group4 MBs were also reproducible. These findings suggest importance of molecular properties of MBs are preserved beyond ethnic differences, and will contribute to develop new therapeutic strategies.
PATH-10. UTILIZATION OF TUMOR-DERIVED EXTRACELLULAR VESICLES FOR PATIENT STRATIFICATION AND BIOMARKER DISCOVERY
Authors: Havranek Katie , Seibold Claire , Seibold Tia , Kinnersley Margie , Van Vaerenberghe Kelley , Blohm Tre , Short-Miller Rachel , Lodmell Sean , Mast Amanda , Kemp Riley 
Published: November 2024

Abstract
Liquid biopsy is poised to play an increasingly important role in clinical decision making by enabling earlier cancer detection, diagnosis, patient stratification, and treatment monitoring. Most approaches rely on detection of cell-free circulating tumor DNA or circulating tumor cells in the peripheral blood of cancer patients. However, there are several limitations to these approaches, including miniscule abundance, unfavorable signal to noise ratios, and limited insight into mechanisms driving disease. Extracellular vesicles (EVs) are an alternative liquid biopsy analyte comprising lipid membrane encapsulated particles carrying diverse protein, nucleic acid, and metabolite cargos. Blood plasma of cancer patients contains EVs derived directly from tumor tissue that serve as rich sources of insight into tumor biology and disease pathology. We have developed a clinically applicable, multi-omic EV subpopulation interrogation pipeline that robustly profiles tumor-derived EVs in biofluids. We have demonstrated the ability of the platform to enrich cancer markers and detect activation of pathways driving oncogenesis across several different cancers, including brain cancer. There is a particularly compelling need for liquid biopsy-based solutions in neuro-oncology. We have applied our EV-omic (EVO) pipeline in combination with machine learning to distinguish adult high-grade gliomas from benign brain tumor and healthy patients, using blood-based EV proteomic and transcriptomic signatures. Marker profiles found to be most important for patient stratification combine markers known to be relevant in tumor tissue along with novel features. Furthermore, IDH status and MGMT methylation metadata derived from matched patient tissue for select cases was used to generate unique blood-based profiles for glioma subtypes. Lastly, we show preliminary longitudinal data demonstrating the utility of EVs to track tumor changes post-surgical resection and post-treatment. This work demonstrates that EV-omics can add significant value in the neuro-oncology space.
PATH-14. UTILITY OF DNA METHYLATION ANALYSIS IN HISTOLOGICALLY-CONFIRMED PA PATIENTS WITH POOR PROGNOSIS
Authors: suruga yasuki , Satomi Kaishi , Otani Yoshihiro , Fujii Kentaro , Ishida Joji , Uneda Atsuhito , Tsuboi Nobushige , Makino Keigo , Hirano Shuichiro , Kemmotsu Naoya , Imoto Ryoji , Mizuta Ryo , Tomita Yusuke , Yasuhara Takao , Washio Kana , Yanai Hiroyuki , Matsushita Yuko , Hibiya Yuko , Yoshida Akihiko , Ichimura Koichi , Tanaka Shota 
Published: November 2024

Abstract

INTRODUCTION
Pilocytic astrocytoma (PA) is a circumscribed low-grade astrocytic glioma, generally considered to be associated with a good prognosis. However, some PA patients experience unfavorable outcomes; advanced age was known as an independent poor prognostic factor. This study retrospectively reviewed PA patients and conducted molecular analyses for elderly patients.

METHODS
We analyzed data from 29 histologically confirmed PA patients treated at a single center from 2002 to 2021 and conducted integrated molecular analyses including DNA methylation profiling for elderly PA patients.

RESULTS
The median age at diagnosis was 14 years (range 3-82 years), with 4 patients (14%) being elderly (patients≥60years old). Elderly patients had significantly worse progression-free survival and overall survival. DNA methylation analysis was performed on 2 of the 4 elderly patients. Despite histological diagnoses of PA, methylation profiling classified one case as high-grade astrocytoma with piloid features (methylation class scores below 0.3 in both v11b4 and v12.5) and the other as glioblastoma, IDH-wildtype (score over 0.5 in both v11b4 and v12.5), using classifiers from the German Cancer Research Center and t-SNE analysis.

CONCLUSION
Elderly patients with PA morphology showed unfavorable outcomes in this cohort. In those patients, DNA methylation profiling revealed the possibility of high-grade astrocytic tumors, including newly defined entities.
PATH-17. MOLECULAR CLASSIFICATION OF H3K27-WILDTYPE SPINAL CORD GLIOMAS: IMPLICATIONS FOR PROGNOSIS AND THERAPEUTICS
Authors: Chai Ruichao , Chen Huiyuan , Chang Qing , Wang Yongzhi , Wang Jiguang 
Published: November 2024

Abstract

BACKGROUND
H3K27-wildtype spinal cord gliomas (H3WT-SCGs) are rare and heterogeneous tumors that present significant challenges in pathological classification. Traditional histologic diagnoses often do not align well with the underlying molecular characteristics of these tumors.

METHODS
We characterized 55 cases of H3WT-SCGs using a comprehensive approach that included DNA methylation array, whole-exome sequencing, transcriptome sequencing, proteomics, and single-cell RNA sequencing. Unsupervised clustering analysis was performed to identify distinct molecular subtypes.

RESULTS
The analysis identified seven distinct spinal cord methylation (SCM) clusters: pilocytic astrocytomas (PA-SPINE), PA-immune enriched (PA-IME), diffuse leptomeningeal glioneuronal tumor (DLGNT), subependymoma (SUBEPN-SPINE), glioblastoma-like (GBM-like), and pleomorphic xanthoastrocytoma-like (PXA-like). There was a 61.8% discordance between SCM classes and traditional histologic diagnoses. The new molecular classification provided a better correlation with molecular features and patient prognosis. BRAF fusions were enriched in PA-SPINE and DLGNT (p = 0.04), and DLGNT showed significant chromosomal alterations, including 1p loss (p = 6.5e-08) and 1q gain (p = 3.6e-05). Notably, we identified two distinct classes of PA-SPINE: adult (older than 18 years) and pediatric. Adult PAs exhibited lower frequencies of BRAF fusions (p = 1.4e-03), shorter tumor lengths (p = 3.7e-04), and longer progression-free survival (p = 0.062). Adult PA neoplastic cells were less differentiated, with higher expression of EGFR and neuronal markers, and lower cytokine and chemokine expression compared to pediatric cases. Single-cell analysis revealed reduced infiltration of monocyte-derived macrophages and proliferative myeloid cells in adult cases. Both PA-IME and PA-pediatric clusters were characterized as immune-hot tumors with high immune cell enrichment.

CONCLUSION
This study defined clinically relevant molecular classes of H3WT-SCGs that better reflect patient prognosis and molecular characteristics compared to traditional histologic diagnoses. The findings suggest potential therapeutic implications, especially in immune-hot tumors like IME and PA-pediatric, which could benefit from targeted immunotherapies.
PATH-18. CURRENT STATUS OF CANCER GENOMIC PROFILING (CGP) TESTS IN BRAIN TUMOR TREATMENT - COMPLEMENTING BRAIN TUMOR PATHOLOGICAL DIAGNOSIS WITH CGP-
Authors: Kurozumi Kazuhiko , Shinichiro Koizumi , Kida Satoru , Tomoya Oishi , Yamasaki Tomohiro , Baba Satoshi 
Published: November 2024

Abstract

INTRODUCTION
Cancer genomic profiling (CGP) tests are currently used in the search for therapeutic targets and have become an auxiliary tool in diagnosis according to the new WHO classification (WHO 2021), which requires the integration of pathomorphological and molecular diagnostics. Here, we report on brain tumor cases at our institution that underwent CGP testing.

METHODS
From May 2020 to the present, 27 brain tumor cases that underwent CGP testing at our institution were included in this study. There were 14 males and 13 females, ranging from 18 to 70 years (average 48.4 years). The tests conducted included Foundation One CDx, GeneMineTop, and NCC OncoPanel.

RESULTS
The cases that underwent CGP testing included 13 cases of glioblastoma IDH-wildtype, 3 cases of astrocytoma, IDH-mutant, grade 4, 4 cases of astrocytoma IDH-mutant, grade 3, 3 cases of oligodendroglioma, 1p/19q codeleted, grade 3, 1 case of astrocytoma, IDH-mutant, grade 2, 1 case of ependymoma, 1 case of pilocytic astrocytoma and 1 case of PitNEC. CGP testing enabled molecular diagnostics such as IDH mutation and TERTp mutation. Based on the results, therapeutic suggestions were possible for 5 out of 25 cases (20%) (BRAF V600E mutation 1 case, IDH1 R132H mutation 1 case, TMB high 3 cases). Checkpoint inhibitors were used in a case with high TMB. Genetic risk assessment by a genetic counselor was conducted for all cases, and one high TMB case was diagnosed as hereditary cancer. A germline pathogenic variant in MSH6 was detected, leading to a diagnosis of Lynch syndrome.

CONCLUSION
Molecular diagnostics through CGP testing served as an aid in diagnosis according to WHO2021. Cases where drug suggestions were feasible underwent treatment with targeted molecular therapies and checkpoint inhibitor. We experienced cases where hereditary cancer syndromes such as Lynch syndrome were diagnosed through the detection of germline pathogenic variants.
PATH-19. DIAGNOSTIC UTILITY OF MOLECULAR PROFILING IN ADULT DIFFUSE GLIOMA
Authors: Ohno Makoto , Nakashima Takuma , Sugino Hirokazu , Yanagisawa Shunsuke , Kawauchi Daisuke , Omura Takaki , Aoki Takuma , Yoshida Akihiko , Suzuki Hiromichi , Narita Yoshitaka 
Published: November 2024

Abstract

INTRODUCTION
With the publication of World Health Organization Classification of the Central Nervous System Tumors (WHO CNS5), molecular profiling has become essential for the diagnosis of CNS tumors. To test for the diagnostic molecular alterations, we developed a targeted DNA sequencing panel (Nakashima et al. 2024) to analyze 113 genes, chromosomal abnormalities, and MGMT promoter methylation. This study aimed to evaluate our diagnostic approach using the targeted sequencing panel.

PATIENTS AND METHODS
We included 72 cases of diffuse adult gliomas diagnosed at our institute between June 2023 and May 2024. We analyzed the tumor diagnoses based on the pathological and immunohistochemical findings as well as the targeted sequencing panel findings.

RESULTS
The tumor diagnoses were as follows: glioblastoma, IDH-wildtype: 32 cases, astrocytoma, IDH-mutant: 17 cases, oligodendroglioma, IDH-mutant and 1p/19q-codeleted: 15 cases, others: 8 cases. Among 32 cases of IDH1/2 mutations, 28 cases (87.5%) with IDH1 R132H mutation were diagnosed by immunohistochemistry using anti-IDH1 R132H antibody, whereas 4 (12.5%) (3 with IDH2 mutation, and 1 with IDH1 R132S) were diagnosed by the targeted sequencing panel. Of the 32 glioblastoma cases, 6 (18.8%) did not show necrosis or microvascular proliferation and were diagnosed based on either TERT promoter mutation, EGFR amplification, or chromosome 7/chromosome 10 abnormalities. Moreover, 24 out of 26 resected cases (92.3%) were diagnosed morphologically, whereas 4 of 6 biopsy cases (66.7%) were diagnosed molecularly (p=0.0056). Among the 17 cases of astrocytoma, IDH-mutant, 2 (11.8%) showed homozygous deletion of CDKN2A/B. There were 4 cases (5.6%) out of 72 that did not satisfy the diagnostic criteria for glioblastoma, astrocytoma, oligodendroglioma.

CONCLUSION
Approximately 95% of cases were diagnosed based on WHO CNS5 criteria with molecular profiling. We also demonstrate molecular profiling is useful in glioblastoma diagnostics, especially in biopsy cases where morphological diagnostic evidence is not recognized.
PATH-22. SINGLE-CELL RNA (SCRNA) SEQUENCING OF PAIRED PRIMARY AND RECURRENT ATYPICAL TERATOID/RHABDOID TUMORS (AT/RT) REVEALED MOLECULAR DIFFERENCES AND THERAPY-RESISTANT PRIMARY TUMOR CELLS
Authors: Altendorf Lea , Roy Rajanya , de Faria Flavia W , Hack Karoline , Koch Arend , Schuhmann Martin U , Hauser Peter , Johann Pascal D , Hasselblatt Martin , Kerl Kornelius , Frühwald Michael C , Schüller Ulrich 
Published: November 2024

Abstract
Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors during infancy. They split into four molecular types. The major three (AT/RT-SHH, AT/RT-TYR, and AT/RT-MYC) all carry mutations in SMARCB1, the fourth smaller type is characterized by SMARCA4 mutations (AT/RT-SMARCA4). AT/RT are associated with a dismal outcome, and 50% of the patients suffer a progress or recurrence of the tumor. Molecular mechanisms of disease recurrence are currently unclear. Here, we identified molecular characteristics of AT/RT primaries and recurrences, which could help to improve the therapy for relapsed patients. Previously, we investigated tumor tissue from 26 patients revealing signatures of recurrences in comparison to matched primary tumor samples using histology, DNA methylation analysis, and bulk RNA sequencing. To further identify mechanisms regarding tumor progression and recurrence, we performed single-cell RNA (scRNA) sequencing for five of these primary-recurrence pairs so far using formalin-fixed paraffin-embedded (FFPE) tissue. Using Uniform Manifold Approximation and Projection (UMAP) for dimensionality reduction, we observed a distinct separation in the gene expression profiles of primary and recurrent tumor cells. In addition, we aimed to identify primary tumor cells which potentially persisted after therapy and developed to recurrences. Therefore, we identified primary tumor cells showing highest similarity to recurrent tumor cells using CIBERSORT and trajectory analysis. Differentially expressed genes of these specific primary tumor cells were investigated. They are involved in cell migration, -adhesion, -proliferation, and -stability, among others. Overall, molecular characteristics that occur in the course of the disease were identified, which may help to define new therapeutic targets for AT/RT recurrences.
PATH-23. SARCOMATOUS TRANSFORMATION OF GLIOBLASTOMA IS ASSOCIATED WITH A DISTINCT MOLECULAR SIGNATURE
Authors: Lucas Calixto-Hope , Al-Adli Nadeem , Young Jacob , Gupta Rohit , Morshed Ramin , Wu Jasper , Ravindranathan Ajay , Shai Anny , Bush Nancy Ann Oberheim , Taylor Jennie , de Groot John , Villanueva-Meyer Javier , Pekmezci Melike , Perry Arie , Bollen Andrew , Theodosopoulos Philip , Aghi Manish , Chang Edward , Hervey-Jumper Shawn , Raleigh David , Diaz Aaron , Costello Joseph , Clarke Jennifer , Butowski Nicholas , Phillips Joanna , Berger Mitchel , Chang Susan , Solomon David 
Published: November 2024

Abstract
A subset of IDH-wildtype glioblastoma (GBM) undergo sarcomatous transformation to gliosarcoma at recurrence which is associated with a propensity for dural and calvarial invasion. However, the underlying biology of sarcomatous transformation and predictive biomarkers for these aggressive tumors are unknown. We performed comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent GBM from 106 patients. Eighteen patients (17%) developed sarcomatous transformation at recurrence as defined by fascicular growth, intercellular reticulin deposition, and immunohistochemical evidence of glial to mesenchymal transdifferentiation. Compared to conventional GBM, patients who developed gliosarcoma had shorter interval between initial surgery and first recurrence (8.3 vs. 11.2 months, p=0.002) and reduced overall survival (18.2 vs. 21.9 months, p=0.164). While there were no differences in sex, age, tumor location, or adjuvant therapy, we found differences in the molecular signatures of GBM that transformed to gliosarcoma at recurrence, including a significant enrichment in NF1, TP53, and RB1 alterations and an absence of EGFR amplification. GBM which underwent sarcomatous transformation were enriched for the Mesenchymal epigenetic class at initial surgery (69% vs. 25%) and became enriched for the novel Mesenchymal subclass B at recurrence (43% vs. 2%). Among approximately 850,000 interrogated CpG sites, we identified 1,503 and 2,090 CpG sites within gene regulatory regions that were significantly more hypermethylated or hypomethylated in those initial GBM that transformed to gliosarcoma at recurrence compared to those that did not. Gene Ontology biologic processes enriched in these differentially methylated genes include immune cell signaling, cell-cell adhesion, and TGF-beta signaling. Together, these findings reveal GBM which undergo transformation to gliosarcoma represent a biologically distinct subtype with aggressive clinical course. Enrichment for NF1 and RB1 alterations and differentially methylated immune cell and TGF-beta signaling suggests potential unique therapeutic vulnerabilities for affected patients.