bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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 &gt;= 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&lt; 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

Abstract
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&lt; 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

Abstract
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&lt; 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

Abstract
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract
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

Abstract

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.