bluuebunny/crossref_metadata_2025_split huggingface dataset:
PATH-38. MOLECULAR CHARACTERIZATION OF GLIOMA TISSUE AFTER TTFIELDS TREATMENT
Authors: Mawrin Christian , Luchtmann Michael , Kirches Elmar 
Published: November 2023

Abstract

INTRODUCTION
This study aims to investigate the molecular characterization of glioma tissue after treatment with Tumor Treating Fields (TTFields). TTFields therapy utilizes low-intensity alternating electric fields to disrupt cancer cell division and is approved for treatment of glioblastoma as well as mesothelioma. Understanding the histological, cellular, and epigenetic changes induced by TTFields treatment can help identify biomarkers for TTFields response and elucidate potential resistance mechanisms. MATERIAL AND

METHODS
Tumor tissue samples (FFPE) were collected from newly diagnosed glioblastoma patients treated with TTFields, including both the primary tumor and matching recurrent tumor samples. Molecular analyses using a glioma-targeted next-generation sequencing (NGS) panel sequencing were performed to assess genetic alterations in both primary and recurrent tumors.

RESULTS
Genomic analysis of paired samples from 5 patients (4 glioblastoma, one astrocytoma, IDH-mutated WHO grade 4) revealed an identical molecular pattern (TERT mutation) in 2 patients, one patient with a gain of an ATRX mutation in the recurrent tumor, one patient with gain of two EGFR mutations, and the IDH1-mutated astrocytoma showing a loss of a TP53 mutation in the recurrent tumor.

CONCLUSION
This pilot study provides valuable insights into the molecular characterization of glioma tissue after TTFields treatment. It appears that the spectrum of mutations may vary in a substantial number of TTF-treated tumors. Further validation and larger-scale studies are needed to confirm and expand upon these preliminary results.
PATH-40. “DE NOVO REPLICATION REPAIR DEFICIENT GLIOBLASTOMA, IDH-WILDTYPE” IS A DISTINCT GLIOBLASTOMA SUBTYPE IN ADULTS THAT MAY BENEFIT FROM IMMUNE CHECKPOINT BLOCKADE
Authors: Hadad Sara , Bush Nancy Ann Oberheim , Clarke Jennifer , Taylor Jennie , Young Jacob , Villanueva-Meyer Javier , Zhang Yalan , Gupta Rohit , Wu Jasper , Ravindranathan Ajay , Hervey-Jumper Shawn , Chang Susan , Berger Mitchel , Molinaro Annette , Solomon David 
Published: November 2023

Abstract
Glioblastoma is clinically and molecularly heterogeneous, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a subgroup (2%, 8/459) defined by somatic hypermutation and DNA replication repair deficiency due to mismatch repair gene inactivation and/or proofreading domain mutation in the DNA polymerase POLE. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining wildtype allele, consistent Lynch syndrome-associated glioblastomas. All tumors were hypermutated ( &gt;20 somatic nonsynonymous mutations/Mb), while the three tumors with POLE mutations were “ultrahypermutated” with &gt;150 mutations/Mb. The median age at diagnosis was 52 years (range 27-78), compared with median age of 63 years for the other 451 patients with conventional glioblastoma. All tumors were diffuse astrocytic gliomas of the giant cell histologic subtype. They lacked EGFR amplification and only rarely had TERT promoter mutation (1/8), CDKN2A homozygous deletion (1/8), or the combination of trisomy 7 and monosomy 10 (1/8). Instead, they harbored frequent inactivating mutations in the TP53, NF1, PTEN, ATRX, and SETD2 genes ( &gt;50% each) and recurrent activating mutations in PDGFRA (4/8). DNA methylation profiling revealed they did not align with known glioblastoma methylation classes, but instead mostly classified as “Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A (novel)”. Some patients were treated with immune checkpoint blockade (nivolumab or pembrolizumab) and survived over three years. The median overall survival for the cohort was 37.4 months (95% CI: 22-not reached), compared to 15.4 months (95% CI: 14.7-17.9) for the other 451 patients. We speculate that “de novo replication repair deficient glioblastoma, IDH-wildtype” represents a biologically distinct subtype that may benefit from prospective identification and treatment with immune checkpoint blockade.
PATH-41. INTEGRATED MOLECULAR ANALYSIS REVEALS HYPERMETHYLATION AND OVEREXPRESSION OF HOX GENES TO BE POOR PROGNOSTICATORS IN IDH MUTANT GLIOMA
Authors: Mamatjan Yasin , Voisin Mathew , Nassiri Farshad , Bunda Severa , von Deimling Andreas , Aldape Kenneth , Zadeh Gelareh 
Published: November 2023

Abstract

BACKGROUND
Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Within IDH-mutant gliomas there is a high variability in survival and a need to more accurately predict outcome.

METHODS
To identify and characterize a predictive signature of outcome in gliomas, we utilized an integrative molecular analysis (using methylation, mRNA, copy number variation (CNV) and mutation data), analyzing a total of 729 IDH-mutant samples including a test set of 99 from University Health Network (UHN) and two validation cohorts including the German Cancer Research Center (DKFZ) and The Cancer Genome Atlas (TCGA).

RESULTS
Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into two prognostic groups strongly predicting survival that were validated using two independent cohorts from TCGA and DKFZ (all p-values&lt; 0.0001). The methylation signatures that predicted poor outcome also exhibited high CNV instability and hypermethylation of HOX gene probes. Integrated multi-platform analyses using mRNA and methylation (iRM) showed that parallel HOX gene overexpression and simultaneous hypermethylation were significantly associated with increased mutational load, high aneuploidy and worse survival (p-value&lt; 0.0001). A 7-HOX gene signature was developed and validated using the most significantly associated HOX genes with patient outcome in both 1p/19q codeleted and non-codeleted IDHmut gliomas.

CONCLUSIONS
HOX gene methylation and expression provide important prognostic information in IDH-mutant gliomas that are not captured by current molecular diagnostics. A 7-HOX gene signature of outcome shows significant survival differences in both 1p/19q codeleted and non-codeleted IDH-mutant gliomas.
PATH-42. UNCOVERING AN ASSOCIATION BETWEEN OLIGODENDROGLIOMA AND THE HUMAN PAPILLOMAVIRUS (HPV) THROUGH MOLECULAR SUBPOPULATION ANALYSIS USING NETRAAI
Authors: Qorri Bessi , Tsay Mike , Spiegel Josh , Cook Douglas , Geraci Joseph 
Published: November 2023

Abstract
Oligodendrogliomas (OGs) are a rare subset of primary brain tumors, accounting for approximately 5% of all brain tumors. While the etiology of OG has yet to be fully characterized, genomic heterogeneity is linked to clinical heterogeneity with variability in progression and survival. Currently, OGs are stratified into three molecular subtypes based on IDH mutation and 1p/19q co-deletion with additional molecular heterogeneity related to EGFR, PTEN, 10q deletion, and several other markers observed among 1p/19q co-deleted OGs. Using a public OG dataset, we assembled a set consisting of 156 primary OG tumors, 14 primary glioma samples, and 9 normal samples profiled using mRNA expression arrays. Using NetraAI, a novel machine learning platform, we identified three OG patient subpopulations based on survival and differentially expressed genes. Examining low- versus high-grade OG, we identified two subpopulations: (1) 26 low-grade and 21 high-grade OGs characterized by higher RPS6KV1 expression, and (2) 6 low-grade and 61 high-grade OGs characterized by higher LFNG expression. A third subpopulation emerged examining 1p/19p co-deletion, consisting of 60 no co-deletion and 3 co-deletion OGs characterized by higher HDAC1 expression. These driving genes have a common link to human papillomavirus (HPV) infection based on functional genomic analysis. HDAC1 is a histone deacetylase involved in gene expression regulation, LFNG is implicated in the Notch signaling pathway, and RPS6KB1 is a kinase regulating protein synthesis and cell growth. We hypothesize that concomitant HPV infection may negatively impact OG prognosis, warranting further investigation into the precise molecular interactions linking HPV infection to clinical outcomes. Furthermore, exploring the link between HPV infection and vaccination to OG outcomes on a population basis may provide valuable insights. The identification of these subpopulations, not previously described by other groups, demonstrates the utility of the NetraAI approach in uncovering subpopulations with potential implications in developing targeted therapies for OG.
PATH-47. MOLECULAR MARKERS ASSOCIATED WITH SURVIVAL IN GRADE 3 MENINGIOMA
Authors: Tosefsky Kira , Rebchuk Alexander , Wang Justin , Chornenka Karina , Zadeh Gelareh , Makarenko Serge , Yip Stephen 
Published: November 2023

Abstract
Meningiomas have historically been graded using histologic features. However, a subset of meningiomas progress in manners inconsistent with their histologic grading. While TERT promoter (TERTp) mutations and CDKN2A/B homozygous deletion were recently added to the WHO 2021 classification criterion for grade 3 meningioma, the precise prognostic implications of these and other molecular features remain to be fully characterized. In this case series, we explored whether molecular markers were associated with clinical outcomes in a single-center cohort of grade 3 intracranial meningiomas. Demographic, clinical and histopathological information were obtained from the electronic medical records of all grade 3 meningioma cases surgically treated at a tertiary center between 2007-2020. Tissue blocks were reviewed by a neuropathologist and tested for TERTp mutations, BAP1 and CDKN2A/B copy number profiles, and BAP1, p16 and MTAP expression by immunohistochemistry (IHC). Predictors of survival were identified by Cox regression. Fifteen patients (8 female, 7 male) with a median age of 64 (IQR: 48, 74) years were included. Eight (53%) tumors were classified as anaplastic, 6 (40%) as rhabdoid and 1 (6.7%) as papillary. One (7%) rhabdoid tumor exhibited BAP1 loss, while four (27%) tumors harbored TERTp mutations and 3 (20%) demonstrated homozygous CDKN2A/B loss. All three tumors exhibiting homozygous CDKN2A/B loss were MTAP-negative, while two were p16-negative and the third showed focal (&lt; 50%) p16 loss by IHC. TERTp mutations and CDKN2A/B copy number status were associated with significant reductions in RFS (HR = 6.90, 95% CIs: 1.13-42.2 and HR = 12.0, 05% CIs: 1.51-95.4, respectively) and OS (HR = 8.72, 95% CIs: 1.87-40.6 and HR = 6.18, 95% CIs: 1.30-29.4, respectively). The associations between reduced OS and TERTp mutations and CDKN2A/B status remained significant after adjusting for Simpson resection grade. Our findings support using TERT p mutations and CDKN2A/B status for prognostication in grade 3 meningioma.
PATH-56. SUPRATENTORIAL NEUROEPITHELIAL TUMORS WITH NOVEL PLAGL1 FUSIONS: 2 CASE REPORTS
Authors: Helfer Cassandra , McDonald Malcolm , Patel Akash , Sheth Sameer , Rao Ganesh , Jalali Ali , Katlowitz Kalman , Echeverria Alfredo , Ogunbona Oluwaseun , Aldape Kenneth , Abdullaev Zied , Lu Hsiang-Chih , Holloman Ashley , Mandel Jacob 
Published: November 2023

Abstract
Neuroepithelial tumors with pleomorphic adenoma gene-like (PLAGL1) fusions represent a distinct subgroup of neoplasms that have been recently identified. These fusions are quite rare and most commonly associated with fusions in the EWSR1 or FOXO1 genes. Limited reports in literature have indicated a median age of diagnosis of 6.2 years and poor progression-free survival at 35 months. Here we present two cases of patients with neuroepithelial tumors with PLAGL1 fusions. Case 1 was a 49 year old male who underwent resection of a left frontal lobe mass at 2 year old that was reported as a low grade ependymoma. He did not receive radiation or chemotherapy and subsequently developed seizures in childhood. At age 47, he presented with worsening seizures and MRI brain revealed a 4.5 cm mass in the left frontal lobe with serpiginous enhancement. He underwent surgical resection and molecular profiling demonstrated PLAGL1-FOXO1 fusion. Case 2 was an 18 year old female presenting with generalized tonic-clonic seizures. MRI brain demonstrated a 1.4 x 1.2 cm cortical and subcortical lesion in the right parietal lobe. Following surgical resection, pathology reported a low grade neuroepithelial neoplasm with ependymal-like features. Molecular profiling showed PLAGL1-EWSR1 fusion. As PLAGL1 fusions are not yet characterized in the WHO classification system, these cases aid in tumor characterization and highlight the importance of molecular and methylation analysis for accurate tumor classification. Case 2 presents a notable variation from reported age of presentation of 6.2 years with diagnosis at 18 years of age, indicating these tumors may also present in young adulthood. Additionally, Case 1 demonstrated 45 years progression-free survival compared to previously reported median of 35 months, suggesting outcomes may be heterogeneous with potential for prolonged survival. Further research is needed to better elucidate the imaging, clinical course, and prognosis for tumors with this novel fusion.
PATH-57. WHOLE EXOME SEQUENCING OF INTRACRANIAL EPIDERMOID CYSTS (IECS) REVEALS POTENTIAL SOMATIC DRIVERS
Authors: Kondaboina Shruthi , Parada Carolina Da Silva , Ferreira Manuel 
Published: November 2023

Abstract
Intracranial Epidermoid Cysts (IECs) are benign, slow-growing, asymptomatic tumors with an incidence rate of 1% of all intracranial tumors. They are significantly enlarged when discovered and can cause seizures. IECs are suspected to form due to disruptions in neural tube closure. Given their rarity, formation of IECs is under-investigated and surgery is the only treatment option. However, because the cyst lining can be adherent to important brain structures, resection is challenging and can result in post-operative complications, highlighting the need to investigate the pathogenesis of IECs to develop drug therapeutic options. We performed paired-end Whole Exome Sequencing (WES) on DNA from six sporadic IECs. Data processing of raw unmapped reads was performed in tumor-normal and tumor-only mode as appropriate, following GATK best practices for variant calling. We identified 2,850 SNPs and 2,102 indels in this cohort. We identified two common variants, NKX2.5 (p.P214del) and STIM-1 (p.T576del, p.T502del) across all samples, which is a novel finding. We also identified 27 genes and variants shared variably across the samples. Gene enrichment analysis revealed that the Sonic Hedgehog (SHH) pathway is implicated in these gene sets due to activating mutations in the SMO gene (p.L23del). We are using an immunohistochemical stain to validate this finding. The mutant NKX2.5, a transcription factor (TF) responsible for stem-cell differentiation in embryogenesis, strongly indicates that the tumor microenvironment (TME) is disrupted. Deletions in the STIM-1 gene indicate loss of interaction with Orai1 calcium channels, disrupting store operated Ca2+ entry (SOCE) and preventing typical cell migration, resulting in trapped fibroblasts. Digital droplet PCR (ddPCR) of these samples is underway to validate the low tumor allele frequencies (&lt; 4%). The discovery of activating mutations in SMO is significant because it potentiates FDA-approved SMO-inhibitors like Vismodegib and Sonidegib as viable treatment options for patients with IECs.
PATH-65. INTEGRATING DNA METHYLATION AND SEQUENCING TECHNOLOGIES FOR ADVANCED BRAIN TUMOR DIAGNOSIS
Authors: Goebel Kirsten , Schrimpf Daniel , Ippen Franziska Maria , Pfister Stefan M , Jones David , Wick Wolfgang , von Deimling Andreas , Sahm Felix , Suwala Abigail 
Published: November 2023

Abstract
DNA methylation has emerged as an indispensable tool in neuropathological diagnostics, improving the diagnosis of various brain tumor entities. At our institution, methylation arrays as well as DNA and RNA sequencing from Formalin-Fixed Paraffin-Embedded (FFPE) tissue blocks have become routine diagnostic practices for several years. In this study, we present an integration of DNA methylation analyses with targeted gene panel sequencing and RNA sequencing data in an extensive cohort comprising 5749 cases. The cohort encompassing both adult and pediatric patients with central nervous system (CNS) tumors. Only those cases conclusively classified by the Heidelberg brain tumor classifier (v12.5, cutoff &gt; 0.9) and possessing available sequencing data were included in the analyses. The study includes several rare and less characterized brain tumor entities, unveiling frequent mutations and gene fusions that will improve the diagnostic process. Our study offers an unparalleled comprehensive overview of the prevalence of genetic alterations in brain tumors, precisely defined by their unique methylation classes. The profound implications of our results extend far beyond diagnosis alone, significantly augmenting the evaluation of targeted treatment options for patients undergoing DNA methylation analyses.
PATH-67. SHH/GLI3 SIGNALOPATHIES AND NEURO-ONCO-GENETIC COUNSELING : A TUNISIAN PEDIGREE
Authors: Abdelmoula Nouha Bouayed , Abdelmoula Balkiss 
Published: November 2023

Abstract
Here, we present a 3-generation pedigree of a Tunisian non-consanguineous family with six offspring affected by heterogeneous forms of the GLI3-related PHS spectrum. Our aim was to assess the neuro-onco-genetic risks and provide counseling for appropriate clinical follow-up. A non-consanguineous couple was referred to our genetic counseling due to the termination of their first pregnancy, which was diagnosed with multiple congenital anomalies. An autopsy examination, including pathological and radiographic analysis, was conducted. Furthermore, a medical genetic assessment considering a family history spanning over three generations as well as cytogenetic analysis were carried out. The index case was diagnosed with GLI3-related PHS based on facial dysmorphic features, auricular malformations, and unilateral postaxial toe syndactyly, along with brain macro-calcifications. The index case's father and his brother exhibited facial dysmorphic features. Furthermore, two cousins from one of their paternal uncles presented another form, associated respectively with unilateral renal agenesis and unilateral hand agenesis. The remaining three cases, who belong to the first generation, and passed away during infancy, exhibited the same condition, associated to congenital heart defect in one of them. The heterogeneity of GLI3-related overlapping conditions (SHH/GLI3 signalopathies) result from the location of GLI3 mutations in different domains of the gene, as well as the resulting functional balance between activating and repressive forms of GLI3 during development. The report of a late diagnosis of GLI3-related PHS following the discovery of hypothalamic hamartomas as well as the description of a new nonsense germline mutation in a child with Greig syndrome and medulloblastoma, support that neuro-oncological investigation of GLI3 families could be beneficial.
NIMG-03. IMPACT OF CONCURRENT IMMUNOTHERAPY AND STEREOTACTIC RADIOSURGERY ON METASTATIC BRAIN DISEASE: A THREE-DIMENSIONAL MAGNETIC RESONANCE FINGERPRINTING RADIOMIC ANALYSIS
Authors: McClelland III Shearwood , Gongala Sree , Hodges Tiffany , Korakavi Nisha , Flask Chris , Ma Dan , Badve Chaitra 
Published: November 2023

Abstract

BACKGROUND
Unlike traditional chemotherapy (limited by the blood-brain barrier), the central nervous system penetrance of immunotherapy allows for synergy with stereotactic radiosurgery (SRS), the standard-of-care management of limited brain metastases. Magnetic resonance fingerprinting (MRF) is a novel technology allowing for simultaneous imaging quantification of multiple tissue properties. We present the first serial MRF results in concomitant SRS/immunotherapy for metastatic brain disease.

METHODS
A patient with known history of small cell lung cancer (SCLC) presented with a seizure. MRI revealed a solitary 1 cm right occipital metastasis, subsequently receiving SRS rather than whole-brain radiation therapy to optimize cognition preservation. Durvalumab (with carboplatin/etoposide) was given one week before SRS (22 Gy single-fraction). Pre-SRS MRF scans were obtained with the Gamma Knife stereotactic headframe in place. Post-SRS MRF scans were obtained at 1, 3, and 5 months. MRF data was processed and region of interest analysis was performed to measure T1 and T2 values within the lesion using MATLAB.

RESULTS
The mean T1 and T2 values of the solid tumor (ST) in precontrast MRF maps decreased over time with a slight increase at final follow-up. Specifically, the T1 values decreased from 2131 ms (Pre-SRS) to 1018 ms, then 996 ms followed by a slight increase to 1296 ms. Similarly, the T2 values progressively decreased from 143 ms (Pre-SRS) to 45 ms (first follow-up) to 43 ms (3-month follow-up), with an increase (51 ms) at last follow-up.

CONCLUSIONS
In this first report of MRF in concomitant immunotherapy/Gamma Knife SRS (and the first in a SCLC patient). MRF demonstrated serial drop in T1 and T2 over time followed by slight increase at 5 months follow-up. The alterations observed in T1 and T2 MRF are compatible with post-treatment effects in the tumor's tissue characteristics, including decreased cellularity, water content, and presence of paramagnetic substances.
NIMG-04. PRE-RADIATION PROGRESSION PREDICTION IN GLIOBLASTOMA PATIENTS
Authors: Farzana Walia , Basree Mustafa M , Diawara Norou , Shboul Zeina A , Dubey Sagel , Lockhart Marie M , Hamza Mohamed , Palmer Joshua , Iftekharuddin Khan M 
Published: November 2023

Abstract
Pre-Radiation Progression (PRP) has been identified as an increase ( &gt; 25%) in the size of the residual brain tumor or interval development of a new tumor after surgical resection but prior to radiation therapy. Glioblastoma (GB) patients with PRP have worse survival outcome compared to patients without PRP (non-PRP).The standardized approach to identify PRP in GB patients is to manually compare early post-operative MRI to radiation planning MRI. In this study, we investigate the efficacy of traditional radiomics and sophisticated multi-resolution fractal texture features to differentiate PRP from non-PRP. Radiation-planning T1C magnetic resonance imaging (MRI) of 13 PRP and 13 non-PRP patients is analyzed to develop the classification method. For each patient, around 600 conventional radiomics and fractal texture features are obtained from tumor tissue and entire brain areas. We propose a two-step feature selection process followed by ensemble classification. In the first step of feature selection, we apply a beta-mixture based graphical model to identify correlations between the extracted features. The features are the nodes of the graph and the edges of the graph denote the correlations among the features and adjacency to PRP node. After the first step feature selection, the 21 selected features are used in the second step feature selection based on accuracy, similarity, and stability of each feature to yield the final 12 features. Lastly, we utilize the final 12 selected features for ensemble classification of PRP from non-PRP. With leave-one-out cross validation, the predictive model has an area under curve (AUC) of 0.79 and accuracy of 80% which indicates the discriminatory function of imaging features to differentiate PRP patients from non-PRP. The experimental results show the diagnostic ability of radiation planning imaging features to predict PRP from non-PRP.