bluuebunny/crossref_metadata_2025_split huggingface dataset:
INNV-23. MANAGING CENTRAL NERVOUS SYSTEM MANIFESTATIONS OF CHRONIC GRAFT VERSUS HOST DISEASE FOLLOWING HEMATOPOIETIC STEM CELL TRANSPLANTATION: A CASE REPORT
Authors: Kundalia Ronak , Hanini Anas , Gatewood Tyra , Mishra Asmita , Pina Yolanda , Mokhtari Sepideh 
Published: November 2022

Abstract
Central nervous system (CNS) manifestation of chronic graft versus host disease (cGVHD) is a rare, difficult to diagnose phenomenon that can follow allogeneic hematopoietic stem cell transplantation (HSCT). CNS-cGVHD typically onsets 2-31 months post-transplant, involves diffuse infiltration of inflammatory cells, demyelination, and cerebral vasculitis, and is associated with an extremely poor prognosis. We present a case of a 37-year-old man who developed seizures, myopathy, bilateral upper and lower extremity weakness, confusion, and irritability almost 2 years after HSCT for acute myeloid leukemia (AML). CNS-cGVHD diagnosis was confidently determined via magnetic resonance imaging (MRI) demonstrating enhanced focal white matter lesions, cerebrospinal fluid (CSF) studies demonstrating elevated globulin (12.7 mg/dL; normal range: 0-6 mg/dL) and elevated immunoglobulin G (IgG) synthesis rate (13.9 mg/d; normal range: ≤ 8 mg/d), and a right brain biopsy demonstrating encephalitis, perivascular inflammation, microglial activation, and gliosis with predominately intramural and perivascular CD3+ T-cells, CD4+ and CD8+ cells. Complete resolution of neurological symptoms, including seizures, was achieved with a combination of steroids, ibrutinib, intravenous immunoglobulin (IVIG), and anti-seizure medications. Improvements to CNS-cGVHD was further indicated by normalized MRI studies without abnormal enhancements and improved CSF studies with reduction in globulin levels (11.3 mg/dL) and complete normalization of IgG synthesis rate (≤ 0 mg/d). It is imperative that CNS-cGVHD be considered in patients that present with neurological signs post-transplant. An early, confident diagnosis generates prompt intervention and as demonstrated, can lead to complete resolution of neurological symptoms.
INNV-33. FUNCTIONAL EX VIVO TESTING PROSPECTIVELY IDENTIFIES NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS SENSITIVE TO TEMOZOLOMIDE TREATMENT IRRESPECTIVE OF MGMT METHYLATION STATUS
Authors: DesRochers Tessa , Lipinski Lindsay , Abad Ajay , Fenstermaker Robert , Fabiano Andrew , Edenfield Jeffery , Kanos Charles , Redjal Navid , Rodriguez Analiz , Mansouri Alireza , Zacharia Brad , Butowski Nicholas , Jia-Xin Liu Jesse , Han Seunggu , Ziu Mateo , Cohen Adam , Smith Ashley , Vibat Cecile Rose , Ledford Aubrey 
Published: November 2022

Abstract

Standard of care (SOC) therapy for newly diagnosed (ND) glioblastoma (GBM) patients consist of temozolomide (TMZ) concurrent with radiation therapy. It is well known that patients with an unmethylated MGMT promoter are less likely to respond to TMZ, however, this trend is not universal. We have previously shown that 3D Predict™ glioma can identify patient response to TMZ, often differentially than the methylation status would predict. Here we present expanded clinical data relating to functional ex vivo testing capable of identifying patients responsive to alkylating therapies such as TMZ, regardless of methylation status.

METHODS
Fresh tissue specimens taken from ND GBM patients enrolled into the 3D PREDICT clinical study were examined by 3D Predict glioma to evaluate ex vivo therapeutic response to TMZ. Overall Survival (OS) and Progression Free Survival (PFS) in patients having â‰¥ 6 months follow-up post-surgery or &lt; 6 months follow up but experiencing progression/death as of September 1, 2022 will be presented. Prospective correlation of clinical response and test-predicted response will be demonstrated in this expanded cohort of ND GBM patients.

IMPACT
This data has the potential to change treatment for ND GBM patients by stratifying according to functional therapeutic response rather than epigenetic factors that are not completely predictive of clinical response. It is feasible that 3D Predict glioma could dramatically impact patient care by determining which unmethylated patients should be treated with TMZ, and methylated patients who would potentially derive greater benefit from clinical trials or other treatment regimens.
PATH-03. IMPACT OF GAP-43 AND ACTIN EXPRESSION ON THE OUTCOME AND OVERALL SURVIVAL IN DIFFUSE AND ANAPLASTIC GLIOMAS
Authors: Krigers Aleksandrs , Demetz Matthias , Moser Patrizia , Kerschbaumer Johannes , Brawanski Konstantin , Fritsch Helga , Thomé Claudius , Freyschlag Christian 
Published: November 2022

Abstract
Background. Distant intercellular communication in gliomas is based on the expansion of tumor microtubuli (TMs), where actin forms cytoskeleton and GAP-43 mediates the axonal conus growth. We aimed to investigate the impact of GAP-43 and actin expression on overall survival (OS) as well as crucial epidemiologic, radiological and neuropathological prognostic factors. Methods. FFPE tissue of adult patients with diffuse and anaplastic gliomas, who underwent first surgery in our center between 2010 and 2019, were selected. GAP-43 and actin expression was analyzed using immunohistochemistry and semi-quantitatively ranked. Clinical, neuropathological as well as follow-up-data were gained from the institutional neuro-oncological database. Results. 118 patients with a median age of 46 years (IqR: 35 – 57) were evaluated. 48 (41%) presented with a diffuse glioma and 70 (59%) revealed anaplasia. 96 (82%) cases presented with intermediate or strong GAP-43 expression and 78 (67%) with no or light actin expression. Tumors with higher expression of GAP-43 (p=0.024, HR=1.71/rank) and actin (p&lt; 0.001, HR=2.28/rank) showed significantly reduced OS. IDH1 wildtype glioma demonstrated significantly more expression of both proteins: GAP-43 (p=0.009) and actin (p&lt; 0.001). The same was confirmed for anaplasia (GAP-43 p=0.028, actin p=0.029), higher proliferation rate (GAP-43 p=0.016, actin p=0.038), contrast-enhancement in MRI (GAP-43 p=0.023, actin p=0.037) and age (GAP-43 p=0.004, actin p&lt;0.001). Conclusions. The intercellular distant communication network in diffuse and anaplastic gliomas formed by actin and GAP-43 is associated with a negative impact on overall survival and with oncologically unfavorable prognostic features.
PATH-04. CURRENT STATUS AND PROSPECTS OF MALIGNANT BRAIN TUMOR TREATMENT IN CANCER GENOMIC MEDICINE
Authors: Koizumi Shinichiro , Yamasaki Tomohiro , Oishi Tomoya , Kurozumi Kazuhiko 
Published: November 2022

Abstract

INTRODUCTION
The cancer gene panel test was covered by insurance in June 2019 in Japan. Our institution started the test in May 2020 and has experienced 16 cases. We will report on the current status and future prospects.

METHODS
The subjects were 16 patients (Average age 48.4) who underwent the cancer gene panel test with FoundationOne CDx. [Results] The cases included 9 glioblastomas, 3 anaplastic astrocytomas, 2 anaplastic oligodendrogliomas, an ependymoma, and a pituitary carcinoma. On average, 11.0 genetic changes were detected totally, oncogene mutations were 4.4, and gene mutations of unknown relevance to cancer were 5.6. Major oncogene mutations were IDH1 mutation in 5 cases, ATRX mutation in 2 cases, TP53 mutation in 9 cases, CDKN2A/2B mutation in 5 cases, and BRAF V600E mutation in 1 case. Based on our results, a 25-year-old man with BRAF V600E mutation and a 47-year-old male with IDH1 mutation could be given molecular-targeted drugs. Furthermore, a 59-year-old male with pituitary carcinoma had more than 10 mut/Mb in tumor mutational burden (TMB), indicating that anti-PD-1 antibody drugs can be administered. The chance of finding an appropriate drug by cancer gene panel test is approximately 10-20%. In cases that are resistant to standard treatment, the benefits can be expected if the drugs associated with the cancer gene panel test can be used.

CONCLUSIONS
Comprehensive cancer gene panel test has the potential to provide personalized medicine. And we suggest that the active use of cancer gene panel test may contribute to the development of new drugs with high response rates and the improvement of prognosis.
PATH-08. A COMPREHENSIVE GENOMIC STUDY OF 390 H3F3A-MUTANT PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMAS WHO CNS GRADE 4
Authors: Williams Erik , Brastianos Priscilla , Wakimoto Hiroaki , Santagata Sandro , Cahill Daniel , Juratli Tareq 
Published: November 2022

Abstract

OBJECTIVES
Histone gene mutant malignant gliomas - H3K27-altered diffuse midline glioma (DMG) and diffuse hemispheric glioma (DHG) H3G34-mutant - occur in all age groups and can have significant variation in clinical outcomes. Here, we report comprehensive genomic profiling from one of the largest collections of H3F3A-mutant gliomas analyzed to date, identifying subsets defined by recurrently co-mutated genes.

METHODS
We identified 390 H3F3A-mutant diffuse gliomas WHO grade 4 (201 females and 189 males) that were profiled in the comprehensive genomic profiling program at Foundation Medicine between 2013-2020. Information from pathology reports, histopathology reviews, and clinical data was assessed.

RESULTS
Our cohort comprised 304 (77.9%) H3K27M-mutant DMG WHO grade 4 (156 females and 148 males) and 86 H3G34-mutant DHG (45 females and 41 males) with a median age of 20 years (1-74 years). H3K27M-mutant DMG distributed equally between pediatric and adult patients, with 52% of the patients older than 20 years, 30% older than 30 years, and 18% older than 40 years at the time of first diagnosis. Clonal FGFR1 hotspot mutations were exclusively detected in K27M-mutant DMG (n = 64/304, 21%; p=0.0001), with a significant association with a higher age at first diagnosis (median 32.5 years), and with a wide tumor distribution across the diencephalon. Additional genes which were significantly more frequently altered in K27M-mutant compared to G34-mutant diffuse gliomas included NF1 (31% vs. 8.1%; p=0.0001) and PIK3CA/PIK3R1 (27.9% vs. 15.1%; p=0.016). Conversely, targetable alterations of the cell-cycle pathway (CDK4/6 amplifications and CDKN2A/B deletions) were enriched in H3G34-mutant DHG (26%) compared to H3K27M-mutant DMG (7%). Potentially targetable PDGFR alterations were present in 32.5% of H3G34-mutant DHG and in 18% of H3K27M-mutant DMG.

CONCLUSIONS
These data expand our understanding of the tumor-specific molecular features of pediatric-type high-grade gliomas, identifying cohort sub-structure by recurrent co-mutations, which can inform diagnosis and clinical trial design.
PATH-17. DISTINCT MOLECULAR SUBCLASSES OF H3F3A-WILDTYPE, EGFR-ALTERED PEDIATRIC-TYPE DIFFUSE MIDLINE GLIOMAS WHO CNS GRADE 4
Authors: Williams Erik , Brastianos Priscilla , Wakimoto Hiroaki , Cahill Daniel , Santagata Sandro , Juratli Tareq 
Published: November 2022

Abstract

OBJECTIVES
Histone gene H3K27-altered diffuse midline glioma (DMG) are malignant tumors that occur in all age groups. In this study, we report comprehensive genomic profiling from H3F3A-wildtype, EGFR-altered DMG, as a distinct and newly recognized subset of pediatric-type DMG.

METHODS
Tumors were profiled in the comprehensive genomic profiling (CGP) program at Foundation Medicine between 2013-2020. Information from pathology reports, histopathology review, and patient clinical data was assessed.

RESULTS
We collected demographic and genomic data from 39 pediatric patients with H3F3A-wildtype, EGFR-altered HGG (17 females, 22 males; median age: 8.5 years, range 1-18 years). Female patients were younger at first diagnosis compared to male (median age 7 years vs. 10 years). All cases were microsatellite stable (MSS). The EGFR alterations consisted of 30 mutations and 9 amplifications. The mutations were distributed across the entire gene with no clear hotspot location. Our genomic data converged to identify three distinct molecular patterns. The first and most common group contained TP53 mutations (n = 17, 43.5%), showed no association with patient sex (8 females, 9 males), contained ATRX mutations (n = 3) and CDKN2A deletions (n = 5); these tumors did not harbor pathogenic mutations in TERTp, PIK3CA/PIK3R1, BCOR/BCORL1, STAG2, or SETD2. The second group featured TERTp-mutant tumors (n = 10), were more common in males (70%), and often demonstrated additional mutations in PIK3CA/PIK3R1 (n = 4), BCOR/BCORL1 (n = 4), CDKN2A/B (n = 4), and SETD2 (n = 2). The third group (n = 12) lacked TERTp and TP53 mutations and had a heterogeneous spectrum of non-recurrent mutations, including one CDKN2A/B deletion.

CONCLUSIONS
We have identified three distinct molecular subclasses that defined specific genomic tumor subgroups in pediatric-type EGFR altered DMG. Overall, these data increase our understanding of the pathobiology of this DMG subset and can guide the design of clinical trials.
PATH-20. CILIA-ASSOCIATED GENE EXPRESSION PREDICTS SURVIVAL IN LOW-GRADE GLIOMAS
Authors: Kaculini Christian , Singh Komudi , Springer Megan , Jung Mi-Yeon , Johnson Kory , Brown Desmond 
Published: November 2022

Abstract
Low-grade gliomas (WHO II and III) encompass a histopathologically and clinically heterogeneous constellation of neoplasms. Molecular biomarkers play an increasingly important role in glioma classification, therapy, and prognostication. Primary cilia are microtubule-based organelles that regulate several canonical signal transduction cascades and they have been implicated in the pathogenesis of many malignancies. We hypothesized that LGGs differentially express ciliary genes resulting in unique molecular and prognostic clusters. Four-hundred-sixty-seven LGG patients within The Cancer Genome Atlas (TCGA) were stratified based on differential expression of cilia-associated genes. Four statistically distinct clusters (P &lt; 0.0001) were identified including a high- (median overall survival [OS] 95.5 months; CI [52.1-NA]), mid- (median OS 63.5 months; CI [43.9-NA]) and a low-surviving (median OS 23.7 months; CI [19-134]) cluster. OS was independent of IDH status, 1p/19q codeletion or MGMT promoter methylation status on multivariate analysis. Orthogonal validation was performed using 442 LGGs from the Chinese Glioma Genome Atlas (CGGA). Again, four discrete clusters were found including a high- (median OS 78.4 months, CI [45.8-NA]) and a low-surviving (median OS 16.5 months, CI [12.2-25.5]) cluster. While LGGs with 1p/19q codeletions were present in all clusters, they were overrepresented in the high-surviving groups. The most robustly differentially expressed genes were compared across clusters to find cluster-defining genes most associated with OS. LGGs in the high-surviving group are defined by the expression profiles of 13 genes while low-surviving LGGs are identified by the differential expression of 15 non-overlapping genes. LGGs can be classified into four distinct clusters that are independently associated with OS based on cilia-associated gene expression alone. Within these clusters, there is a high- and a low-surviving group, each with their own unique genetic profiles. These new molecular markers may inform novel therapeutic targets and predictors of clinical outcomes.
PATH-21. INVESTIGATING CHANGES IN IDH MUTATION STATUS AT GLIOMA RECURRENCE
Authors: Voisin Mathew , Gui Chloe , Zadeh Gelareh 
Published: November 2022

Abstract

PURPOSE
Isocitrate dehydrogenase (IDH) mutation status is a key diagnostic and prognostic feature of gliomas. It is thought to occur early in glioma tumorigenesis and remains stable over time. We investigated our tumour bank to identify patients where IDH mutation status changed after glioma recurrence.

METHODS
We identified four patients with immunohistochemistry-recorded IDH mutation statuses that conflicted between multiple tumour samples taken over time. Tissue samples from the tumour bank were analyzed using methylation profiling and Sanger sequencing of IDH1 and IDH2 to verify IDH status.

RESULTS
In all four instances, we found that IDH mutation status in fact remained stable, and there were reasonable explanations as to why mutation status was misinterpreted. One tumour had a non-canonical IDH2 R172K mutation that is not routinely tested for. Two patients had perilesional samples, revealed by methylation profiling to contain a mixture of tumour and normal brain. One patient had a IDH wildtype sample with a methylation profile consistent with reactive brain tissue rather than tumour.

CONCLUSIONS
All four cases of IDH mutation change at glioma recurrence were due to either misinterpreting perilesional or reactive tissue as tumour or overlooking a non-canonical mutation. This finding supports the concept that IDH mutation is a fixed characteristic of gliomas and highlights the importance of accurate surgical biopsy and molecular testing at initial diagnosis.
PATH-24. ACCURATE IDENTIFICATION OF GLIAL MALIGNANCIES FROM PERIPHERAL BLOOD
Authors: Anichini Giulio , Fulmali Pooja , O'Neill Kevin , Datta Vineet , Crook Timothy , Syed Nelofer 
Published: November 2022

Abstract
Symptomatic presentation of patients with intra-cranial malignancy is frequently non-specific and differentiating such patients from those with benign conditions is challenging. Accordingly, GBM presents as a medical emergency more frequently than any other common cancer, implying that effective strategies for rapid and simple diagnostic stratification of such patients are urgently required. Here we describe the detection of glial malignancies based on the enrichment and identification of Circulating Glial Cells (CGCs) in peripheral blood. The first case controlled study included blood from 189 participants split into discrete training and test sets (145 GBM, 44 benign CNS conditions). The second case controlled study included 40 cases of glial malignancies, 22 benign CNS conditions, 24 solid tumors with brain metastases, and 500 healthy individuals with no prior diagnosis of cancer and no current suspicion of cancer. A third prospective study was also carried out in 68 individuals with radiologically evident intracranial space-occupying lesion suspected of glial malignancies. Blood specimens were blindly evaluated for detection of CGCs through TruBlood assay to determine clinical sensitivity and specificity. 98% sensitivity and specificity was observed in detecting glial malignancies and differentiating them from benign CNS conditions in both case controlled studies. We detected and differentiated glial malignancies from benign CNS, healthy samples, and brain metastases. In the prospective study, 56 were positive for CGS, and 12 were negative for CGCs. All CGC positive specimens were confirmed glial malignancies and all CGC negative specimens benign CNS conditions. We present a non-invasive approach to the diagnostic stratification of patients presenting with suspicious but non-specific neurocognitive symptoms and hence early detection of glial malignancies. Moreover, immunocytochemistry facilitates the differentiation of GBM from metastatic intra-cranial epithelial cancers.
PATH-27. INTRAOPERATIVE ASSESSMENT OF IDH MUTATION AS A SURROGATE FOR TUMOR INFILTRATION VIA DESORPTION ELECTROSPRAY MASS SPECTROMETRY IN GLIOMAS
Authors: Brown Hannah , Moniz-Garcia Diogo , Chen Rong , Jentoft Mark , Middlebrooks Erik , Chaichana Kaisorn , Quiñones-Hinojosa Alfredo , Cooks Robert 
Published: November 2022

Abstract

BACKGROUND
Despite advances in cancer biology, surgery and its extent of resection remains the most important prognostic modulator in gliomas, with the distinction between infiltrated and non-infiltrated tissues being an issue at the penumbra. Isocitrate dehydrogenase (IDH) mutation is unique to IDH-mutant glioma cells and can be used as a potential surrogate for tumor infiltration. Here we evaluate desorption electrospray ionization-mass spectrometry (DESI-MS) as a near real-time method for detecting infiltration at the margin of IDH-mutant gliomas.

METHODS
We conducted a prospective study in which DESI-MS analysis was performed on freshly obtained tissue biopsies to detect the presence of 2-Hydroxyglutarate (2HG), with subsequent review of each sample by a board-certified neuropathologist.

RESULTS
A total of 247 biopsies from a 49-patient study were previously collected and analyzed at Indiana University. Assessment of IDH mutation status of 71 core biopsies yielded sensitivity, specificity, and accuracy values of 89, 100, and 94%, respectively. Subsequent improvement of the method, including the measurement of 2HG relative to an internal control (Glutamate, Glu), allowed for detection of IDH-mutant infiltration at surgical margins. We have collected 183 biopsies (116 core and 67 margin) from 23 patients. Preliminary results of IDH mutation assessments of core biopsies indicate 93% sensitivity, 100% specificity, and 98% accuracy and margin biopsies indicate 88% sensitivity, 100% specificity, and 94% accuracy. Tumor infiltration at the margin of the surgical resection by detection of IDH-mut infiltration was detected in 88% of margin biopsies from IDH mutant tumors (30 of 34 biopsies).

CONCLUSION
We present a novel method to allow intraoperative evaluation of IDH mutation presence in glioma margin biopsies. Our method and its ongoing validation identified tumor infiltration beyond surgical margins and serves as a foundation for molecularly guided surgery in IDH-mut gliomas via DESI-MS.
PATH-31. ECDNA PROMOTES TUMORIGENICITY AND INTRATUMORAL HETEROGENEITY IN MEDULLOBLASTOMA
Authors: Chapman Owen , Sridhar Sunita , Wang Shanqing , Mesirov Jill , Chavez Lukas 
Published: November 2022

Abstract
Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive cancers, including medulloblastoma (MB), the most common pediatric brain tumor. To assess the clinical importance of ecDNA in MB, we applied computational methods to detect ecDNA in the genomes of a cohort of 468 MB patients and 31 MB model systems. Among patients, ecDNA was detected in 18% of tumors and carried over twofold greater risk of mortality. Affected genomic loci harbor up to hundredfold amplification of oncogenes including MYC, MYCN, TERT, and other novel putative oncogenes. Between sequential patient biopsies at initial diagnosis and subsequent relapse, we observed structural variation at ecDNA loci and generation of new ecDNA sequences. Among model systems, ecDNA was found in 19 of 31 genomes (61%). Although ecDNA was far more prevalent among MB models than patients, the ecDNA genomic sequences were conserved between most patient-derived xenograft (PDX) models and the human tumors from which they were made. To elucidate the functional regulatory landscapes of ecDNAs in MB, we generated transcriptional (RNA-seq), accessible chromatin (ATAC-seq), and chromatin interaction (Hi-C) profiles of 6 MB tumor samples. In each case, we identified regulatory interactions that cross fusion breakpoints on the ecDNA, representing potential “enhancer rewiring” events which may contribute to transcriptional activation of co-amplified oncogenes. To test this hypothesis, we conducted an in vitro CRISPRi screen targeting regulatory regions on the ecDNA of a MB cell line and identified distal enhancers which promote proliferation. Using single-cell sequencing, we have also developed methods to explore intratumoral heterogeneity of ecDNA in a p53-mutant SHH MB patient tumor and its corresponding PDX model. In summary, our study analyzes the frequency, diversity, and functional relevance of ecDNA across MB subgroups and provides strong justification for continued mechanistic studies of ecDNA in MB with the potential to uncover new therapeutic approaches.