bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIOM-09. MULTIPLEX ANALYSIS OF CSF EXTRACELLULAR VESICLES OF INTRASPINAL TUMORS
Authors: Ricklefs Franz , Stevic Ines , Mende Christian , Welsh Joshua , Jones Jennifer , Westphal Manfred , Lamszus Katrin , Eicker Sven 
Published: December 2020

Abstract
BACKGROUND: Extracellular vesicles (EVs) play an important role in cell-cell communication in different types of tumors, carrying multiple layers of biological functional molecules, including proteins, RNA, DNA and lipids. We previously demonstrated that extracellular vesicles (EV) from central nervous system tumors reflect the molecular subtype of the original tumor and mediate an exchange of pro-oncogenic signals. Their implication as biomarkers in tumor disease is under current investigation. It is unclear, however, to what extent cerebrospinal fluid (CSF) EVs from intraspinal tumors are utilizable for diagnostical purposes and how their marker profiles overlap with EVs derived from non tumorous EVs. We analyzed CSF EVs of intraspinal tumors to define CSF EV profiles that allow tumor subtype classification. METHODS: EVs were isolated from CSF of patients suffering from intraspinal meningioma (n=5), ependymoma (n=7) and neurinoma (n=5). Patients suffering from normal pressure hydrocephalus were used as controls (n=5). EVs were analyzed by multiplex bead based assay, immunoblotting, electron microscopy and NTA. RESULTS: CSF EVs were 97.21 ± 3.37nm (intraspinal tumor patients) and 101.6 ± 3.68nm (controls) in sizes and showed vesicular structures by electron microscopy. Particle number were not significantly different between both groups (p = 0.103). Using our 37 protein mutliplex EV profiling kit we found 29 proteins to be expressed in a sufficient manner on CSF EVs. CSF EVs of intraspinal meningioma showed elevated CD62P, HLA-DR, CD40, CD42a and CD45 expression levels, while ependymoma showed decreased levels of CD9, CD63, CD81, whereas neurinomas had elevated levels of SSEA-3 and CD25. CONCLUSION: This is the first comprehensive analysis of CSF EV of intraspinal tumor patients. CSF EV display distinct subpopulations that may allow tumor classification and long-term surveillance. However as tumor-specific EVs may be rare, there is still the need to identify markers that can enrich tumor-specific EVs for molecular profiling.
BIOM-11. ENZYMATIC ASSAY USED TO MONITOR CHANGES IN ONCO-METABOLITE, D2HG, IN RESPONSE TO THERAPY
Authors: Saber Rehan , Rahman Masum , Olson Ian E , Rajani Karishma , Burns Terry C 
Published: December 2020

Abstract

INTRODUCTION
Gliomas are the most common and deadly adult brain cancers with a median survival time of less than 18 months. Many therapeutics have failed translating into effective therapies due to incomplete understanding of the disease and heterogeneity of tumors between patients. There is a need for methods that allow for continual access and analysis of glioma biomarkers. We sought to establish a reliable method for quantifying the onco-metabolite, D2HG. After optimizing this method, we used microdialysate and microperfusate to test our hypothesis that analysis of D2HG in response to therapy can indicate therapeutic efficacy sooner than current methods permit.

METHODS
Microdialysate and microperfusate were collected from the tumor centers and lateral ventricles of athymic nude mice implanted with IDH1 mutant PDX line GBM196. We performed microdialysis and microperfusion on consecutive days to determine baseline D2HG concentration. Following a five day period of TMZ treatment, we collected another round of microdialysis and microperfusion one week after treatment and again two weeks after treatment. We then used our optimized D2HG enzymatic assay to quantify the changes in D2HG in response to therapy.

RESULTS
Using our enzymatic D2HG assay, we were able to quantify D2HG as low as 30nM (30fmol/uL). We found a ~20% decrease in D2HG concentration in the tumor center and right lateral ventricle after 1 week of TMZ treatment (n=2), and ~36% decrease after 2 weeks of TMZ treatment (n=2).

CONCLUSION
Using a D2HG quantification assay to monitor changes in concentration of D2HG in microdialysate/microperfusate can predict sensitivity to therapy.
BIOM-13. DNA METHYLATION MARKS GLUCOCORTICOID PATHWAY RESPONSE IN DEXAMETHASONE-TREATED BRAIN TUMOR PATIENTS
Authors: Wiencke John , Molinaro Annette , Warrier Gayathri , Rice Terri , Clarke Jennifer , Taylor Jennie , Wrensch Margaret , Tamaki Stanley , Lee JiYoon , Hansen Helen , McCoy Lucie , Bracci Paige , Salas Lucas , Koestler Devin , Christensen Brock , Kelsey Karl 
Published: December 2020

Abstract
Dexamethasone (DEX) is routinely prescribed in brain tumor patients to limit vasogenic edema but may also exacerbate immunosuppression and adversely affect survival. The wide spectrum of dosing and individual variation in glucocorticoid (GC) response makes it difficult to assess the impact of DEX exposures. A potential marker of steroid pathway activation and GC load affecting the immune system are induced changes in chromatin structure marked by DNA methylation. We identified DEX-responsive DNA methylation sites in blood leukocytes from glioma patients treated with the drug at various doses and times during the course of their disease. Using weighted co-methylation network analysis, we show that DEX-induced hypomethylation includes well-known regulators of GC receptor (GR) sensitivity (e.g., FK506 binding protein 51: FKBP5) and inflammation (e.g., myeloperoxidase: MPO) and is enriched at genomic locations containing glucocorticoid receptor (GR) binding sites. Elastic net regression modeling was used to train a multilocus GC methylation index (GCMI) that discriminates current DEX users and non-users. GCMI scores showed wide interindividual variation among cases and DEX naïve control subjects. Using independent samples of DEX naïve and exposed glioma patients we show that the GCMI is a sensitive and specific indicator of DEX exposure. GCMI measured in non-glioma controls indicated sensitivity to non-DEX steroid treatments (e.g. prednisolone, fluticasone). Subjects with elevated neutrophil and decreased lymphocyte counts demonstrated high GCMI scores, reflecting the clinically relevant in vivo impact of this marker. Among 195 IDH wildtype and hTERT non-mutant glioma subjects, the GCMI was associated with a HR of 1.11 (95% CI 1.06–1.17) p&lt; 0.0001 in Cox survival models that included age and tumor grade. We conclude that epigenetic remodeling in the peripheral immune compartment in response to DEX exposures is a rich source of potentially powerful markers of individual response to GC pathway activation and associated alterations in the immune response.
BIOM-18. TUMOR LOCATION IS ASSOCIATED WITH CDKN2A STATUS IN IDH-MUTANT ASTROCYTOMAS
Authors: Graber Jerome , Cimino Patrick 
Published: December 2020

Abstract

BACKGROUND
Astrocytomas with isocitrate dehydrogenase (IDH) mutations have a better prognosis and response to therapy than matching tumors without IDH mutations. IDH-mutant tumors of any grade or histology that carry homozygous deletions in cyclin-dependent kinase inhibitor (CDKN2A) have a worse prognosis compared to tumors with intact CDKN2A. Within a retrospective cohort of IDH-mutant astrocytomas with known CDKN2A status, we examined whether there was any correlation of CDKN2A status with anatomic location.

METHODS
Astrocytomas of any grade carrying IDH mutations with further molecular sequencing that included CDKN2A status were identified from a tissue database, as well as a clinical cohort of patients seen at the neuro-oncology clinic who had genomic analysis by clinical request. Imaging was reviewed for tumor location. Fisher’s exact test was used to analyze differences between groups.

RESULTS
Six of 35 IDH-mutant astrocytomas (17%) had CDKN2A deletions. None of the six patients with CDKN2A mutant tumors had contact with the insula, whereas 16 of 29 tumors (55%) with intact CDKN2A contacted the insula (p=0.02). The majority of tumors in both groups were located completely or partially in the frontal lobe, as is common in IDH-mutant astrocytomas, and all CDKN2A deleted tumors were in the frontal lobe.

DISCUSSION
Astrocytomas with IDH mutations that also carry CDKN2A deletions have been shown to have a worse prognosis than similar grade tumors with intact CDKN2A status. This has important prognostic implications, but CDKN2A testing is not standard currently or used to stratify patients in clinical trials. Our sample size is small, but if confirmed in a larger cohort could help guide efficient testing for CDKN2A status and improve prognostication.
BIOM-20. PROTEOMICS PROVIDES POTENTIAL THERAPEUTIC APPROACHES TO GLIOBLASTOMA TREATMENT: RESULTS FROM THE CLINICAL PROTEOMICS TUMOR ANALYSIS CONSORTIUM (CPTAC)
Authors: Barnholtz-Sloan Jill S 
Published: December 2020

Abstract
Glioblastoma (GBM) is the most common type of primary malignant tumor in adults and contributes disproportionately to cancer morbidity and mortality. The ability to augment current knowledge based on the genome and transcriptome with information regarding protein abundance and post-translational modifications with small molecule and lipid abundance has provided novel biological insights into GBM tumorigenesis. In this presentation we will discuss results from proteogenomic and metabolomic investigations of prospectively recruited, newly diagnosed, treatment-naive glioblastomas (GBMs; N=99). Multiple key findings emerged that were not known from traditional genomic analyses as implemented in most currently available datasets. Analysis of protein phosphorylation identified key signaling intermediates in the RTK/RAS pathway common to multiple RTK genomic alterations, potentially offering common therapeutic targets for different oncogenic drivers in GBM. Phosphoproteomics also identified potential druggable targets based on kinase-substrate pathway analysis, as well as novel phosphoprotein targets associated with the regulation of telomere length by ATRX in IDH mutants. Identification of distinct Immune High and Immune Low phenotypes in GBM from whole genome interrogation of the proteome were driven by tumor-associated macrophage markers, and associated with distinct epigenetic modifications and histone acetylation patterns. Identification of key metabolic changes in IDH mutants facilitating the accumulation of oncometabolite 2-HG were also associated with lipidomic changes. Taken all together this work identifies additional therapeutic channels for GBM and novel information useful for more accurate stratification patients for effective treatment.
BIOM-21. CORRELATION BETWEEN EPHRIN-A2 EXPRESSION AND PROGNOSIS IN PATIENTS WITH GLIOBLASTOMA
Authors: Hirai Nozomi , Ichinose Toshiya , Tamai Sho , Nakajima Riho , Sabit Hemragul , Nakada Mitsutoshi 
Published: December 2020

Abstract
The Eph receptor/ephrin ligand system is the largest family of tyrosine kinase with signaling modality through cell to cell adhesion. Eph/ephrin is involved in malignant phenotype such as cell proliferation, migration, and invasion in cancer cells. Although the functions of the Eph receptors in glioblastoma have been elucidated, little is known on ephrin ligands, especially ephrin-A2. Here, we analyze the expression of ephrin-A2 in gliomas using surgical specimens. The expression level of ephrin-A2 mRNA in 14 normal brains and glioma (WHO grade II 13, III 10, and IV 40) was measured by quantitative real-time PCR. Ephrin-A2 expression level was significantly lower in glioblastoma than in normal brain (p= 0.0127). When we divided the glioblastoma cases into high and low ephrin-A2 expression groups based on the median value, the overall survival (OS) was significantly longer in the high expression group compared with the low expression group (p= 0.034, median 24.0 and 14.0 months, respectively). Furthermore, multivariate analysis of factors related to OS with ephrin-A2 expression level and general prognostic factors (age, sex, preoperative KPS, surgical resection rate, radiochemotherapy, IDH1 mutation, MGMT promotor methylation) was performed. Ephrin-A2 expression level (p= 0.039), MGMT promotor methylation (p= 0.0001), and surgical resection rate (p= 0.017) were identified as independent prognostic factors. Taken together, ephrin-A2 is an independent favorable prognostic factor in glioblastoma.
BIOM-31. PROGNOSTIC VALUE OF MGMT METHYLATION IN IDH MUTANT GLIOMAS
Authors: Lam Keng , Eldred Blaine , Kevan Bryan , Ji Matthew , Lou Jerry , Pianka Sean , Yong William , Liau Linda , Nghiemphu Phioanh , Cloughesy Timothy , Green Richard , Lai Albert 
Published: December 2020

Abstract

BACKGROUND
Patients with isocitrate dehydrogenase (IDH) mutant gliomas have been associated with longer survival time than those with IDH wildtype. Previous studies have also shown the predictive value of O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for glioblastoma. However, little is known in the prognostic value of MGMT methylation status for IDH mutant gliomas.

METHODS
We retrospectively identified IDH mutant gliomas patients from University of California Los Angeles and Kaiser Permanente Los Angeles that had been tested for MGMT methylation status. We performed Kaplan-Meier and Cox regression analyses of overall survival (OS) to compare the MGMT methylated versus MGMT unmethylated patients.

RESULTS
We identified a total of 375 IDH mutant gliomas with MGMT testing. Subgroups include 52 glioblastoma, 191 astrocytoma, and 132 oligodendroglioma. The median OS for all MGMT methylated patients was 20.0 years and for unmethylated patients 14.3 years (log-rank P=0.008). Cox regression analysis also confirmed patients with MGMT methylated to have better survival than those with MGMT unmethylated (hazard ratio of 0.47, P= 0.005). During subgroup analysis, MGMT methylated glioblastoma patients have a median OS of 13.7 years compared to MGMT unmethylated patients 3.2 years (log-rank P=0.004) with a hazard ratio of 0.14 (P=0.005). However, we see no difference yet for astrocytoma (hazard ratio of 1.09, P= 0.81) and oligodendrogliomas (hazard ratio of 0.36, P= 0.193), possibly as a result of immature survival data.

CONCLUSIONS
MGMT promoter methylation is associated with better outcomes in IDH mutant glioblastoma patients. Progression free survival will be analyzed to determine predictive benefit of MGMT methylation for other glioma subtypes.
BIOM-32. HIGH AFFINITY FLUORESCENT NANOPARTICLES FOR DETECTION IL13Rα2-POSITIVE EXTRACELLULAR VESICLES AND CELLS
Authors: Khristov Vladimir , Madhankumar Achuthamangalam , Zacharia Brad , Connor James 
Published: December 2020

Abstract
Glioblastoma (GBM) is both the most common and deadly malignant primary brain tumor with a 1-year survival of 37.2% and a 5-year survival of just 5.1%. The standard of care for GBM is surgical excision followed by radiation with concurrent and adjuvant temozolomide-centered chemotherapy (TMZ). Despite advances in imaging technology, early identification of treatment failure or impending resistance remains problematic. A unique characteristic of GBM is the overexpression of the α2 variant of IL-13 receptor (IL13Rα2) in 78–96% of patients while virtually undetectable in normal brain tissue. We hypothesize that the blood of patients with GBM contains sufficient IL13Rα2-positive extracellular vesicles (EV) to inform the clinical picture regarding disease status such as tumor recurrence and response to therapy. To detect IL13Rα2 as a specific molecular target for diagnostic testing, we have developed a modified version of IL-13 with increased affinity and specificity for IL13Rα2, and conjugated this ligand to fluorescent/ magnetic nanoparticles using an 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) linker. Furthermore, we demonstrated that the EV plasma fraction of patients with GBM is enriched for the IL13Rα2 receptor. We also demonstrated the ability of the ligand-bound nanoparticles to aggregate with IL13Rα2-positive cells and EVs in vitro. This ligand-based affinity purification particle has the potential to both quantify IL13Rα2 EV levels in patient blood and isolate these EVs for further interrogation of genomic and proteomic molecular markers.
BIOM-43. GLUTAMATE RECEPTOR AND GLUTAMINE METABOLISM PROFILING BY GENE EXPRESSION ANALYSIS AMONG PATIENTS WITH HIGH GRADE GLIOMA (HGG)
Authors: Castro Michael , Badra-Azar Nilofar , Kessler Thomas , Schütte Moritz , Lange Bodo , Yaspo Marie-Laure 
Published: December 2020

Abstract

BACKGROUND
Glutaminolysis and excessive glutamate production are among the metabolic hallmarks of HGG. In addition to a probable role in causing seizures, autocrine stimulation of metabotropic and ionotropic (NMDA, AMPA, and kainate) receptors are capable of activating intracellular signaling pathways that are tumorigenic and contribute to drug and radiation resistance. While hints of a survival benefit from glutamate receptor targeting have occasionally emerged from the clinic, no single strategy has consistently demonstrated efficacy. Hence, we sought to characterize the magnitude of glutamate receptor overexpression and its diversity across a population of HGG patients.

METHODS
A set of 41 genes related to glutamate metabolism was selected from the literature. RNA gene counts for TCGA glioblastoma multiforme (N=163) and Grade 3 glioma samples (Astrocytoma=82, Oligodendroglioma=47, Oligoastrocytoma=39) were downloaded from https://portal.gdc.cancer.gov/. Annotation on subtypes and PFS values were obtained from PMID: 24120142 and 26061751. Gene expression normalization as FPKM and hierarchical clustering were performed using R-3.6.0 genes.

RESULTS
A heatmap with hierarchical clustering for glutamate and glutamine-related genes for the TCGA GBM and grade III glioma samples cohort was generated including colored annotation for the subtype and progression free survival. The graph shows a rough separation into two groups, with grade III gliomas and proneural samples tentatively clustering together and showing higher expression for most of the glutamate related genes. The magnitude of glutaminolysis-related gene over-expression varied significantly across the cohort suggesting a wide variety in the extent of glutamine addiction.

CONCLUSION
Specific glutamate receptors are commonly upregulated in HGG patients, however the heterogeneity underlying this phenomenon suggests that uniform drug strategies are unlikely to succeed in a diverse population. However, gene expression analysis has utility to identify specific glutamate receptor and glutamine profiles and to inform the treatment strategies for discrete subsets of patients using drugs that are already in the armamentarium.
BIOM-48. PTEN MUTATIONS PREDICT BENEFIT FROM TUMOR-TREATING FIELDS THERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Dono Antonio , Mitra Sonali , Takayasu Takeshi , Zhu Jay-Jiguang , Tandon Nitin , Esquenazi Yoshua , Ballester Leomar Y 
Published: December 2020

Abstract

BACKGROUND
Glioblastoma IDH-wildtype (GBM-IDH-WT) recurs despite the standard of care which includes surgical resection and concurrent chemoradiotherapy. Optimal treatment for recurrent GBM-IDH-WT (rGBM) is not standardized and multiple therapeutic approaches are utilized. Clinical trials have shown that Tumor-Treating Fields (TTF) provide equal benefits compared to physician’s chemotherapy choice for patients with rGBM. However, not all rGBM patients respond equally to TTF and understanding which patients will benefit from TTF therapy is critical.

METHODS
We reviewed clinical, molecular, and outcome characteristics of rGBM patients between 09/2009 to 2/2019 in our institution. Patients who received TTF-treatment at the time of 1st recurrence were selected for analysis. Tumors were analyzed for mutations in 315 cancer-related genes by next-generation sequencing. Post-progression survival (PPS) defined as the interval from 1st recurrence to death or the time of analysis, was examined using the Log-rank test and multivariable Cox-regression model.

RESULTS
149 rGBM patients were identified of which 29 (19%) were treated with TTF. Overall, no significant difference in survival was observed in rGBM patients who received TTF therapy (13.9-months vs 10.9-months, p= 0.06). However, among TTF-treated patients (n= 29), there was improved survival in PTEN-mutant (n= 14) patients compared to PTEN-wt (n= 15), (22.2-months vs 11.6- months, p= 0.017). No differences in TTF usage were observed between groups. Within the PTEN-mutant patients (70/149, 47%), those treated with TTF (n= 14) had longer PPS (22.2-months vs 9.3-months, p= 0.005). No survival benefit with TTF-treatment was observed in PTEN-wt patients (79/149, 53%).

CONCLUSIONS
Patients with GBM-PTEN-mutant tumors show a significant improvement in survival when treated with TTF at recurrence. Understanding the molecular mechanism underpinning the differences in response to TTF therapy could help elucidate the mechanism of action of TTF and identify patients that will benefit the most from this therapeutic option.
BIOM-52. A PROGNOSTIC GENE EXPRESSION RISK SCORE FOR MENINGIOMA
Authors: Chen William , Vasudevan Harish N , Choudhury Abrar , Lucas Calixto-Hope G , Magill Stephen , Susko Matthew S , Braunstein Steve , Boreta Lauren , Nakamura Jean , Sneed Penny K , Bush Nancy Ann Oberheim , Villanueva-Meyer Javier , Perry Arie , Solomon David , McDermott Michael , Theodosopoulos Philip , Raleigh David 
Published: December 2020

Abstract

BACKGROUND
Clinical biomarkers for identifying patients at risk for recurrence after resection of meningioma are lacking and are needed for guiding adjuvant therapy. The aim of this study was to identify a prognostic gene expression signature for meningioma.

METHODS
Targeted gene expression analysis was performed on a discovery dataset of 96 meningiomas with suitable tissue identified from a retrospective institutional biorepository. Recurrence was dichotomized based on the median time to local recurrence (TTR). With median follow-up of 6.4 years, the discovery dataset was enriched for clinical endpoints of local recurrence (58%), mortality (42%), and disease-specific mortality (49% of deaths). A 266 gene expression panel was used to interrogate the discovery dataset, and a prognostic gene signature and risk score was generated using prediction analysis for microarrays (PAM) and elastic net regression. The risk score was validated using gene expression data (GSE58037) from 56 meningiomas resected at an independent institution (20% local recurrence, 18% mortality, median follow-up 5.4 years).

RESULTS
A 36-gene signature was identified achieving an AUC of 0.86 for TTR faster than the median in the discovery cohort. A risk score between 0 and 1 based on this signature was strongly associated with shorter TTR (F-test, P&lt; 0.0001), and on multivariate Cox regression (MVA), was independently associated with recurrence (RR 1.56 per 0.1 increase, 95% CI 1.30–1.90, P&lt; 0.0001) and mortality (RR 1.32 per 0.1 increase, 1.07–1.64, P=0.01) after adjusting for WHO grade, age, extent of resection, and sex. Similarly, in the validation dataset, the gene risk score was correlated with shorter TTR (P=0.002) and associated with mortality on MVA (RR 1.86 per 0.1 increase, 1.19–2.88, P=0.005) after adjustment for WHO grade.

CONCLUSIONS
The prognostic meningioma gene expression risk score presented here could be useful in identifying patients at higher risk of progression after resection.