bluuebunny/crossref_metadata_2025_split huggingface dataset:
EPCO-30. MACHINE-LEARNING PREDICTIVE MODELS BASED ON DNA METHYLATION SIGNATURES DETECTED IN LIQUID BIOPSY SPECIMENS ACCURATELY PREDICT THE DIAGNOSIS AND PROGNOSIS OF MENINGIOMAS
Authors: Herrgott Grayson , Sabedot Thais , She Ruicong , Wells Michael , Asmaro Karam , Malta Tathiane , Mosella Maritza , Nelson Kevin , deCarvalho Ana , Poisson Laila , Robin Adam , Lee Ian , Snyder James , Walbert Tobias , Kalkanis Steven , Rock Jack , Noushmehr Houtan , Castro Anavaleria 
Published: November 2021

Abstract

BACKGROUND
Detection of distinct epigenetic features in circulating cell-free DNA (cfDNA) of liquid biopsy specimens (e.g. blood) provides an opportunity to diagnose and prognosticate central nervous system (CNS) tumors. Utilization of distinctive cell-type genome-wide DNA methylation patterns allows for development of machine-learning (ML) models with the ability to predict tumor diagnosis and prognosis, and remains widely unexplored in meningiomas using LB.

METHODS
We profiled the cfDNA methylome (EPIC array) in serum specimens from patients with meningiomas, other CNS tumors and nontumor conditions (n= 63, 190 and 18, respectively) and harnessed internal and external meningioma tissue methylome data. For diagnostic model development, we identified “meningioma specific” signatures through comparison of meningioma and non-meningioma serum specimens (Wilcoxon rank-sum test) which exhibited tissue methylation similarities named Meningioma- epigenetic Liquid Biopsy (MeLB), and were then employed to develop and cross-validate a Random-Forest derived “MeLB” score to discriminate meningiomas from the other conditions. To predict recurrence risk (RR), we classified a meningioma tissue cohort as ‘favorable’ or ‘unfavorable’ (low and high RR, respectively), using a validated ML outcome model and identified outcome-specific methylation markers with serum subgroup specificities used as input to train a Random-Forest to predict RR in serum-based specimens.

RESULTS
Prediction models based on meningioma-specific methylation markers detected in the serum presented a high accuracy in classification of samples as meningioma or not (Accuracy: 89.6%, Sensitivity: 80%, Specificity: 93.8%). The prognostic model using tissue-serum matching methylation markers was validated across an independent tissue-based cohort (Accuracy: 88%, Sensitivity: 86%, Specificity: 88%) and allowed for classification of serum samples according to RR.

CONCLUSIONS
Machine-learning models using DNA methylation markers identified in the serum can accurately diagnose and predict prognosis in patients with meningioma. After validation in an external cohort, these approaches may improve presurgical diagnosis and therapeutic management of patients with this type of tumor.
EPCO-31. GERMLINE AND SOMATIC MUTATIONS IN PEDIATRIC GERM CELL TUMORS
Authors: Song Dong , Zhao Yang , Mu Quanhua , Liang Zhuangzhuang , Wang Jiajia , Cao Liangliang , Chen Luonan , ma jie , Wang Jiguang 
Published: November 2021

Abstract
Pediatric germ cell tumors (pGCTs), a group of germ-cell-originated neoplasms, currently lack sufficient study. Although somatic activation of KIT/AKT and RAS/MAPK pathways have been revealed, no driver mutations have been detected in most of GCT cases. To extensively explore germline and somatic mutations, we analyzed genomic and/or transcriptomic sequencing data of 236 pGCTs, including data from not only public datasets but also newly collected whole-genome-sequencing data of tumor samples together with case-unaffected-parents trios collected in Shanghai Xinhua Hospital. A new computational pipeline was developed and carried out to identify functional germline and somatic variants. Overall, &gt; 30,000 germline and &gt; 100,000 somatic mutations were detected and prioritized. Particularly, we found germline trisomy 21 in three cases, germline XXY in five cases, and one germline XO, demonstrating the enrichment of germline chromosomal abnormality in pGCTs (p-value &lt; 0.0001). We identified 196 loss-of-function-like inherited germline mutations involving CBL (4/212), PTEN (3/212), TEX11 (2/212), and ATM (1/212). In addition, we detected 2,160 de novo germline mutations (DNMs), and showed an average of 69.7 DNMs per proband, which is compatible to the previously reported incidence. Moreover, we discovered recurrent somatic mutations in known driver genes such as KIT (27/110), KRAS (10/110), NRAS (4/110), MTOR (5/110), PTEN (3/110), and CBL (2/110). Interestingly, somatic hotspot RRAS2 mutations were detected in seven of 110 cases. Subsequent clinical association analysis showed that patients who harbored RRAS2 mutations were younger than those harboring KRAS mutations (p-value &lt; 0.05). Somatic copy number changes were frequently observed, including chr12p+ (47/110), chr21q+ (47/110), chrX+ (34/110), chr13q- (27/110), and chr20q+ (26/110). Furthermore, we identified chromoplexy in nine out of 62 cases, and this alteration is significantly enriched in yolk sac tumors with the occurrence 7/11. Collectively, portraying the mutational landscape of pGCTs, we revealed its disease etiology and potential new drug targets.
BIOM-16. NTRK (NEUROTROPHIC TYROSINE RECEPTOR KINASE) FUSIONS IN GLIOMA PATIENTS: A PROMISING MOLECULAR TARGET?
Authors: Vernadou Anastasia , Argyrakos Theodoros , Papadopoulou Eirini , Rigakos Georgios , Tsoukalas Konstantinos , Labropoulos Stefanos , Avgoustidou Maria , Razis Evangelia 
Published: November 2021

Abstract

BACKGROUND
NTRK gene fusions are rare in gliomas (less than 2%). The use of TRK inhibitors in NTRK-fused solid tumors has generated significant clinical interest. It is likely that the unmet need for effective therapies in glioma will lead to routine testing for NTRK fusions.

METHODS
We performed a retrospective review of 22 patients with malignant gliomas accrued between 2007 and 2021. We collected tumor samples from those patients and NTRK fusions were tested using either immunohistochemistry or FISH or NGS. We then evaluated their association with clinical characteristics, histology and other markers (IDH1/2 mutation, MGMT methylation, BRAF mutation, EGFR expression, ATRX expression, TERT mutation).

RESULTS
Median age at diagnosis was 50 years. NTRK1 translocation was detected in 3 out of 22 patient tumors, while NTRK1 duplication was present in 1 patient (probably related to a translocation, but not proven). All NTRK1 translocations were not found in glioblastomas and their median survival was 15.8 months. On the other hand, median survival of gliomas without NTRK translocations was 11 months. In one NTRK1-translocated patient a TRK inhibitor (entrectinib) was used (for a few days), but we cannot evaluate its efficacy as the patient deteriorated and died. As far as the other biomarkers are concerned, 2 out of 3 NTRK1-translocated gliomas were MGMT methylated.

CONCLUSION
NTRK fusions are rare in gliomas, as confirmed in our small sample analysis. Although adult NTRK-fused gliomas are considered to predominantly involve high-grade histology, in our study all patients had initially lower grade gliomas. NTRK alterations can be detected by different laboratory assays, but each of these approaches has specific advantages and limitations and more data are needed in order to identify the best method. For glioblastomas, NTRK fusions and TRK inhibitors are potentially a new targeted therapeutic strategy but more data are needed.
BIOM-17. DIFFERENCES IN THE IMMUNE MICROENVIRONMENT OF GLIOMAS HARBORING IDH2 VERSUS IDH1 MUTATIONS
Authors: Ostrom Quinn , Xiu Joanne , lopez Giselle , Sumrall Ashley , Aulakh Sonikpreet , Glantz Michael , Pan Edward , Khasraw Mustafa , Ashley David M , Walsh Kyle 
Published: November 2021

Abstract

INTRODUCTION
IDH mutations are a defining feature of lower-grade glioma and secondary glioblastoma. Approximately 95% of glioma-associated IDH mutations are in codon 132 of IDH1, but a small proportion are in IDH2. IDH mutations produce the oncometabolite 2-hydroxyglutarate, which induces global DNA hypermethylation and is associated with an immunosuppressive tumor microenvironment. IDH1 is localized in the cytosol while IDH2 is found in the mitochondrial matrix, and mutations in these genes may have differing effects on the tumor microenvironment.

METHODS
Formalin-fixed, paraffin-embedded tissue from 633 IDH-mutant gliomas (615 IDH1-mutant, 18 IDH2-mutant) underwent whole-exome and whole-transcriptome sequencing at Caris Life Sciences (236 grade 2/3 astrocytoma, 158 grade 2/3 oligodendroglioma, 202 IDH-mutant glioblastoma, 37 glioma, NOS). QuantiSEQ was used to infer tumor-infiltrating immune cell populations from RNAseq data, and gene-set enrichment analyses (GSEA) were performed using Wikipathway.

RESULTS
IDH1-mutant gliomas had higher levels of pro-inflammatory M1 macrophages (P=0.04), modestly higher levels of monocytes (P=0.08), and lower levels of neutrophils (P=0.04) – typically considered immunosuppressive – compared with IDH2-mutant gliomas. No differences were observed in levels of B cells, dendritic cells, NK cells, or T cell subsets (Treg, CD4+, CD8+). IDH2-mutant gliomas were enriched for hallmark oligodendroglioma mutations (TERT promoter, CIC, FUBP1), while IDH1-mutant gliomas were enriched for hallmark astrocytoma mutations (ATRX, TP53). However, associations with tumor-infiltrating immune cells persisted after excluding 1p/19q co-deleted oligodendroglioma from analyses. GSEA revealed upregulation of the microglial TYROBP signaling pathway, the microglial phagocytic pathway, and of Type II Interferon signaling in IDH1-mutant gliomas versus IDH2-mutant gliomas.

CONCLUSIONS
Although IDH2 mutations are generally thought to function similarly to IDH1 mutations, we observe differences in tumor-infiltrating immune cells across groups. IDH2-mutant gliomas appeared to have a more immunosuppressive tumor microenvironment than their IDH1-mutant counterparts. Early-phase immunotherapy trials should consider covariate-adaptive randomization approaches to equally allocate IDH2-mutant gliomas across treatment arms.
BIOM-18. METHYLATION ANALYSIS TO REVEAL THE CELLULAR ORIGIN OF PROGNOSTIC CIRCULATING CELL-FREE DNA IN GLIOBLASTOMA
Authors: Till Jacob , Abdalla Aseel , Wang Zhuoyang , Zhou Wanding , Nabavizadeh S Ali , Binder Zev , Hussain Jasmin , Black Taylor , Yee Stephanie , Desai Arati , Bagley Stephen J , Carpenter Erica 
Published: November 2021

Abstract
We have previously demonstrated an independent association between high levels of plasma circulating cell-free DNA (ccfDNA) concentration and poor survival outcomes in patients with newly diagnosed glioblastoma. Given that somatic mutations are rarely detected in glioblastoma patient plasma, we reasoned that DNA shed by tumor (circulating tumor DNA, ctDNA) was not likely to be a driver of prognostic increases in ccfDNA. To investigate the tissue of origin for this prognostic ccfDNA, we analyzed the plasma ccfDNA methylation signatures of 23 patients with newly diagnosed glioblastoma using the Illumina Infinium EPIC array, a genome-wide DNA methylation technique covering over 850,000 CpG sites. Deconvolution of the ccfDNA methylation signatures based on published reference methylomes revealed an increased proportion of ccfDNA derived from granulocytes in glioblastoma specimens compared to healthy controls (p &lt; 0.0001). Further, this granulocyte proportion was increased in patients with high ccfDNA levels (above median value) compared to patients with low ccfDNA (p = 0.0001). Granulocyte proportion correlated with ccfDNA concentration (Spearman r = 0.64, p = 0.001). The top two gene sets identified by differential methylation analysis followed by gene set enrichment analysis (methylGSA) between high- and low-ccfDNA specimens were “neutrophil activation involved in immune response” (GO:0002283, p = 3.4E-23) and “neutrophil degranulation” (GO:0043312, p = 3.4E-23). Additional analysis of ccfDNA fragment size identified larger fragments ( &gt; 700 bp) as the major source of the prognostic signal (log-rank p = 0.002 for progression-free survival) compared to traditionally sized ccfDNA fragments (50-700 bp, log-rank p = 0.12). Taken together, these data suggest that granulocytes are the primary contributing source of prognostic ccfDNA in glioblastoma. Future studies are needed to determine the mechanism through which granulocyte-derived ccfDNA is associated with clinical outcomes in glioblastoma and to explore related therapeutic opportunities.
BIOM-20. TUMOR-INTRINSIC AND PERIPHERAL FEATURES ASSOCIATE WITH SURVIVAL AFTER POLIO VIROTHERAPY IN RECURRENT GBM
Authors: Brown Michael , Zhang Gao , Stevenson Kevin , Lin Xiang , Chen Yeqing , Wei Zhi , Beaubier Nike , Yan Hai , He Yiping , Desjardins Annick , Herndon James , Varn Frederick , Verhaak Roel , Zhao Junfei , Friedman Allan , Friedman Henry , McSherry Frances , Muscat Andrea , Lipp Eric , Khasraw Mustafa , Peters Katherine , Randazzo Dina , Sampson John , McLendon Roger , Bigner Darell , Gromeier Matthias , Nair Smita , Ashley David M 
Published: November 2021

Abstract

BACKGROUND
PVSRIPO is a live-attenuated recombinant rhino:poliovirus that mediates antitumor efficacy by engaging antitumor immunity. A subset (~20%) of patients with recurrent GBM (rGBM) survive &gt;24 months after therapy. We previously reported that low tumor mutation burden (TMB) is associated with longer survival after PVSRIPO and immune checkpoint blockade therapy in rGBM, and that low TMB associates with higher inflammatory gene expression signatures in rGBM tumors.

METHODS
Clinical features were tested for association with survival after PVSRIPO therapy. Whole exome sequencing and RNA-sequencing of tumors were used to correlate mutational landscape, tumor mutation burden (TMB), and gene expression signatures of patient tumors with survival. An in vitro assay that measures inflammatory responses of patient PBMCs to PVSRIPO was performed. An independent cohort of paired primary and recurrent GBM tumors was used to assess longitudinal changes in TMB and gene expression signatures after standard of care treatment.

RESULTS
A short time to recurrence and low TMB associated with longer survival after PVSRIPO therapy; these features were not prognostic for longer survival in immunotherapy naïve rGBM cohorts. Unexpectedly, higher pre-treatment polio neutralizing antibody titers were also associated with longer survival after PVSRIPO therapy in two independent clinical cohorts. PBMCs from patients surviving longer after PVSRIPO therapy mounted higher TNF, but lower IFN-a responses after in vitro challenge with PVSRIPO. In analysis of paired primary vs recurrent GBM tumors, we discovered that patients with low TMB upon recurrence were more likely to experience increased tumor inflammation and suppression of overall TMB. Low TMB in rGBM tumors was also associated with neoantigen depletion. Collectively, these observations imply that patients with low TMB and/or shorter duration of standard of care therapy may have intact immune surveillance, and that pre-treatment immunological status may dictate survival response to polio virotherapy.
BIOM-29. ASSOCIATION OF PLASMA microRNA-21 EXPRESSION WITH KARNOFSKY PERFORMANCE SCALE SCORES IN GLIOMA PATIENTS
Authors: Malueka Rusdy , Dwianingsih Ery , Alethea Maria , Wicaksono Adiguno , Dananjoyo Kusumo , Asmedi Ahmad , Hartanto Rachmat 
Published: November 2021

Abstract
Gliomas are one of the most common primary brain tumors. MicroRNA-21 (miRNA-21) has been shown in previous studies to be associated with prognosis in glioma patients. However, similar studies in the Asian population, particularly in Indonesia, are very limited. This study aimed to find the association of plasma miRNA-21 expression with functional status measured by Karnofsky Performance Scale (KPS) in Indonesian glioma patients. The patients were enrolled from a neuro-oncology referral center in Yogyakarta, Indonesia. MiRNA-21 expression from plasma was measured by real-time quantitative PCR. Clinical data were obtained from medical records. KPS scores were classified as low (&lt; 70) and high (&gt; 70). In total, 50 patients were included in this study. Most patients were diagnosed with WHO grade IV gliomas (30.4%), followed by grade II (30.4%), grade III (21.4%), and grade I (5.4%). Most patients (64%) have low KPS scores (&lt; 70). Patients in the low KPS scores group have significantly higher miRNA-21 expression compared to patients in the high KPS scores group (2-∆CT 4.26 vs. 0.68, p=0.002). In conclusion, higher expression of plasma miRNA-21 is associated with worse functional status in glioma patients as measured by KPS.
BIOM-30. BLOOD COUNTS THROUGH TREATMENT COURSE IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS RECEIVING CHEMORADIATION
Authors: Deng Davy , Hammoudeh Lubna , Cagney Daniel , McFaline-Figueroa J Ricardo , Chukwueke Ugonma , Reardon David , Lee Eudocia Quant , Nayak Lakshmi , Lim-Fat Mary Jane , Ligon Keith , Bi Wenya Linda , Arnaout Omar , Alexander Brian , Wen Patrick , Rahman Rifaquat 
Published: November 2021

Abstract

BACKGROUND
Glioblastoma (GBM) patients are treated with radiation therapy (RT), temozolomide, and corticosteroids which can affect hematologic and immunologic parameters. We examined lymphocytes, neutrophil-to-lymphocyte ratio and platelet measurements and their association with progression-free survival (PFS) overall survival (OS).

METHODS
We identified 759 newly diagnosed adult GBM patients treated at our institution in the temozolomide (TMZ) era with blood counts that could be automatically extracted from the electronic medical record during chemoradiation (CRT, defined as within 42 days of RT) and at first recurrence. Linear regression and Cox modeling were used to evaluate outcomes.

RESULTS
Median age was 60.3 years; 87% had KPS ≥ 70, 37.5% had gross total resection, and 90% received TMZ. Prior to RT, 56.4% (375/665) patients had a lymphocyte measurement &lt; 1.0 × 1000 cells [K]/μL. Within 42 days of CRT, 81.7% (536/656) had a lymphocyte measurement &lt; 1.0 K/μL, 37.8% (248/656) &lt; 0.5 K/μL. 10.7% (58/544) patients developed grade 2 or higher neutropenia, 9.1% (50/547) patients developed grade 2 or higher thrombocytopenia. On multivariable analysis (MVA), older age (AHR1.03, p&lt; 0.001), unmethylated MGMT status (AHR2.56,p&lt; 0.001), lower RT dose (&lt;54Gy, AHR 3.45, p&lt; 0.001), male sex (AHR1.45, p=0.02), non-gross total resection (AHR1.63, p&lt; 0.001), lymphopenia during CRT (AHR0.63, p=0.008) and higher NLR during CRT (AHR1.02, p=0.001) were significantly associated with worse OS.
Older age (AHR1.01, p=0.02), unmethylated MGMT status (AHR2.44, p&lt; 0.001), lower RT dose (AHR1.82, p=0.02), higher NLR during CRT (AHR1.03, p &lt; 0.001) were significantly associated with worse PFS on MVA. At first recurrence, median lymphocyte count was 0.7 K/μL with 74% (348/468) patients &lt; 1.0 K/μL and 27% &lt; 0.5 K/μL.

CONCLUSION
Lymphopenia and higher neutrophil-to-lymphocyte ratio are associated with inferior outcomes. Persistent lymphopenia at time of first recurrence may have implications for clinical trial eligibility and immunotherapy approaches in recurrent GBM.
BIOM-37. ELUCIDATION OF THE TRANSCRIPTOMIC CONSEQUENCES OF KLF4 AND TRAF7 MUTATIONS IN SECRETORY MENINGIOMAS
Authors: Michaelsen Signe , Cloos Paul , Broholm Helle , Johansen Jens , Ahmedov Ulvi , Mathiesen Tiit , Kristensen Lasse , Kristensen Bjarne , Hansen Klaus 
Published: November 2021

Abstract
Secretory meningioma (SM) is a benign histological meningioma subtype frequently located in the central skull-base, complicating surgical removal, highlighting the need of gentle targeting treatment alternatives. SM tumors arise from the arachnoid layer in the meninges and are associated with a hotspot p.K409Q mutation in KLF4 combined with different mutations in TRAF7. The objective of this study was to identify how KLF4 and TRAF7 mutations alter signaling in SM tumors. The study includes 16 FFPE samples from SM tumors and three arachnoid cysts as normal-tissue reference. All tissues were histologically confirmed, followed by genomic sequencing of KLF4, TRAF7, NF2 and TERT-promoter (C220T/C228T) using a customized NGS panel. Gene expression profiles were analyzed using NanoString Pan-cancer Progression and Pan-cancer Pathways panels, which resulted in measurement of 1,202 unique transcripts over background level. All 16 SM tumors presented the KLF4p.K409Q mutation, of which 12 had mutation in TRAF7 (four being p.N520S), while no cysts had mutations in these genes. Neither tumors nor cysts had NF2 or TERT-promoter mutations. PCA analysis showed different RNA expression profiles for SM tumors and cysts, while TRAF7 mutation was without influence on the overall gene expression patterns in the tumors. Sub-analysis found increased KLF4 expression in TRAF7-mutated SM tumors versus non-mutated tumors and cysts at the RNA level, while TRAF7 expression was stable in all samples. In total 98 genes were found differentially expressed (54 up- and 44 downregulated) with a log2-fold change over 1 and an adjusted p-value under 0.05 in tumors versus cysts. Further analyses are planned to explore and validate these results. In conclusion, we find that the KLF4p.K409Q mutation correlates more strongly with SM histology, than the TRAF7 mutation, and that SM tumors have gene expressions profiles that are distinct from normal arachnoid tissue for a number of disease relevant genes.
BIOM-43. CROSS-PLATFORM ROBUSTNESS IN THE GLUCOCORTICOID RESPONSE PHARMACODYNAMIC BIOMARKER
Authors: Tang Emily , Wiencke John , Warrier Gayathri , Hansen Helen , McCoy Lucie , Rice Terri , Bracci Paige , Wrensch Margaret , Taylor Jennie , Clarke Jennifer , Koestler Devin , Salas Lucas , Christensen Brock , Kelsey Karl , Molinaro Annette 
Published: November 2021

Abstract
The neutrophil dexamethasone methylation index (NDMI) is an algorithm-based biomarker to assess individuals’ exposures to dexamethasone, a synthetic glucocorticoid commonly administered for inflammation. Cortisol is the main endogenous glucocorticoid that controls vital processes including the immune response and lipid and carbohydrate metabolism. Variations in the NDMI score reflect individuals’ sensitivities of exposures to both exogenous and endogenous glucocorticoids, and this biomarker was trained using elastic net regression on Illumina’s most recent DNA methylation beadarray, the EPIC array, which contains 850,000 cytosine-guanine (CpG) sites. While technology for microarray research continues to advance over time, researchers are capable of conducting more comprehensive epigenome-wide association studies (EWAS). However, many studies are still run and archived using Illumina’s historical 450K platform with approximately 450,000 CpGs, and there are fewer published databases using the 850K EPIC array. To evaluate the cross-platform bioinformatic comparability, we performed elastic net regression modeling using predictors available in the 450K to train the NDMI. Among the 135 pre-surgery glioma cases from the UCSF Immune Profiles Study (IPS), NDMI scores between the 450K and 850K model were strongly correlated (r = 0.99, p &lt; 0.0001). In the 311 controls from the UCSF Adult Glioma Study (AGS), similar correlations were observed (r = 0.96, p &lt; 0.0001). We observe that NDMI remains a robust tool using historical 450K data and conclude that this algorithmic tool is capable of detecting the variations in individuals’ responses to dexamethasone.