bluuebunny/crossref_metadata_2025_split huggingface dataset:
GENE-38. IDH1MUT INDUCES N6-METHYLADENOSINE (m6A) RNA HYPERMETHYLATION VIA D-2-HG IN GLIOMA
Authors: Pianka Sean , Li Tie , Ji Matthew , Lai Albert 
Published: November 2019

Abstract

INTRODUCTION
IDH1 MUT confers slower tumor growth rates and improved prognoses for glioma patients, but the precise mechanisms underlying these clinically relevant benefits remain largely unknown. IDH1MUT gliomas produce high levels of D-2-HG, a putative oncometabolite that inhibits a range of α-ketoglutarate-dependent dioxygenases. D-2-HG-mediated inhibition of TET-family proteins involved in DNA demethylation is known to be a key driver leading to the oncogenic DNA hypermethylation phenotype (known as G-CIMP) seen in IDH1MUT gliomas. Recent evidence indicates that D-2-HG also functionally inhibits FTO and AlkBH5, two dioxygenases responsible for demethylation of RNA N6-methyladenosine (m6A) sites. This study sought to determine if D-2-HG mediates an increase in m6A content in IDH1MUT gliomas.

METHODS
Total RNA was isolated from patient tumor samples, patient-derived gliomaspheres, human embryonic kidney cell (HEK293T), normal human astrocyte (NHA), and U87 glioma model systems expressing either IDH1MUT or IDH1WT. Relative abundance of m6A modifications was determined both quantitatively and qualitatively using colorimetric ELISA-like assays and m6A-antibody dot blots, respectively.

RESULTS
Quantification of m6A abundance in IDH1MUT patient tumor samples and patient-derived gliomaspheres revealed an increase in m6A content compared to IDH1WT samples. Forced expression of IDH1MUT in HEK293T, NHA, and U87 cells increased intracellular D-2-HG content and global m6A abundance in purified RNA. Additionally, D-2-HG treatment of IDH1WT cell lines increased m6A abundance, including in IDH1WT gliomaspheres. Conversely, inhibition of D-2-HG generation in IDH1MUT cell lines decreased m6A abundance. Data will also be presented suggesting that increased m6A abundance is associated with decreased cellular proliferation.

CONCLUSIONS
These results indicate that increased intracellular D-2-HG arising in the context of IDH1MUT mediates increases in RNA m6A methylation in glioma. The association with m6A hypermethylation and reduced growth suggests that RNA methylation provides a novel therapeutic target.
GENE-44. BRD4 DELETION LEADS TO CEREBELLAR DEFICITS AND ATAXIA
Authors: Ayad Nagi 
Published: November 2019

Abstract
Cerebellar neuronal progenitors undergo a series of divisions before irreversibly exiting the cell cycle and differentiating into neurons. Dysfunction of this process underlies many neurological diseases including ataxia and the most common pediatric brain tumor, medulloblastoma. To better define the pathways controlling the most abundant neuronal cells in the mammalian cerebellum, cerebellar granule cell progenitors (GCPs), we performed RNA-sequencing of GCPs exiting the cell cycle. Time-series modeling of GCP cell cycle exit identified downregulation of activity of the epigenetic reader protein Brd4. Brd4 binding to the Gli1 locus is controlled by Casein Kinase 1δ (CK1 δ-dependent phosphorylation during GCP proliferation, and decreases during GCP cell cycle exit. Importantly, conditional deletion of Brd4 in vivo in the developing cerebellum induces cerebellar morphological deficits and ataxia. These studies define an essential role for Brd4 in cerebellar granule cell neurogenesis and are critical for designing clinical trials utilizing Brd4 inhibitors in neurological indications.
GENE-57. COMPARATIVE MOLECULAR LIFE HISTORY OF SPONTANEOUS CANINE AND HUMAN GLIOMA
Authors: Amin Samirkumar , Anderson Kevin , Bourdreau Beth , Martínez Emmanuel , Kocakavuk Emre , Johnson Kevin C , Barthel Floris , Varn Frederick , Kassab Cynthia , Ling Xiaoyang , Kim Hoon , Barther Mary , Yee Ngan Chew , Dickinson Peter , Packer Rebecca , Taylor Amanda , Rossmeisl John , Heimberger Amy , Levine Jonathan , Verhaak Roel 
Published: November 2019

Abstract
Diffuse gliomas are the commonest of malignant brain tumors with high-grade tumors carrying dismal prognosis. Preclinical models have proven themselves as poor predictors of clinical efficacy, attributed to the lack of a comparable tumor microenvironment. Comparative genomics of canine and human gliomas provide an attractive alternative modality to identify conserved drivers and underlying mutational processes of glioma as well as evaluate life history tradeoffs related to tissue context and aging that can shape type and relative timing of drivers in gliomagenesis. We performed a comparative genomics analysis between whole genome-, exome-, transcriptome- and methylation-sequencing of 77 canine gliomas, and human pediatric (n=217) and adult gliomas (n=822). We found alterations in common with those in human pediatric and adult gliomas in the Tp53 and cell cycle pathways, receptor tyrosine kinase and Idh1 R132 mutations. Canine gliomas showed similarity to human pediatric gliomas in terms of lower mutational rates (0.2–0.29 per megabase), hotspot mutations and amplifications of Pdgfrα, and robust aneuploidy constrained within the syntenic regions of Pdgfrα and Myc, but also in the known pediatric drivers, Hist1 and Acvr1 genes. A mutational signature reflecting homologous repair defect was detected in canine and pediatric but not adult gliomas, potentially resulting in the observed higher rates of genomic instability. Canine gliomas in majority classified as pediatric tumors using a commonly used human brain methylation classifier (Capper et al. 2018) and cell-of-origin analysis by deconvoluting canine transcriptome using lineage-specific gene signatures. By providing a large canine glioma genomic-sequencing dataset and comparing it with human glioma, our study provides unique insights into glioma etiology and the chronology of glioma-causing somatic alterations. Further, our results effectively position preclinical models of spontaneous canine glioma for use in understanding glioma drivers, and evaluate novel therapies targeting aneuploidy, especially for pediatric brain tumors.
GENE-58. ACTIVE TRANSCRIPTION START SITES OF MENINGIOMA SAMPLES ASSOCIATED WITH RISK OF RECURRENCE
Authors: Malta Tathiane , Sarraf Sabedot Thais , Carlotti jr Carlos , Noushmehr Houtan 
Published: November 2019

Abstract
Meningiomas are mostly benign brain tumors but have a substantial risk of recurrence, sometimes to more aggressive subtypes. Recently, a DNA methylation signature in meningioma was described as able to stratify patients by recurrence risk (favorable and unfavorable). It is well recognized that epigenetic deregulation at distinct genomic elements can affect changes in gene expression and contribute to cancer initiation and progression. Our goal for this study is to define genes that are actively expressed or repressed by both DNA methylation and chromatin histone modification (defined by H3K4me3). For this pilot study, we selected two favorable (grades I and II) and two unfavorable (grades II and III) meningioma primary tumor samples (N=4) and mapped H3K4me3 genome-wide and whole-genome DNA methylation, in an attempt to identify active transcription start sites at known promoters. After data alignment, preprocessing and peak calling, we identified 29,514 consensus peaks for H3K4me3. The differential binding analysis resulted in 5,752 H3K4me3 regions that distinguish favorable from unfavorable meningioma, mostly gain of peaks in the unfavorable group. We identified 1,505 peaks overlapping with known promoters, 51% associated with gain of peaks in the unfavorable group. Promoter-associated chromatin changes coincided with hypomethylation in 23 unique genes in the unfavorable group. Genes such as MET, PTEN, and the long non-coding RNA RP11-60L3.1 were identified as potential regulators of meningioma recurrence. Our preliminary results describe the identification of distinct genome-wide changes in chromatin associated with meningioma patient with high risk for recurrence. Identification of candidate genes will provide knowledge of the role of epigenomics in the development of malignant meningioma and of opportunities for targeted therapy.
GENE-63. GENOMIC CHARACTERIZATION OF HUMAN BRAIN METASTASES IDENTIFIES NOVEL DRIVERS OF LUNG ADENOCARCINOMA PROGRESSION
Authors: Nayyar Naema , Shih David , Bihun Ivanna , Dagogo-Jack Ibiayi , Gill Corey , Aquilanti Elisa , Bertalan Mia , Kaplan Alexander , D’Andrea Megan , Chukwueke Ugonma , Ippen Franziska , Alvarez-Breckenridge Christopher , Camarda Nicholas , Lastrapes Matthew , McCabe Devin , Kuter Benjamin , Kaufman Benjamin , Strickland Matthew , Carlos Martinez-Gutierrez Juan , Nagabhushan Deepika , De Sauvage Magali , White Michael , Castro Brandyn , Hoang Kaitlin , Kaneb Andrew , Batchelor Emily , Ha Paek Sun , Park Sung-Hye , Martinez-Lage Maria , Berghoff Anna , Merrill Parker , Gerstner Elizabeth , Batchelor Tracy , Frosch Matthew , Frazier Ryan , Borger Darrell , John Iafrate A , Johnson Bruce , Santagata Sandro , Preusser Matthias , Cahill Daniel , Carter Scott , Brastianos Priscilla 
Published: November 2019

Abstract
Although lung adenocarcinomas frequently metastasize to the brain, treatment options for lung adenocarcinoma brain metastases are limited. We discovered novel candidate drivers of progression by using case-control analyses to compare whole-exome sequencing data from a cohort of 73 lung adenocarcinoma brain metastases to a control cohort of 503 primary lung adenocarcinomas. We identified 3 genomic regions with significantly more frequent amplifications in brain metastases compared to the control cohort: MYC (12% vs 6%), YAP1 (7% vs 0.8%) and MMP13 (10% vs 0.6%). We also identified CDKN2A/B as a region deleted at a significantly greater frequency in brain metastases compared to primary lung adenocarcinomas (27% vs 13%, respectively). We confirmed frequent amplifications of MYC and YAP1/MMP13 in an independent validation cohort of 105 lung adenocarcinoma brain metastasis samples using fluorescence in situ hybridization. We further validated that MYC, YAP1 and MMP13 can drive brain metastases in a patient-derived xenograft mouse model. We found a higher incidence of metastases to the brain in mice receiving intracardiac injections of tumor cells expressing the candidate drivers compared to tumor cells expressing LacZ as a control. These results indicate that somatic alterations can drive lung adenocarcinomas to metastasize to the brain. The candidate brain metastasis drivers that we identified may serve as therapeutic targets in patients with lung adenocarcinomas who develop this devastating complication.
HOUT-02. TREATMENT PATTERNS AND OUTCOMES FOR PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA MULTIFORME IN A US COMMUNITY ONCOLOGY SETTING
Authors: Fu Alex , Robert Nicholas , Pham Trang , Marshall Alexander , Annavarapu Srinivas 
Published: November 2019

Abstract

BACKGROUND
This study aims to describe real world characteristics and outcomes of newly-diagnosed glioblastoma multiforme (GBM) patients in relationship to O6-methylguanine DNA methyltransferase promoter (MGMT) testing and methylation status, in the US.

METHODS
Patients receiving care for GBM were identified in the US Oncology Network database from 1/1/2013 to 6/30/2018 and followed up to 9/30/2018. Structured data and chart reviews were used to assess demographic and clinical characteristics, treatment patterns, type of surgery, MGMT methylation, and clinical outcomes.

RESULTS
Of 600 patient charts planned for review, 195 have been randomly selected and reviewed thus far. Of these, 165 (84.6%) had surgical resection and 30 (15.4%) had biopsy only. Eighty-eight (45.1%) patients were tested for MGMT status and 107 (54.9%) were not. Of those tested, 33 (37.5%) were methylated, and 45 (51.1%) unmethylated. Median ages in the overall (including tested and untested), methylated and unmethylated cohorts were 63.7, 58.8, and 66.7 years, respectively. Most common first-line (1L) treatment in overall, methylated, and unmethylated cohorts was radiation concurrent with temozolomide received by 86.2%, 93.9%, and 91.1%, respectively. Median duration of 1L treatment in the overall cohort was 15.1 weeks (95% confidence interval [CI]: 11.9, 21.6) and higher in the methylated vs. unmethylated cohort (25.9 [18.1, 34.6] vs. 15.1 [9.3, 23.4] weeks, p=0.0375). Unadjusted median overall survival and progression-free survival in the overall cohort were 11.4 [9.4, 14.0] months and 5.2 [3.9, 5.8] months, and higher in the methylated vs. unmethylated cohort (20.5 [14.9, not realized] vs. 12.2 [7.1, 17.0] months, p=0.0052, and 9.4 [5.6, 14.0] vs. 5.5 [3.3, 6.8], p=0.0092, respectively).

CONCLUSIONS
Fewer than half of GBM patients were tested for MGMT methylation in the US community. Clinical outcomes, while better among patients with methylated MGMT, remain poor and current treatment options are limited.
HOUT-16. A RETROSPECTIVE ANALYSIS OF SURVIVAL OUTCOMES BASED ON CONSOLIDATION REGIMENS IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Gelhard Savannah , Maxwell Amiee , Cohen Adam , Mendez Joe 
Published: November 2019

Abstract

BACKGROUND
Currently, Primary Central Nervous System Lymphoma (PCNSL) is treated with induction therapy consisting of polychemotherapy followed by consolidation therapy. Besides the incorporation of high-dose methotrexate as the backbone of induction therapy, there is no accepted standard induction or consolidation regimen for patients with PCNSL in the US. In this study, we compared three consolidation techniques by analyzing overall survival (OS) and progression free survival (PFS) in patients treated for PCNSL.

METHODS
Patients treated for newly diagnosed PCNSL at Huntsman Cancer Institute after July 1, 2012 with induction followed by consolidation therapy were retrospectively reviewed. Patients who completed one of the following regimens were included: rituximab/methotrexate/vincristine/procarbazine (R-MVP), rituximab/methotrexate/temozolomide (R-MT), or rituximab/methotrexate (R-M) for induction followed by consolidation with etoposide/cytarabine (EA), high-dose cytarabine (HIDAC), or autologous stem cell transplant (ASCT). Patients were excluded if there was evidence of systemic lymphoma on PET/CT or if the patient received radiation as consolidation therapy. Survival was calculated from the date of diagnosis and last date of known survival.

RESULTS
Twenty-three patients met eligibility criteria and received the following four treatment regimens: R-MT+EA (12), R-MT+ASCT (4), R-M+ASCT (1), and R-MVP+HIDAC (6). The median age of diagnosis was 61. Patients receiving ASCT (5) had a trend towards a more favorable OS (p=0.0675) compared to the other two consolidation therapies with no recurrence or death in those patients treated with ASCT. When comparing non-transplanted patients, R-MVP-HIDAC had a trend towards better OS and PFS compared to R-MT-EA.

CONCLUSION
This small retrospective review provides evidence that ASCT may be a superior treatment consolidation strategy in patients with PCNSL compared to EA and HIDAC, and that R-MT-EA may be less successful in practice than in published trials. These findings suggest that consolidation with ASCT should be strongly considered in all patients with PCSNL despite which induction therapy was received.
HOUT-20. TIME-DEPENDENT ANALYSIS OF SELECTIVE SEROTONIN REUPTAKE INHIBITOR TREATMENT ON OVERALL SURVIVAL OF PATIENTS WITH GLIOBLASTOMA
Authors: Otto-Meyer Sebastian , DeFaccio Rian , Dussold Corey , Ladomersky Erik , Lukas Rimas , Amidei Christina , Zhai Lijie , Lauing Kristen , Scholtens Denise , Wainwright Derek 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most common and aggressive form of primary brain tumor in adults. We recently investigated the hypothesis that treating GBM patients with psychosocial modifiers would be associated with improved overall survival (OS). Our study retrospectively analyzed 497 patients with GBM treated at Northwestern Medicine with or without selective serotonin reuptake inhibitors (SSRI) between the years 2000 and 2018. Information from the Northwestern Medicine Enterprise Data Warehouse was analyzed for baseline covariates including sex, age at diagnosis, type of surgery, and Charlson Comorbidity Index Score. Approximately one-third of analyzed patients were prescribed SSRIs, with highly variable treatment times. Several statistical methods were used to perform adjusted analyses including: (i) an extended Cox Proportional Hazards Model with SSRI as a time-dependent variable; (ii) a Cox Model using inverse probability weights; and (iii) a Cox Proportional Hazards model with landmark analyses. The hazard ratios (95% CIs) for each statistical model analyzing the association between SSRI treatment and OS were (i) 1.26 (0.97–1.63), (ii) 1.06 (0.8–1.4), and (iii) ranged from 1.01 (0.74–1.38) to 1.26 (0.75–2.09). Our analysis found no significant association between the time of SSRI treatment and GBM patient OS. Future work will study additional considerations for psychosocial modifier treatment and their potential effect(s) on GBM patient OS including: (i) confounders due to the extent of cancer treatment; (ii) comorbidities not associated with tumor burden; (iii) absolute leukocyte counts; and (iv) length of treatment time required for enhancing immune-mediated anti-GBM mechanisms.
HOUT-22. EVALUATING CLINICAL IMPACT UTILIZING THE RANO-PRO COLLABORATIVE’S STANDARDIZED PRIORITY CONSTRUCTS
Authors: Vera Elizabeth , Gilbert Mark , Aboud Orwa , Antony Ramya , Boris Lisa , Bryla Christine , Burton Eric , Cordova Christine , Crandon Sonja , Leggiero Nicole , Penas-Prado Marta , Reyes Jennifer , Siegel Christine , Theeler Brett , Wall Kathleen , Wu Jing , Armstrong Terri 
Published: November 2019

Abstract
Increasing recognition of the symptom burden and functional limitations among primary brain tumor (PBT) patients has led to proposing clinical outcomes assessments as an additional measure of a treatment’s effectiveness. The RANO-PRO Collaborative recommended core symptoms for evaluation in clinical care and research for malignant glioma are weakness, walking, seizures, communication, memory, and treatment-specific symptoms. We evaluated these symptoms using the MDASI-Brain Tumor (BT) in the PBT patient sample of the NCI-NOB Natural History Study, in relation to disease progression, by descriptive statistics, and independent- and paired-samples t-tests. The sample included 434 PBT patients (59% male, median age=50 (18–83), 82% white, 43% with a prior recurrence). In the 60% with a malignant glioma, weakness, walking, seizures, difficulty remembering, and fatigue were significantly worse in the group with progression at time of imaging compared to the group with stable disease (p< 0.05). In a subset of 114 patients with progression after study entry, reported severity in all symptoms (except seizures) significantly worsened from study entry to time of progression (-1.7< mean difference< -0.1, p< 0.02, 0.3< r< 0.5). Walking, weakness, difficulty remembering, and fatigue each had a difference greater than 1-point, the minimally important difference for MDASI-BT. No one core symptom accounted for the severity change; each was reported by 17%-35% of patients as their largest change in severity. Utilizing the symptom with the largest change increased the magnitude of the worsening and its effect size (mean difference=-2.9, r=0.5). The analysis was repeated in the larger PBT sample with similar statistical findings but with smaller mean differences. RANO-PRO Collaborative core symptoms were shown to worsen at time of progression on imaging, highlighting the importance of continual symptom assessment and validating this core symptom group. Further analysis will focus on degree of change with each core symptom and validation in other datasets.
HOUT-29. THE INFLUENCE OF PSYCHIATRIC ILLNESS ON OUTCOME AND CANCER CARE RECEIVED IN PATIENTS WITH GLIOMAS
Authors: Patel Palak , Li Terry , Chou Janice , Patel Amie , Crispino Sylvia , Utate Minerva , Kurz Sylvia 
Published: November 2019

Abstract

BACKGROUND
Data related to the prevalence of different psychiatric disorders and their impact on survival and compliance in patients with glioma is scarce and mostly anecdotal. We aimed to study the prevalence of psychiatric disorders in glioma patients and the possible influence on compliance with cancer care and outcome.

METHODS
We performed a retrospective, observational study and compared compliance with medical care and outcome in patients who had or did not have a psychiatric illness at time of diagnosis. Kaplan-Meier method was used to compare survival between groups.

RESULTS
We identified 22 subjects (M=13, F=9) with intracranial glioma with psychiatric diagnosis and 22 matched control subjects (M=13, F=9) without psychiatric illness. Psychiatric diagnoses included depression (12%), anxiety disorder (6%), Adjustment disorder & substance use problems (2% each), bipolar disorder (1%) and panic attacks (1%). Psychiatric diagnoses were predating tumor diagnosis in 9/22 (41%) subjects and occurred around tumor diagnosis in 11/22 (50%) patients. The time of diagnosis with psychiatric illness was unknown in 2/22 (9%) of cases. Tumor diagnoses were glioblastoma in 50%, anaplastic astrocytoma in 9%, anaplastic oligodendroglioma in 13%, oligodendroglioma in 4%, and astrocytoma in 9% of cases. MedianOS was not reached for cases with psychiatric illness (not reached due to censoring) but was 4.2 years (95% CI 1.1 – 7.4) in controls (p=0.263). Subjects with psychiatric illness had an increased risk (OR 7.5, 95% CI 0.81 -68.8) of poor compliance with cancer care (medication, clinic and MRI follow-up compliance) compared to controls (p=0.046).

CONCLUSION
A variety of psychiatric conditions were observed in patients with glioma and presence of psychiatric illness may influence compliance with treatment and follow-up. Studies with larger population and longer follow-up are warranted to clarify true association between psychiatric conditions and compliance and survival.