bluuebunny/crossref_metadata_2025_split huggingface dataset:
DRES-13. DUAL KINASE INHIBITION TO COMBAT EGFR-INHIBITOR RESISTANCE IN GLIOBLASTOMA
Authors: Smithberger Erin , Shelton Abigail , Butler Madison , Flores Alex , Bash Ryan , Angus Steven , East Michael , Sciaky Noah , Dhruv Harshil , Johnson Gary , Berens Michael , Furnari Frank , Ryan Miller C 
Published: November 2019

Abstract
Glioblastoma (GBM) is an aggressive primary brain tumor with a poor survival rate. One of the most common molecular alterations seen in GBM is amplification and/or mutation of the Epidermal Growth Factor Receptor (EGFR), which has made it an attractive therapeutic target. However, several EGFR tyrosine kinase inhibitors have been tested clinically in GBM with minimal success. One reason for this lack of efficacy could be due to acute, adaptive resistance via alternative pathway activation. To investigate this mechanism of tumor resistance, we used RNA-seq and multiplex inhibitor bead/mass spectrometry (MIB-MS) to analyze the transcriptomes and kinomes of genetically engineered murine astrocytes with common GBM genotypes. We have previously shown that 38% of the expressed kinome varied among a panel of diverse nGEM astrocytes harboring Cdkn2a deletion (C) plus Pten deletion (CP), wild-type human EGFR (CE) or EGFRvIII (CEv3) overexpression or both EGFRvIII overexpression and Pten deletion (CEv3P). Although CE have a similar transcriptional profile to C cells at baseline, when treated with the EGFR inhibitor afatinib, CE respond more similarly to CEv3 cells. When cells containing endogenous murine EGFR (C and CP) are treated with afatinib, fewer than 0.5% of kinases showed differential expression. In cells with EGFR overexpression alone, more than 6% of kinases were differentially expressed upon afatinib treatment, including Ntrk3, Fgfr2 and 3, Lyn, Bmx, Epha2 and 5, Fn3k, a kinase involved in fructosamine processing, and Nrbp2, a kinase involved in regulation of apoptosis. This effect was blunted in cells lacking Pten in addition to having EGFRvIII (CEv3P), resulting in less than 2% of kinases being differentially expressed. The only kinase upregulated in all three EGFR-overexpressing cell types was Coq8a, which is involved in electron transport and response to DNA damage. Given this overlap in response, Coq8a could be a potential dual treatment target for GBM.
EPID-04. ASSOCIATION BETWEEN URBANICITY AND SURGICAL TREATMENT AMONG PATIENTS WITH PRIMARY GLIOBLASTOMA IN THE UNITED STATES
Authors: Cioffi Gino , Cote David , Patil Nirav , Wright James , Wright Christina , Sloan Andrew , Ostrom Quinn , Kruchko Carol , Barnholtz-Sloan Jill 
Published: November 2019

Abstract

BACKGROUND
Glioblastoma (GBM) is the most common malignant brain and other central nervous system (CNS) tumor and also the most fatal. Extent of surgical resection is one of the most significant factors associated with improved survival. Historically, patients living in non-metropolitan counties have limited access to optimal treatment and healthcare services. The aim of this study is to determine if there is an association between urbanicity and surgical treatment patterns among patients with primary GBM.

METHODS
Cases with histologically-confirmed, primary GBM diagnosed between 2005 and 2015 were obtained from the Central Brain Tumor Registry of the United States (CBTRUS). Site specific surgery codes for brain and CNS defined surgery were grouped as follows: gross total resection (GTR; 30,55), subtotal resection (STR; 21, 40), biopsy only (20) and none (00). Urbanicity was defined using the 2013 USDA Rural Urban Continuum (RUC) Code Definitions (metropolitan: RUC 1–3, non-metropolitan: RUC 4–9). Multivariable logistic regression models were constructed to assess the association between urbanicity and receipt of surgical treatment (GTR/STR vs. biopsy only/none) and extent of resection (GTR vs. STR), adjusted for age at diagnosis, sex, race, U.S. regional division, and primary site of tumor.

RESULTS
Residence in a metropolitan county was significantly associated with receiving surgical treatment among patients with GBM, with patients residing in non-metropolitan counties 7% less likely to receive surgical treatment (adjusted OR=0.93, 95% CI: 0.89–0.96, P value: < .0001). Among those who received surgical treatment, metropolitan status was not significantly associated with receiving GTR vs. STR (adjusted OR=0.99, 95% CI: 0.94–1.04, P value: 0.620).

CONCLUSIONS
Among U.S. patients with GBM, urbanicity is associated with receipt of surgical treatment, but among patients who receive surgery, was not associated with extent of resection. These results point to potential differences in access to healthcare for those in non-metropolitan areas that warrant further exploration.
EPID-05. PREDIAGNOSTIC SYMPTOMS AND SIGNS OF ADULT GLIOMA: THE PATIENTS’ VIEW
Authors: Peeters Marthe , Dirven Linda , Koekkoek Johan , Gortmaker Ellen , Fritz Lara , Vos Maaike , Taphoorn Martin 
Published: November 2019

Abstract

BACKGROUND
Little is known about the symptoms/signs glioma patients experience in the year before diagnosis, either or not resulting in health care usage. The objective of this study was to determine the incidence of symptoms/signs glioma patients experienced in the year prior to diagnosis, as well as visits to a general practitioner (GP) related to these issues.

METHODS
Glioma patients were asked to complete a 30-item study-specific questionnaire, if possible with input of a proxy, focusing on symptoms and signs they experienced in the 12 months before diagnosis. For each indicated symptom/sign, patients were asked whether they consulted the GP for this issue.

RESULTS
Between July 2016 and April 2019, 59 patients completed the questionnaires, 54 (93%) with input of a proxy. Forty (68%) patients were men, with a median age of 60 years and the median time since diagnosis was 4 months (range 1–12). The median number of symptoms/signs experienced in the year before diagnosis was 9 (range 2–19) in low-grade and 5 (range 0–24) in high-grade glioma (p=0.230). The five most frequently mentioned problems were fatigue (34, 58%), mental tiredness (30, 51%), sleeping disorder (24, 41%), headache (23, 39%) and stress (20, 34%), with no differences between low- and high grade glioma. Twenty-six (44%) patients had visited the GP with at least one issue. We found that patients who did consult their GP reported significantly more often muscle weakness (11 vs 3, p =0.003) than patients who did not, which remained significant after correction for multiple testing, which was not the case for paralysis in hand/leg (10 vs 4), focussing (11 vs 6) or a change in awareness (9 vs 4).

CONCLUSIONS
Glioma patients experience a range of problems in the year prior to diagnosis, but patients who consult the GP report significantly more often neurological problems.
EPID-06. IMMUNE-RELATED PLASMA BIOMARKERS IN GLIOBLASTOMA
Authors: Bjørnbak Holst Camilla , Jarle Christensen Ib , Skjoeth-Rasmussen Jane , Skovgaard Poulsen Hans , Hamerlik Petra , Sidenius Johansen Julia 
Published: November 2019

Abstract

BACKGROUND
Glioblastoma (GBM) is an aggressive and malignant primary brain tumor with limited treatment options and a dismal prognosis. Immunotherapy is advancing in other types of cancer but has not yet proven effective in glioblastoma. Prognostic and predictive biomarkers and new treatment targets are urgently needed.

MATERIAL AND METHODS
158 patients with glioma WHO grade II-IV were included in the study. Plasma was analyzed for interleukin (IL)-6, YKL-40 (Gene: CHI3L1) and 91 other immune-related protein biomarkers by ELISA or/and Olink technology. CHI3L1 rs4950928 genotyping was analyzed on DNA extracted from whole-blood.

RESULTS
Fourteen of 92 immune-related biomarkers in plasma detected with the Olink immuno-oncology array were related with tumor grade or/and type (p< 0.05) (corrected for age), whereas plasma IL-6 and YKL-40 did not change with tumor grade. In univariate analysis of plasma from 94 patients with newly diagnosed GBM higher baseline IL-6 was associated with short OS (HR=1.19 (per 2-fold change in IL-6), p=0.04), YKL-40 showed a similar trend (HR=1.20 (per 2-fold change in YKL-40), p=0.056) and high/low baseline levels of additional 15 immune-related biomarkers (e.g. CD244, Granzyme B, ICOS ligand, IL-8 and Pleiotrophin) were associated with short OS (p< 0.05). Genetic variation in YKL-40 was associated with plasma YKL-40 levels (+/+ vs. -/+ vs. -/-, p=0.0004) but not with OS in patients with GBM (HR= 0.78 (+/+ vs. -/+), p=0.32).

CONCLUSION
High levels of several immune-related biomarkers in plasma including IL-6, IL-8, CD244, Granzyme B, ICOS ligand, and Pleiotrophin from patients with glioblastoma were related or inversely related to OS.
EPID-11. OCCURRENCE OF SYSTEMIC CANCER IN PATIENTS WITH GLIOBLASTOMA: POPULATION CHARACTERIZATION AND COMPLICATIONS
Authors: Horta Erika , Walbert Tobias , Snyder James 
Published: November 2019

Abstract
It is unclear how the diagnosis of a second cancer influences the treatment and complications of patients with glioblastoma (GBM). A chart review of adults with primary or secondary GBM and another systemic cancer seen in the last five years was performed. Demographic data, thromboembolic events, cytopenia and deviations from the standardized GBM treatment protocol (EBRT with 60 Gy plus concurrent temozolomide followed by adjuvant temozolomide) were analyzed. Exclusion criteria was the diagnosis of genetic syndromes that predispose to tumorigenesis. A total of 56 GBM patients with 61 systemic cancers were identified. The most common systemic cancers were breast and prostate each representing 27 %. Men were 55% of patients (p=0.3) but older (69+11 years, p=0.003) than when compared to CBTRUS data. Systemic cancer was diagnosed before GBM in 82% of the cases. Age at the diagnosis of systemic cancer was 64 +11 years. Patients with systemic cancer diagnosed prior to GBM, had shorter survival (1.15+1.08 years versus 4.4+ 3.4 years, p < 0.001), but survival was not shorter than expected when compared to historical survival of GBM. Thromboembolism was seen in 27% of patients, only once it was seen before the diagnosis of GBM. Although all patients with hematological malignancies had low platelets, thrombocytopenia was not associated to prior chemotherapy. Deviation of GBM treatment was seen in 15% of the cases, a delay in the systemic cancer once. This is the largest documented series of patients with GBM and systemic cancer. We conclude that although this population is older than expected, thromboembolism rates and survival are similar to the literature for patients with GBM. In the light of all those considerations, patients with GBM and the diagnosis of a systemic cancer should be treated according to guideline.
EPID-12. IMPACT OF RACE AND GEOGRAPHIC LOCATION ON IDH MUTATIONS AND GLIOBLASTOMA SURVIVAL
Authors: McCormack Ryan , Zhu Ping , Takayasu Takeshi , Hines Gabriella , Zeineddine Hussein , Tandon Nitin , Moreno Jimenez Sergio , Gonzalez Alberto , Ballester Leomar Y , Esquenazi Yoshua 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor of the central nervous system with a 5-year survival of < 5%. Population studies have demonstrated that among all ethnicities, non-Hispanic whites (NHW) have the worst prognosis; however, differences within the oncogenome based on ethnicity have not been assessed. We utilized the Texas Cancer Registry (TCR) for population-based analysis including 4,134 GBM patients between the years of 1995 to 2013 with 75.6% NHW and 16.5% Hispanics. In accordance with previously published findings, within the TCR we detected a 12% relative survival improvement in Hispanics compared to NHW when controlling for known survival mediators including age, resection, chemotherapy, and radiation. In order to assess for oncogenic differences, we utilized a prospectively maintained database of 257 GBM patients within the city of Houston, TX (14.9% Hispanic) and 48 GBM patients from the National Institute of Neurology and Neurosurgery in Mexico City, Mexico (100% Hispanic) to assess for oncogenomic differences attributable to ethnicity. Next generation sequencing of GBM within the Houston cohort, for 315 tumor-related genes, identified no significant differences in genomic alterations owing to ethnicity. However, when we compared the multigenerational, mixed-heritage Hispanics present in the Houston cohort to the Mexico cohort (Sanger sequencing), a significant difference was found in the frequency of IDH1and IDH2mutations (29.8 % Mexico Hispanics, 7.9% Houston Hispanics; p=0.014). In particular, the rate of IDH2mutations is significantly enriched in the Mexico population (19%) when compared to the Houston population (0%) or to previously published rates of IDH2 mutations in GBM (~3%). Ultimately, these findings highlight the need for multiethnic trial enrollment as well as the need for improved testing of IDH2 mutations in patients of distinct ethnicities. Future studies are needed to identify the mechanisms promoting the increased frequency of IDH2 mutations in Mexican Hispanics.
EPID-15. GUIDELINES FOR THE OPTIMAL USE OF SOCIAL MEDIA FOR NEURO-ONCOLOGISTS
Authors: Hamidi Nima , Mansouri Alireza 
Published: November 2019

Abstract

BACKGROUND
Approximately 80,000 new Americans are diagnosed with a brain tumor annually. Social media (SM) has emerged as a powerful tool for patient empowerment. Its effective utilization by healthcare professionals is vital for better connection to patients and dissemination of evidence-based information. OBJECTIVES: To develop guidelines for optimal utilization of SM by neuro-oncologists, through a review of user engagement with content posted on SM relating to brain tumors.

METHODS
Facebook (FB) and Twitter (TW) were searched using the term Brain Tumor. Page/account information such as user type, media (image/video) utilization in posts, and audience size (likes / followers) were recorded. Average activity and account annual growth (AAG) were calculated. Top qualitative themes were assigned. Correlations were assessed with Pearson’s test.

RESULTS
FB was predominantly used by organizations (64% of accounts) and provided a larger audience (67 pages,581 likes) than TW (25 accounts, 67,295 followers), which had similar proportion of personal (44%) and organizational accounts (52%). Charity & Fundraising (67%) was the top FB theme. Education & Research (72%) was the top TW theme. In FB, the page’s annual growth (PAG) was not related to rate of monthly posting or the length of activity on FB, but presence on other concurrent platforms (Rho: 0.59) was influential for PAG and audience size (p < 0.05). In TW, quantity of monthly tweets (Rho: 0.66) and media utilization (Rho: 0.78) significantly correlated with audience size and AAG (p-values < 0.05).

CONCLUSION
A multi-platform SM presence and use of relatable images/videos have a strong impact on both FB and TW engagement. FB is a stronger platform for organizations valuable for charity and fundraising. Multi-platform presence is more important than frequent posts on FB. TW is equally used by organizations and individuals, serving as an excellent medium for dissemination of research and educational material.
EPID-18. NATIONAL TRENDS IN THE USE OF TARGETED AND IMMUNOTHERAPY IN THE UP FRONT MANAGEMENT OF GLIOBLASTOMA
Authors: Wegner Rodney , White Richard , Abel Stephen , Yu Alexander , Xu Linda , Karlovits Stephen , Ranjan Tulika 
Published: November 2019

Abstract

BACKGROUND
Current standard of care for GBM involves an aggressive multimodality approach including surgical resection followed by adjuvant chemoradiation. Despite this approach, overall survival remains poor and treatment approaches continue to evolve. Given the successes of immunotherapy in other disease sites, implementation in GBM management may improve outcomes.

METHODS
We conducted this retrospective NCDB study to analyze treatment trends and outcomes from 2004–2015 regarding immunotherapy for GBM. We excluded patients treated without surgery, extracranial radiation, or chemotherapy as well as those lost to follow up.

RESULTS
Of the 39,317 eligible patients in this study, 511 were treated with immunotherapy and 38,806 lack thereof. Median overall survival for all patients was 15 months with a 2 and 5 year survival rate of 29% and 8%, respectively. Factors influencing delivery of immunotherapy included younger age, higher income, facility location in a metropolitan location, greater distance to the treatment facility, treatment at an academic facility, treatment outside of the years 2007 to 2009, and Caucasian race. On propensity matched analysis, survival was 18 months and 17 months with and without immunotherapy, respectively (p=0.15). Higher comorbidity, lower income, and male gender predicted for worse survival.

CONCLUSIONS
The results of this analysis show an initial decrease and then increase in the use of immunotherapy in the management of GBM. Propensity-matched analyses did not show an overall survival benefit.
EPID-32. IS THERE ANY EVIDENCE OF REPORTING AND CITATION BIAS AMONG COMPLETED PHASE III INTERVENTIONAL BRAIN TUMOR TRIALS?
Authors: Rayi Appaji , Alnahhas Iyad , Smith Rachel , Giglio Pierre , Puduvalli Vinay 
Published: November 2019

Abstract

OBJECTIVE
Reporting and citation bias based on positive versus negative outcome among completed phase III interventional brain tumor trials (IBTTs) have not been previously reported. Thus, we aimed to assess the evidence.

METHODS
Clinicaltrials.gov was used to obtain all phase III IBTTs completed prior to December 31st 2016. Trials closed due to poor accrual or non-phase III were excluded. Data about the funding source, type of intervention, conducted at U.S or Non-U.S locations, patients enrolled, primary completion date, time to dissemination of results in months (either reported on clinicaltrials.gov or published in a journal), citations per year (from web of science) and outcome (positive or neutral/negative) were abstracted. Median time to dissemination was estimated using Kaplan-Meier estimates and a log rank test for statistical significance. The number of citations per year for positive and negative/neutral studies was compared using a t-test.

RESULTS
65 studies were analyzed. The median time from primary completion to dissemination of results for trials with a positive outcome was 20 months (n = 20; 95% CI: 12–31) compared to 30 months for trials with a negative outcome (n=35; 95 % CI: 22 – 37) (p = 0.095). The average number of citations per year for trials with a positive outcome is 62.4 (n = 21; range 1.1 – 614.8) compared to 25.0 for trials with a negative outcome (n=35; range 0.14 - 158.8) (p = 0.213). There was no significant difference in time to dissemination based on the funding source, type of intervention or the location where the trial was conducted.

CONCLUSION
Positive phase III IBTTs results are disseminated earlier and are cited more frequently compared to negative trials. However, there is no statistically significant evidence of reporting or citation bias.
EXTH-01. A SYNGENIC MOUSE MODEL TO STUDY THE EFFICACY OF KETOGENIC DIET IN HIGH GRADE GLIOMAS
Authors: Salmaggi Andrea , Vasco Chiara , Rizzo Ambra , Padelli Francesco , Zucca Ileana , Pellegatta Serena , Massa Giorgio , Fariselli Laura , Bruzzone Mariagrazia , Ciusani Emilio 
Published: November 2019

Abstract
Glioblastoma multiforme is the most malignant subtype of brain tumor. Despite multimodal treatment (surgical resection and chemo/radiotherapy) the prognosis remains unsatisfactory. Based on the Warburg hypothesis, ketogenic diet (KD) has been suggested in the treatment of GBM. The syngenic, orthotopic GL261 mouse glioma model was used to evaluate the effects of KD on 7T magnetic resonance imaging/spectroscopy and metabolic response of the tumor to diet. Mice were injected with 10^5 GL261 cells into the caudate nucleus. Following implantation, animals were fed standard chow for five days then were randomly assigned to standard diet or ketogenic diet. 18 days after diet start, mice fed at KD displayed significantly higher plasmatic levels of ketone bodies. Mice fed with KD survived longer than those fed with standard diet (p< 0.05). Decreased concentrations of gamma-aminobutyric acid, N Acetyl Aspartate and N-acetylaspartylglutamate were found in tumor tissue after 9 days from the beginning of the KD diet while a huge increase in beta-hydroxybutyrate (bHB) was detected in tumor tissue as compared to normal brain. The addition of bHB at various concentrations to low-glucose culture medium did not significantly improve GL261 in vitro growth suggesting that this cell line has a limited ability to use bHB as a carbon source. The accumulation of bHB in the tumor tissue in KD fed mice, may suggest either elevated uptake of/release of bHB by tumor cells or inability of tumor cells in this context to use it in mitochondrial metabolism; the latter hypothesis is supported by the observation that GL261 cells did not display an increase in in vitro proliferation when exposed to bHB. The far less evident peak of bHB at MRI spectroscopy in the healthy brain tissue of KD fed mice, on the other hand suggests that normal brain is able to use bHB as energy source.
EXTH-17. TREATMENT OF MALIGNANT GLIOMAS WITH DRUG-LOADED MICROBUBBLES: CONCEPTION OF A PROMISING FUTURE THERAPEUTIC STRATEGY
Authors: Schulz Ellina , Mawamba Viviane , Sturm Volker , Ernestus Ralf-Ingo , Schatzschneider Ulrich , Löhr Mario , Hagemann Carsten 
Published: November 2019

Abstract
The major obstacles for an effective chemotherapy of glioblastomas (GBM) are the blood-brain barrier (BBB) and serious systemic side effects of the cytotoxic drugs. A new promising strategy could be the delivery of the chemotherapeutics across the BBB to the tumor site encapsulated in microbubbles. The microbubbles will shield the drug from detrimental systemic effects. Low intensity focused ultrasound (LIFU) allows opening of the BBB and a targeted release of the drugs within the brain tumor. We synthesized microbubbles ≤ 2 µm in diameter by thin-film hydration of lipids, which could be disintegrated applying LIFU. The toxicity was tested on GBM cell lines and neither the intact bubbles nor the lipids alone showed any toxic effects. Additionally, these cells were treated with 6 platinum(II) and palladium(II) complexes conjugated to lipophilic side chains of different length (C1, C8, C10) for 72 h. Cell viability was evaluated with MTT assay and in real-time utilizing the impedance-based xCELLigence DP-System. EC50 values were calculated from both assays and all six drugs were highly effective. Especially the palladium(II) compound with the C1-chain had a very low EC50 value (< 10 µM), while the longer chains and the platinum(II) compounds were less effective (EC50 10 - 30 µM). The real time proliferation assay of the drugs revealed an early and concentration-dependent onset of the cytotoxic effect, about 30 h after application. The lipophilic side chains of the drugs should allow encapsulating them into the microbubbles to develop an effective drug-delivery system for the treatment of GBM.