tbuckley/cabot-search huggingface dataset:
ATIM-03. TTFIELDS AND PULSED BEVACIZUMAB IN PATIENTS WITH BEVACIZUMAB-REFRACTORY RECURRENT GLIOBLASTOMA: A PHASE 2 STUDY
Authors: David Tran, Ashley Ghiaseddin, Jian Campian, Stephen Staal, Sonisha Warren, Anne Allen, Deborah Sampson, Valerie Greene, George Ansstas
Journal: Neuro-Oncology (2018)

Despite aggressive treatment with surgery, radiation therapy and chemotherapy, the median overall survival for recurrent glioblastoma (rGBM) averages 25 weeks. Our prior experience in 8 bevacizumab-refractory GBM patients initially treated with TTFields monotherapy and re-challenged with bevacizumab on progression suggest that successive cycles of on/off (or pulsed) bevacizumab dosing will produce peaks and troughs in the mitotic activities of glioma cells that render these cells more sensitive to the antimitotic activity of TTFields during peak growth rates and may lower disease burden and increase survival. This Phase 2, single arm, open label study [NCT02663271] investigates if TTFields combined with pulsed bevacizumab increases overall survival in bevacizumab-refractory GBM compared to historical controls treated with continuous bevacizumab alone or in combination with standard chemotherapy. Twenty-five adults male or female patients with bevacizumab-refractory rGBM (WHO grade IV) aged 22 years, KPS>60 will undergo 12 months of planned continuous TTFields (200 KHz) (60–75% compliance goal; patients<60% compliance at Month 2 withdrawn) followed by pulsed bevacizumab (10 mg/kg IV/ 2 weeks) on further progression (RANO), with option of extending treatment to 24 months in patients not progressed and/or have adequate performance status at the 12-month mark. Pulsed bevacizumab dosing is defined by at least one cycle on and at least one cycle off. A cycle is defined as 8 weeks in length. Primary endpoint is overall survival between the groups. Secondary endpoints include adverse events, KPS, QoL (Mini-Mental Status Exam) and response rate (RANO). Largest hazard ratio (HR)<1 (or smallest median survival time >3.3 months) that can be detected at 80%, 90%, or 95% power and a 1-tailed significance level of 0.05, by sample size (N=20 to 36, or 10 to 18 months of accrual at 2 patients per month) and shape parameter k=1.50, 2.50. To date 3 patients have been enrolled.
PTU-096 The uptake of pharmacy-based targeted screening for hepatitis c in an isolated network of people who inject drugs
Authors: R Buchanan, J Parkes, K Noble, L Grellier, R Youde, SI Khakoo
Journal: Gut (2017)

Introduction  Hepatitis C (HCV) is increasingly easy to treat but barriers to care remain including undiagnosed cases of infection in people who inject drugs (PWID)1. The objective of this study was to assess the uptake of pharmacy based dry blood spot (DBS) testing within a population of PWID living in a geographically isolated community on the Isle of Wight, UK (IOW).  Method  Twenty-two pharmacies on the IOW were enrolled to offer free dry-blood spot testing to those at risk of HCV. After 24 months the program was evaluated, PWID living on the IOW were recruited to a validated behavioural and social network survey via respondent driven sampling (RDS)2 – a cross-sectional sampling technique designed for use in hidden populations. Population estimates were calculated using RDSanalyst and network measures were calculated using UCInet.  Results  In 24 months, twenty community pharmacies conducted 186 tests, which included 68 individuals who disclosed a primary risk factor of injecting drug use. Recruitment to the survey took a further 3 months, passed through 12 waves and enrolled 69 eligible participants including 5 seeds. The mean age of the sample was 39 years, the majority injected heroin (86%) and had injected in the last 30 days (57%). Seventeen (25%) of the survey participants were positive for HCV RNA. Twenty-three (33%) of the survey sample had reported undergoing a DBS test in a community pharmacy giving an estimated ‘population proportion’ of 36% (95% confidence intervals 19%–55%). There was no significant association between pharmacy based testing and social network position (in-degree centrality) (p=0.5) but there was a significant association with drug support centre attendance (p=0.02) and resident area (p=0.02).  Conclusion  Community pharmacies have the potential to be an effective venue for serial HCV testing in PWID but efforts need to be made to reach those living in remote areas without access to a testing pharmacy and those not already engaged with drug support services.  References  . Public Health England. Hepatitis C in the UK. [Online] 2014. Available from: https://www.gov.uk/government/publications/hepatitis-c-in-the-uk [Accessed Sept 20th 2015].  . Heckathorn D. Respondent-driven sampling: A new approach to the study of hidden populations1997;44(2):174–199.  Disclosure of Interest  None Declared
Abstract 18596: Conjugated Linoleic Acid Targets β2 Integrin Expression to Suppress Monocyte Adhesion
Authors: Monica de Gaetano, Eugene Dempsey, Simone Marcone, Desmond J Fitzgerald, Orina Belton
Journal: Circulation (2012)

Recruitment of monocytes to the damaged endothelium characterizes the early stages of atherosclerosis. Conjugated linoleic acids (CLA) are a group of naturally occurring fatty acids which inhibit the progression and induce regression of pre-established atherosclerosis. We have previously shown that CLA inhibits human peripheral blood monocyte (HPBMC) migration. Here we demonstrate that CLA suppresses adhesion of monocytes to endothelial cells, via inhibition of β2 integrins. We further show that CLA suppresses the CXCR4 signalling pathway thus inhibiting crawling of monocytes towards CXCL12 chemokine. HPBMCs were treated with 10uM of CLA isomers (c9,t11-CLA and t10,c12-CLA), a CLA blend (80:20, c9t,11:t10,c12), control lipids and 5uM of PPARγ agonist (troglitazone) prior to adhesion to HAECs. c9,t11-CLA and CLA blend treatment inhibited monocyte adhesion to HAECs (63±3%, p&lt;0.01 and 68±3%, p&lt;0.01, respectively). Furthermore, c9,t11-CLA and CLA blend inhibited CD18, the β chain of β2 integrin, mRNA (48±14%, p&lt;0.05 and 35±3%, p&lt;0.001) and protein expression (44±13%, p&lt;0.05, and 35±3%, p&lt;0.001) via a PPARγ[[Unable to Display Character: &amp;#61472;]]dependent mechanism. Flow cytometry analysis showed that c9,t11-CLA and CLA blend decreased external surface expression of both β chain (10±4%, p&lt;0.05 and 20±5%, p&lt;0.01), and α subunits (CD11a, 13±6%, p&lt;0.05 and 30±5%, p&lt;0.01; CD11b, 8±3%, p&lt;0.05 and 27±7%, p&lt;0.01), suggesting that CLA’s effect on CD18 transcription results in dysfunctional αβ complex formation, altering expression of LFA-1 and Mac-1 integrins. Furthermore, c9,t11-CLA and CLA blend almost completely abolished (by 82% and 89%, p&lt;0.001) adhesion of monocytes to ICAM-1. Immunocytochemistry of adherent cells further confirmed the inhibition of cell spreading. Importantly, CLA suppresses monocyte response to chemoattraction, preventing crawling of cells through a reduction, of CXCR4 expression (c9,t11-CLA, 47±10%, p&lt;0.05; CLA blend, 33±5%, p&lt;0.01). Our findings suggest that CLA inhibits monocyte recruitment by suppressing their sensitivity to chemokines and by inhibiting their ability to firmly attach to ICAM-1.
Role of oncostatin M (OSM) in prostate cancer
Authors: David Chang, Cheryl L. Jorcyk
Journal: Cancer Research (2006)

3491  Oncostatin M (OSM) is a pleotropic cytokine belonging to the IL-6 family. OSM signals through the OSM receptor (OSMR), a heterodimer of OSMRβ and gp-130, and to a lesser extent, the LIFR, a heterodimer of LIFRβ and gp-130. In prostate cancer, the presence of OSMR is correlated with tumor progression and increasing Gleason score. Our in vitro studies involving human prostate cancer demonstrate that OSM may promote tumor progression by enhancing prostate cancer cell proliferation, expression of pro-angiogenic factors, cell detachment, and invasiveness. In DU-145 cells, OSM stimulates a 200% increase in proliferation and cell detachment and a 400% increase in invasiveness, as measured by the Matrigel invasion chamber assay. In addition, OSM induces expression of vascular endothelial growth factor (VEGF). Collectively, this data suggests that OSM may play a role in the progression of prostate cancer. The inhibition of OSM or blockade of OSM signaling, as a means of slowing tumor progression, is intriguing. Our findings may provide the rationale for experimental anti-OSM therapeutics that inhibit tumor metastasis and slow tumor progression.
EPID-22. RACIAL AND ETHNIC DIFFERENCES IN ADULT GLIOMA INCIDENCE AND SURVIVAL IN THE UNITED STATES
Authors: Quinn Ostrom, David Cote, Mustafa Ascha, Carol Kruchko, Jill Barnholtz-Sloan
Journal: Neuro-Oncology (2018)

Glioma is the most commonly occurring malignant brain tumor in the United States (US), and incidence and survival varies by age, sex, and race/ethnicity. The goal of this analysis was to estimate the racial and ethnic differences in glioma incidence and survival by histologic subtype. Data were obtained from the Central Brain Tumor Registry of the US (incidence data from ~99.9% of the US), and the Surveillance, Epidemiology and End Results program (survival data for ~28% of the US). Histology-specific age-adjusted incidence rates were generated by race, Hispanic ethnicity, sex, and age groups. Histology-specific relative survival rates were generated by race, Hispanic ethnicity, treatment type, insurance status, and age. Overall incidence of glioblastoma, non-glioblastoma astrocytoma, and oligodendroglial tumors were higher among White non-Hispanic (WNH) individuals than among any other group. Most tumors were more common in males than in females across all race/ethnic groups. The majority of tumors occurred in those aged 40+ years, with differences in incidence by race/ethnicity appearing in all three age groups. Survival after diagnosis was similar among non-WNH individuals, but was lower among WNH individuals for glioblastoma, irrespective of treatment. Survival after diagnosis with glioblastoma among those that receive chemo-radiation remains higher in non-WNH groups after adjustment for age and extent of resection. US. Incidence and survival patterns of most glioma histologies varied significantly by race/ethnicity, with WNHs having higher incidence and lower survival compared to individuals of other racial and ethnic groups. Further examination is necessary in order to determine the factors contributing to these differences.
CADD-28. MELATONIN: TARGETING THE CELL’S POWERHOUSE TO FIGHT GLIOBLASTOMA
Authors: Beatriz I Fernandez-Gil, Paula Schiappareli, Carla Vazquez-Ramos, Rachel Sarabia-Estrada, Germaine Escames, Alfredo Quiñones-Hinojosa
Journal: Neuro-Oncology (2018)

Mitochondria are the key organelles that control the metabolic state of tumor cells. In particular, mitochondria regulate the Warburg effect, which is one of the main drivers of tumoral behaviour including stemness and resistance to chemotherapy. In previous studies, melatonin has shown to have oncostatic properties when used alone or in combination with chemo-radiation. These anti-cancer properties are thought to be a consequence of melatonin's effects on the mitochondria. The present study examined the use of high concentrations of melatonin to boost the metabolic switch from anaerobic glycolysis to an oxidative phosphorylation (OXPHOS) state in glioblastoma (GBM) cells. Treatment of GBM cells with 3mM melatonin showed a significant decrease in viability (MTT p <0.001) and proliferation (Ki67/DAPI ratio <0.001, RQ PCNA <0.001) after 48 hours. In addition, a significant rise in the reactive oxygen species production (p<0.001) was found. This phenomenon could be explained by an increase in the OXPHOS, inferred from the decrease in the lactate production (p<0.005) and the expression of pyruvate dehydrogenase kinase. The expression of stemness and differentiation genes was also evaluated. We found a significant increase in neural and oligodendrocytes differentiation markers (p<0.005 and p<0.05 respectively) after 7 days of treatment. Finally, we found that melatonin treatment reduced GBM migration capacity (p<0.005) and reduced matrix metalloproteinases expression. In summary, this study reveals that melatonin can force a metabolic switch inducing cell differentiation, eventually leading to a decrease in the malignant properties of GBM cells in vitro. Our findings highlight melatonin as a relevant therapeutic approach to target GBM by modulating cell metabolism.
GENE-15. CELL AUTONOMOUS MECHANISMS OF SEX DIFFERENCES IN RESPONSE TO TUMOR SUPPRESSOR LOSS
Authors: Lauren Broestl, Jasmin Sponagel, Nicole Warrington, Joshua Rubin
Journal: Neuro-Oncology (2018)

Sex differences in incidence and prognosis are observed for nearly all human diseases, including brain tumors. Males are more likely to develop brain tumors – a phenomenon observed throughout the world and across all ages. Sex differences in brain tumor incidence suggest there may be intrinsic differences in how male and female cells respond to oncogenic stress. Cell autonomous sex differences can arise from one of two mechanisms: differences in sex chromosome complement or organizational effects of gonadal hormones. To investigate whether there are sex differences in the cellular response to tumor suppressor loss and whether sex chromosome genes or organizational effects of gonadal hormones are responsible, we utilized the four core genotypes (FCG) mouse model. In the FCG model, the testis-determining gene, Sry, is removed from the Y-chromosome and inserted onto an autosome. This results in four genotypes, XY/Sry+ (XY with testes), XY/Sry- (XY with ovaries), XX/Sry+ (XX with testes), and XX/Sry- (XX with ovaries), and allows for the separation of gonadal and chromosomal sex effects. Using astrocytes harvested from FCG pups, we introduced loss of function of the tumor suppressor p53, the most commonly mutated gene in cancer, and then assessed cell proliferation. Following loss of p53 function, astrocytes from mice with testes had greater rates of cell proliferation than those from mice with ovaries, regardless of chromosomal sex (p=0.028). These results suggest that organizational effects of gonadal hormones may underlie sex differences in brain tumor incidence. Since organizational effects are established through epigenetic marks, this identifies sex differences in the epigenetic landscape as an important mediator of sex differences in brain tumor incidence, and highlights the need for sex specific analyses in clinical trials of epigenetic therapeutics.
CMET-25. NEOPLASTIC MENINGITIS REGISTRY: USE OF MULTI-NATIONAL COLLABORATIVE EFFORTS TO UNCOVER TRENDS AND IMPROVE OUTCOMES IN LEPTOMENINGEAL DISEASE
Authors: Shwetha Srikanth, Leonard Kishel, Michael Glantz
Journal: Neuro-Oncology (2018)

Neoplastic meningitis (NM) is a devastating complication of both hematologic and solid tumors, with a dismal prognosis. NM can present with a variety of symptoms, prognostic features are still debated, and treatment options vary based on disease status and differences in institutional protocols. AIM: NeMeRe: a Multi-Institutional Retrospective and Prospective Registry of Neoplastic Meningitis in Adults is an electronic clinical data registry that captures information regarding cancer history, diagnoses, treatments, and survival rates from patients with NM to provide an inclusive picture of disease status and management. The registry was designed in REDCap by the Office of Patient Oriented-Research in the Penn State College of Medicine Department of Neurosurgery. Implemented in 2017, NeMeRe currently has nine international sites entering retrospective and prospective data, 480 patients currently enrolled, and new sites are continually applying for access. Data analysis reports are generated to explore the relationships between disease characteristics, comorbidities, and therapies, and enables researchers to investigate a large number of real-world diagnostic, prognostic, and therapeutic questions with greater agility and without the costs and inefficiencies of randomized controlled trials, which have proven challenging in this disease. By adding the features of data entry verification and propensity score matching, registry studies also provide results which are nearly as reliable as RCTs The dynamic nature of clinical registries also allows researchers to suggest edits to the database that reflect real time changes in practice. The authors will present several examples of such studies. NeMeRe is a database with the potential to answer critical questions about an increasingly common disease that has been very challenging to study using more traditional clinical trial paradigms.
PATH-41. PLASMA CELL-FREE DNA (cfDNA) CONCENTRATION IS INDEPENDENTLY ASSOCIATED WITH RADIOGRAPHIC TUMOR BURDEN IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM) PRIOR TO INITIAL SURGICAL RESECTION
Authors: Stephen Bagley, Jacob Till, Jazmine Mays, Seyed Nabavizadeh, Stephanie Yee, Scott Levy, Arati Desai, Erica Carpenter
Journal: Neuro-Oncology (2018)

Distinguishing between radiographic pseudoprogression and true tumor progression is challenging in patients with GBM. Recent data suggests that plasma cfDNA concentration may serve as a viable surrogate for tumor burden in other malignancies. We performed a pilot study to determine the feasibility of detecting cfDNA in patients with newly diagnosed GBM and explored its correlation with radiographic tumor burden and other relevant clinical variables. We collected blood in Streck cfDNA tubes from patients with radiographically suspected high-grade glioma prior to planned initial surgical resection. Plasma was isolated using a 3-step centrifugation protocol. cfDNA was extracted from using a QIAamp Circulating Nucleic Acid Kit. cfDNA concentration (ng DNA/mL) was determined by quantitative real-time PCR (qPCR) for the ALU repeat element. Tumor burden was defined as the sum of products of diameters (SPD) of target enhancing lesions plus the SPD of the T2 FLAIR signal abnormality on preoperative MRI. 22 preoperative patients were enrolled and diagnosed histopathologically with GBM. The median cfDNA concentration was 10.9 ng/mL (IQR 7.2–23.6, range 0.48–37.6). There was a significant correlation between radiographic tumor burden and cfDNA concentration (Spearmans rho = 0.46, p = 0.03). In a multiple linear regression model, cfDNA concentration remained significantly associated with radiographic tumor burden (beta coefficient 1.87, p=0.03) after adjusting for age, sex, tumor Ki-67 proliferation rate, weight, and glomerular filtration rate (GFR). GFR was also independently (negatively) associated with cfDNA concentration. CONCLUSIONS: In this small pilot study, we demonstrated that plasma cfDNA is easily detected and quantified in patients with newly diagnosed GBM prior to initial surgical resection. In addition, plasma cfDNA concentration was independently associated with radiographic tumor burden. A prospective, longitudinal study monitoring cfDNA dynamics during standard treatment for GBM, including gold standard tissue correlates for tumor progression vs. pseudoprogression, is ongoing at our institution.
Abstract 13920: Common Variant in Pitx2 Contributes to the Pathogenesis of Paroxysmal Atrial Fibrillation by Impairing Sinus Node Function and Progression of Atrial Remodeling
Authors: Sunsuke Tomomori, Yukiko Nakano, Takehito Tokuyama, Akinori Sairaku, Hiroya Matsumura, Michitaka Amioka, Naoya Hironobe, Yasuki Kihara
Journal: Circulation (2016)

Introduction: Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with atrial fibrillation (AF). The most notably PITX2 SNPs have been known to show the strong association with AF, but how these SNPs affect clinical phenotype of AF has not been clarified. Hypothesis: We assessed the hypothesis that PITX2 SNPs influence the cardiac structures and electrophysiological properties, and increase the susceptibility to AF. Methods: To investigate the association between the PITX2 SNP and paroxysmal atrial fibrillation (PAF), we genotyped PITX2 SNP (rs6817105) in 344 Japanese PAF patients hospitalized in Hiroshima University hospital and 1,507 healthy controls and compared the allele frequencies of the PITX2 SNP between the PAF patients and controls. The PITX2 SNP was significantly associated with PAF (minor allele (C) frequency: PAF 64.7% vs control 47.3%, P =3.7х10 − 16 , odds ratio (OR)=2.0). We investigated the relationships between the PITX2 C risk allele and clinical characteristics, ECG parameters, parameters of cardiac ultrasound, and electrophysiological study. Results: There were significant linear correlations between the PITX2 genotypes(CC, CT, and TT) and the max sinus node recovery time(SNRT) , corrected sinus node recovery time(CSNRT) and left atrial diameter (LAD) (max SNRT, CC: 1328ms, CT: 1235ms , TT: 1225ms , P =1.5х10 − 2 , CSNRT, CC: 482ms, CT: 418ms, TT: 409ms ,P =1.3х10 − 2 , LAD; CC:37.2±5.6mm, CT:34.4±5.3mm, TT:34.1±5mm, P=1.3х10 − 2 , respectively). Conclusions: To the best of our knowledge, this was the first report showing that PITX2 risk allele was related to the sinus node dysfunction and progression of atrial remodeling in humans. The result was meaningful for considering the mechanism of why PITX2 contributes to the pathogenesis of AF.
EGFR Cooperates with EGFRvIII to Recruit Macrophages in Glioblastoma
Authors: Zhenyi An, Christiane B. Knobbe-Thomsen, Xiaohua Wan, Qi Wen Fan, Guido Reifenberger, William A. Weiss
Journal: Cancer Research (2018)

: Amplification of the EGFR gene and its truncation mutant EGFRvIII are hallmarks of glioblastoma. Although coexpression of EGFR and EGFRvIII confers a growth advantage, how EGFR and EGFRvIII influence the tumor microenvironment remains incompletely understood. Here, we show that EGFR and EGFRvIII cooperate to induce macrophage infiltration via upregulation of the chemokine CCL2. EGFRvIII was significantly enriched in glioblastoma patient samples with high CCL2, and knockout of CCL2 in tumors coexpressing EGFR and EGFRvIII led to decreased infiltration of macrophages. KRAS was a critical signaling intermediate for EGFR- and EGFRvIII-induced expression of CCL2. Our results illustrate how EGFR and EGFRvIII direct the microenvironment in glioblastoma. SIGNIFICANCE: Full-length EGFR and truncated EGFRvIII work through KRAS to upregulate the chemokine CCL2 and drive macrophage infiltration in glioblastoma.
CBMT-41. GLIOBLASTOMA CLONES DERIVED FROM TUMOR CORE AND EDGE DISPLAY SPATIAL METABOLIC HETEROGENEITY
Authors: Daisuke Yamashita, Soujun Zhang, Hai Yu, Hirokazu Sadahiro, Shinobu Yamaguchi, Svetlana Komarova, Soniya Bastola, Sadashib Ghosh, Anutosh Ganguly, Burt Nabors, James Markert, Zhibo Yang, Nicola Zamboni, Ichiro Nakano
Journal: Neuro-Oncology (2018)

The highly heterogeneous nature of glioblastoma (GBM) is a hallmark of limited response to the current therapies and subsequent unfavorable clinical prognosis. Although intratumoral cellular heterogeneity has been recognized in various cancers including GBM, the spatial distributions of tumor-associated cell types and their mechanisms of metabolic pathways that are essential for their heterogeneity remain poorly understood. Here, we utilized the MRI-guided localized biopsy of GBM tumor tissues during surgery, thereby establishing multiple patient-derived GBM clones from both the tumor core and edge tissues in a clonal density, termed core-GBM clones and edge-GBM clones. Using these GBM clones as well as the original tumor tissues, we investigated the underlying molecular mechanisms that drive spatial metabolic heterogeneity in GBM. Comprehensive single cell-metabolome analysis revealed a clear difference between the core and edge clones, as well as between the core and edge tissues. In particular, we noticed metabolic heterogeneity in the nicotinamide adenine dinucleotide (NAD) pathway between the core-GBM clones/tissues and the edge-GBM clones/tissues. Manipulation of the NAD pathway showed distinct phenotypic changes among these clones. These findings suggest that metabolic heterogeneity plays an essential role in therapeutic resistance of glioblastoma.