tbuckley/cabot-search huggingface dataset:
Abstract 14804: Time-Course and Influencing Factors of Ventricular Tachy-Arrhythmias After Initiation of Steroid Therapy in Patients With Cardiac Sarcoidosis
Authors: Masato Segawa, Koji Fukuda, Makoto Nakano, Masateru Kondo, Michinori Hirano, Hiroaki Shimokawa
Journal: Circulation (2015)

Introduction: It is widely known that ventricular tachy-arrhythmias (VTs) are often observed in patients with cardiac sarcoidosis (CS) as one of the presentations of poor prognosis. However, the time-course and influencing factors of VTs after the introduction of corticosteroid therapy in CS patients remain to be elucidated. Methods and Results: We examined the influence of steroid therapy on VTs in 68 consecutive CS patients in Tohoku University Hospital from October 1998 until September 2014 (57±11 years-old, M/F 18/50). CS was diagnosed based on the original guidelines for diagnosis of CS from the Japanese Ministry of Health and Welfare. Corticosteroid therapy was performed in all CS patients. VTs were defined as sustained ventricular tachycardia/fibrillation or appropriate ICD therapy events. During a mean follow-up of 5.5 years, 20 out of 68 patients (29%) experienced VTs after the initiation of corticosteroid therapy, and 14 (70%) of them had VTs in the first 12 months (Figure A). Multivariable analysis showed that the positive gallium scintigraphy was an independent risk factor for VTs (odds ratio, 17.4; 95% CI, 1.03-294, P=0.047). Survival free from VTs events was significantly lower in the Ga-positive group than in the Ga-negative group (P&lt;0.001), where most of the events were developed in the early phase in the Ga-positive group (Figure B). Furthermore, electrical storm (ES) of VTs was noted in 10 patients (14.7%), and most of them (8 out of the 10 patients) had ES in the first 12 months, whereas the recurrence of ES was relatively low (Figure C). Conclusions: VTs or ES in CS patients was frequently noted in the first 12 months after initiation of corticosteroid therapy, possibly representing inflammatory conditions, for which Ga scintigraphy is useful diagnostic strategy and Ga-positive is an independent prognostic factor in CS.
GENE-01. THE GENOMIC LANDSCAPE OF TRIPLE-NEGATIVE GLIOBLASTOMA
Authors: Bill H Diplas, Matthew S Waitkus, Xujun He, Jackie Brosnan-Cashman, Heng Liu, Lee Chen, Zhaohui Wang, Casey Moure, Patrick Killela, Eric S Lipp, Fausto J Rodriguez, Yuchen Jiao, Roger McClendon, Darell D Bigner, Alan Meeker, Hai Yan
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common and deadly primary malignant brain tumor in adults. Mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH1/2) can classify ~80% of GBMs into molecular subgroups with distinct clinical courses. These molecular subgroups utilize distinct genetic mechanisms of telomere maintenance, either TERTp mutation leading to telomerase activation or ATRX-mutation leading to an alternative lengthening of telomeres phenotype (ALT). However, approximately 20% of GBMs lack alterations in TERTp and IDH1/2. These tumors, designated TERTpWT-IDHWT or triple-negative glioblastomas (as they also lack 1p19q co-deletion) do not have well-established genetic biomarkers or defined mechanisms of telomere maintenance. Here we performed whole-exome, whole-genome, and RNA-sequencing on a cohort of triple-negative GBMs to define their genetic landscape. We discovered recurrent inactivating mutations in SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) in 21% (8/39) of triple-negative GBMs. Using telomere maintenance characterization assays, we show that SMARCAL1-mutant cases exhibited the ALT phenotype. Using CRISPR/Cas9 gene editing in GBM cell lines, we found that inducing loss of SMARCAL1 generates features of ALT. Rescue of expression of SMARCAL1 in SMARCAL1-null cell lines markedly suppressed ALT features and was dependent on the enzyme helicase activity. Furthermore, using break-apart FISH and whole genome sequencing, we identified recurrent rearrangements upstream of TERT in ~50% of triple-negative GBMs. These TERT-rearranged tumors exhibited elevated levels of TERT mRNA expression. This represents a novel mechanism of telomerase activation in GBMs lacking the well-known TERT promoter hotspot mutations. Finally, we identify recurrent BRAF V600E mutations in younger patients with GBM. Collectively, our findings define novel molecular subgroups of glioblastoma, including a telomerase-positive subgroup driven by TERT-structural rearrangements (IDHWT-TERTSV, ~50%), and an ALT-positive subgroup (IDHWT-ALT, ~40%) with mutations in ATRX or SMARCAL1. We also establish SMARCAL1 inactivating mutations as a novel genetic mechanism of ALT in cancer.
INNV-35. ROUTINE SEQUENCING OF BRAIN TUMORS UNCOVERS HIGH RATES OF ACTIONABLE OPPORTUNITIES: THE UNC EXPERIENCE
Authors: Simon Khagi, E Claire Dees, Emily Bell, Kathryn Pietrosimone, Amy Garrett
Journal: Neuro-Oncology (2018)

Since November 2017, the University of North Carolina (UNC) Brain Tumor Program has performed next generation sequencing (NGS) on newly diagnosed brain tumors through the Strata Trial, which uses the StrataNGS assay to evaluate genomic variants in 94 genes. Brain tumors were analyzed from 77 patients revealing 137 total molecular alterations. We defined actionable alterations as: (1) revealing potential enrollment into biomarker-driven clinical trials (regardless of histology); (2) allowing for off-label use of targeted therapy; (3) identifying occult and non-canonical alterations that lead to changes in prognosis and management. At UNC we’ve identified 26 brain tumors with actionable alterations (34%), and 18 brain tumors (23%) eligible for a nationally-available biomarker-driven trial. These results have provided useful data to inform feasibility of biomarker-driven clinical trials using targeted therapies to treat brain tumor patients seen at UNC. Furthermore, NGS of brain tumors has allowed us to utilize precision medicine in a population of patients with very few treatment options. In particular, we’ve exploited a BRAF V600E mutation to treat progressive glioblastoma (GBM) with BRAF-targeting agents. The patient rapidly responded to therapy and recovered functionality previously lost while on standard of care therapy. Additionally, NGS identified 1 GBM and 2 anaplastic astrocytoma (AA) patients with MET alterations, which are uncommon in high grade gliomas. Two of these patients enrolled in a biomarker-driven clinical trial at UNC, which would not have been possible without NGS. The patient with GBM has maintained disease control for over 6 months. Our experiences highlight the importance of routine NGS in the management of patients with brain tumors.
NIMG-12. RADIOGENOMICS ON VENUS AND MARS: IMPACT OF SEX-DIFFERENCES ON MRI AND GENETIC CORRELATIONS IN GLIOBLASTOMA
Authors: Leland Hu, Nathan Gaw, Hyunsoo Yoon, Jennifer Eschbacher, Leslie C. Baxter, Kris A. Smith, Peter Nakaji, John P. Karis, Paula Whitmire, Andrea Hawkins-Daarud, Kyle Singleton, Pamela Jackson, Susan Christine Massey, Bernard Bendok, Joseph Mitchell, Teresa Wu, Nhan Tran, Joshua Rubin, Kristin Swanson, Jing Li
Journal: Neuro-Oncology (2018)

MRI-based modeling can help characterize the intratumoral genetic heterogeneity of Glioblastoma (GBM). Yet, published models to date have neglected the potential impact of sex-differences on the accuracy of MRI-genetic correlations. Specifically, there is growing awareness that female GBM patients can display different genetic/molecular aberrations and phenotypic expression compared to male counterparts. In this exploratory study, we compare MRI signal and key GBM driver alterations across a cohort of male and female GBM patients, using image-guided biopsies and spatially matched multi-parametric MRI. We collected 61 image-guided biopsies from 18 primary GBM patients (9/9 male/female). For each biopsy, we analyzed DNA copy number variants (CNV) for 6 core GBM driver genes reported by TCGA: amplifications (++) for EGFR and PDGFRA and deletions (--) for PTEN, CDKN2A, RB1, TP53. We compared regional CNV status with spatially matched MRI texture measurements from co-registered biopsy locations. Advanced MRI features included relative cerebral blood volume (rCBV) on DSC-perfusion, mean diffusivity (MD) and fractional anisotropy (FA) on diffusion tensor imaging. We identified univariate correlations for combined and sex-specific (male, female) subgroups. We also built multivariate predictive decision-tree models for each GBM driver gene and used leave-one-out-cross-validation (LOOCV) to determine area-under-curve (AUC) on ROC analysis to compare accuracies across combined and sex-specific models. We identified multiple univariate correlations between regional CNV status and spatially matched MRI texture features that were specific to either male or female GBM tumors. For instance, EGFR++ specifically correlated with T2W image textures in male biopsies but rCBV textures in female biopsies. In general, sex-specific analyses on decision-tree modeling improved predictive accuracies (AUC) compared to combined (male+female) modeling, particularly for EGFR++ (p<0.05), PTEN--(p<0.025), and TP53-- (p<0.025). Sex-differences impact MRI-genetic correlations and warrant further study in larger GBM cohorts.
Abstract 17622: Targeted Therapeutic Gene Knockdown Using Ultrasound and Microbubble-mediated Delivery of a Transcription Factor Decoy
Authors: Jonathan A Kopechek, Andrew R Carson, Xucai Chen, Charles F McTiernan, Bima Hasjim, Malabika Sen, Jennifer R Grandis, Flordeliza S Villanueva
Journal: Circulation (2014)

Introduction: Ultrasound (US)-based therapies using microbubbles (MB) have the potential for targeted delivery of molecular therapies. Preclinical studies demonstrate that daily intratumoral inject...
IMMU-02. ONCOLYTIC HSV THERAPY ENHANCES GLIOBLASTOMA CONTROL VIA THE EXPANSION OF FUNCTIONAL TUMOR-SPECIFIC T CELLS AND MODULATION OF MYELOID CELL POPULATION
Authors: Quazim Alayo, Hirotaka Ito, Carmela Passaro, Mykola Zdioruk, Ahmad Mahmoud, Hiroshi Nakashima, E Antonio Chiocca
Journal: Neuro-Oncology (2018)

Immunotherapeutic approaches to treating glioblastoma (GBM) such as immune checkpoint blockade or dendritic cell vaccines have so far failed in recent clinical trials, despite showing some success in other cancer types. This failure has been attributed partly to the profound immunosuppressive tumor micro-environment (TME), characterized by dysfunctional cytotoxic T cell response and significant infiltration of regulatory lymphocytes and suppressive myeloid cells. We hypothesize that an oncolytic HSV1 (oHSV) which has a direct tumor cytotoxicity and potent in situ immunostimulation may reverse these immune dysfunction state and therefore improve tumor regression. Using several unique reagents, we found that oHSV treatment led to substantial reduction in tumor volume compared to PBS-control mice (oHSV- 9/11 vs PBS- 0/5; p= 0.0022), translating to longer term survival. Interestingly, oHSV led to improved tumor-specific T cells response with an expansion of tumor antigen-specific CD8+ T cells within the TME on both day 3 (oHSV- 4% vs PBS- 2%; p = 0.02) and day 7 (oHSV- 6.51% vs PBS- 1.33%; p = 0.04) following treatment, and a higher expression of IFNγ by CD8+ T cells compared to control (oHSV- 0.21% vs PBS- 5.60%; p = 0.04), suggesting an improved tumor-specific T cell functionality. Importantly, we found that this expansion of tumor-antigen specific CD8+ T cells inversely correlated with the tumor volume (R2= 0.41, p= 0.008). oHSV also led to a decrease in microglia and suppressive myeloid cell population which correlate negatively with the number of infiltating tumor-specific CD8+ T cells, suggesting they may play a role in modulating oHSV-mediated expansion of tumor specific T cells. Overall, using these novel tools, we demonstrate for the first time, that oHSV, in addition to its direct cytotoxic effect, play an important immunostimulating role through its modulation of tumor-specific T cells and myeloid cell population within the GBM tumor micro-environment.
SAT0105 Losartan but not irbesartan reduces serum uric acid in hypertensive patients with gout
Authors: G Wuerzner, A Chioléro, M Maillard, CL Stubi-Fallab, M Burnier, CA Gerster
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Losartan is the only angiotensin II receptor antagonist with uricosuric properties and has been shown to decrease serum uric acid (SUA) levels in normal subjects as well as in hypertensive patients. <h3>Objectives</h3> To assess and to compare the effects of losartan and irbesartan on serum uric acid in hypertensive patients with gout. <h3>Methods</h3> Prospective, randomised, double-blind, cross-over study preceded by a three weeks run-in period with enalapril 20 mg od. During the first four weeks, patients received a morning dose of either losartan 50 mg or irbesartan 150 mg and a evening dose of placebo. The dose was than increased to losartan 50 mg bid or irbesartan bid. The losartan and the irbesartan phases were separated by three weeks of treatment with enalapril 20 mg od. All drugs were provided in an electronic pill container allowing to monitor compliance (MEMS system). <h3>Results</h3> Thirteen male hypertensive (office blood pressure &gt; 140/90 mmHg or under antihypertensive therapy) and hyperuricemic (SUA over 420 μmol/L or over 7.1 g/dL, without any hypouricemic agents) patients completed this study. The changes in blood pressure induced by losartan and irbesartan were comparable. In contrast to irbesartan which had no effect on SUA, losartan (50 mg od) decreased SUA significantly from 538 ± 26 μmol/L to 491 ± 20 μmol/L (p &lt; 0.01) and to 484 ± 25 μmol/L at 50 mg bid. During the first 4 h after drug intake, the first dose of losartan increased the urinary uric acid/creatinine ratio when compared with irbesartan (0.525 ± 0.071 vs 0.358 ± 0.045, p = 0.019). This increase was still present at week 4 (0.485 ± 0.085 vs 0.331 ± 0.057, p &lt; 0.01) but was not found at week 8 when patients received a bid regimen (0.316 ± 0.043 vs 0.331 ± 0.029, p = ns). The frequency of acute gout episods did not differ between treatments. The monitoring of compliance showed that the adherence to the morning dose was good (89.2 ± 2.8%) and significantly greater than that to the evening dose (78.9 ± 3.1%, p &lt; 0.001). <h3>Conclusion</h3> These results demonstrate the potential benefits of using losartan in hypertensive patients with hyperuricemia and gout. They also suggest that losartan-treated patients reach a new uric acid steady-state during a sustained administration (&gt;1 month). Hence, the uricosuric effect tends to decrease with time as SUA is reduced. Increasing the dose of losartan to 50 mg bid does not appear to induce a further decrease in serum uric acid.
HOUT-05. INVESTIGATION OF Ki-67 PROLIFERATIVE INDEX AND PATIENT SURVIVAL IN GLIOBLASTOMA MULTIFORME
Authors: Lakshmi Ravindra, Matthew Carr, Alper Dincer, Fan Zhang, Erin Donahue, Viviana Rodriguez, Andrew Rock, Charles Opalak, Aravind Somasundaram, Kathryn Workman, Hope Richard, Adam Sima, William Broaddus
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM) is a rapidly growing, aggressive brain tumor. Studies demonstrate that higher Ki-67 proliferative indices predict poorer survival in GBM patients. It remains unclear whether therapeutic responses vary when stratifying patients by Ki-67 index. Our objective was to investigate the relationship between Ki-67 index and post-surgical survival in patients with GBM undergoing radiotherapy and/or chemotherapy. Patients with GBM presenting to VCU Health between January 2005-February 2015 were retrospectively reviewed. Inclusion criteria were: 1) Age > 18, 2) Biopsy/surgery with histopathological testing, 3) Reported Ki-67 index, and 4) Initial T2 post-contrast tumor volumes. Ki-67 indices were stratified into three groups: Ki-67 ≤ 10, 10 < Ki-67 ≤ 20, and Ki-67 > 20. The primary outcome was overall survival, calculated as time between surgery and death. Cox proportional hazards regression compared the relationship between Ki-67 index and overall survival after controlling for age, sex, race, marital status, medical comorbidities, initial T2 tumor volume, radiotherapy and chemotherapy. There were 69 patients in the study. Demographics, comorbidities, radiotherapy and chemotherapy did not differ between Ki-67 groups. Median survival time (weeks) was 61.7 (32.9–132.6), 34.9 (13.6–84.9), and 39.3 (16.7–84.1) for Ki-67 ≤ 10, 10 < Ki-67 ≤ 20, and Ki-67 > 20 groups, respectively. There was no significant difference in survival between Ki-67 groups in unadjusted (p=0.69) or adjusted analyses (p=0.83). However, older age (1.06 hazard ratio, 1.01–1.11 CI, 0.01 p-value), radiotherapy (91.5, 4.38-1911.27, 0.004), arthritis (7.81, 1.30–46.79, 0.03), diabetes (7.22, 42.14, 0.03), and hypercholesterolemia (15.76, 3.40–72.97, < 0.001) were associated with shorter survival. This study demonstrated no relationship between Ki-67 index and survival in patients with GBM when controlling for other factors, but highlighted factors related to poorer survival (older age, radiotherapy, arthritis, diabetes, hypercholesterolemia). Further prospective studies on the association between survival and Ki-67 index in a larger cohort of patients with GBM are warranted.
Predicting the potential for clinical inhibition of EGFR and ErbB2 by ARRY-543 using preclinical models.
Authors: Jennifer Garrus, Karyn Bouhana, Tracy Pheneger, Keith Hoffman, Kevin Litwiler, Shannon Winski, Patrice Lee, Jim Winkler, Duncan Walker
Journal: Cancer Research (2008)

4847   ARRY-543 is an orally active, small molecule tyrosine kinase inhibitor targeting both EGFR- and ErbB2-dependent tumor cell proliferation and survival. It is a reversible, ATP-competitive inhibitor with nanomolar potency against EGFR and ErbB2 phosphorylation in enzymatic and cell-based assays. ARRY-543 also exhibits dose-dependent growth inhibition in a panel of EGFR- and ErbB2-driven human tumors in xenograft models. The purpose of this study was to predict the potential for inhibition of EGFR and ErbB2 in patients by correlating ARRY-543 exposure required for target inhibition in preclinical  in vitro  and  in vivo  models with the exposure observed in clinical studies.  The relationship among ARRY-543 plasma protein binding, inhibition of EGFR and ErbB2  in vivo  and plasma drug concentrations was investigated in cell-based assays and in mice bearing A431 epidermoid carcinoma or BT474 breast carcinoma xenografts. The ability of ARRY-543 to inhibit target protein phosphorylation was determined in cell-based assays in the presence of either human serum or murine plasma. In the presence of 50% human serum, the IC 50  values for inhibition of pEGFR and pErbB2 were approximately 737 ng/mL and 308 ng/mL, respectively. In the presence of 50% murine plasma, the IC 50  values for inhibition of pEGFR and pErbB2 were approximately 420 ng/mL and 233 ng/mL, respectively. To test the pharmacological relevance of this cellular finding, the concentrations of ARRY-543 were measured in  pharmacodynamic models  in vivo . In these studies, the mean plasma concentration of ARRY-543 was well above cell-based IC 50  values following a single, oral 100mg/kg dose of ARRY-543 to mice bearing A431 or BT474 tumors. In agreement with the cell-based data, tumor pEGFR and pErbB2 were significantly suppressed. A reduction in phosphorylation of the downstream effector proteins, AKT and ERK, was observed as well. As previously reported, ARRY-543 was markedly efficacious at this dose in both of these animal models.  Translating these data to the clinic, in a Phase I clinical study of ARRY-543, the mean C max  and C min  plasma concentrations of ARRY-543 at steady-state for 400 mg BID dosing were 7.07 and 4.24 µg/mL, respectively. PK/PD modeling, based on inhibition of EGFR and ErbB2 phosphorylation in the presence of human serum and steady-state exposure with 400 mg BID dosing in patients, predicted a mean inhibition of > 70% for pEGFR and pErbB2 continuously over the dosing period. These results indicate that ARRY-543 should provide clinically significant inhibition of both EGFR and ErbB2 in patients.
Abstract 19361: A Comprehensive Comparison Between Myocardial Infarction With Non Obstructive Coronaries (MINOCA) and Myocardial Infarct Patients With Coronary Artery Disease (MICAD)
Authors: Rosanna Tavella, Sivabaskari Pasupathy, Christopher Zeitz, Matthew Worthley, Ajay Sinhal, Margaret Arstall, John F Beltrame
Journal: Circulation (2017)

Introduction: Myocardial infarction (MI) is typically attributable to obstructive atherosclerotic coronary artery disease (CAD) producing ischemic necrosis, however in 10% of MI patients this may o...
PATH-25. SURVIVAL STRATIFICATION OF IDH MUTANT GLIOMA USING METHYLATION AND mRNA ANALYSIS OF HOX GENES
Authors: Yasin Mamatjan, Severa Bunda, Fabio Moraes, Suganth Suppiah, Pardeep Heir, Abulizi Maimaitiming, Gelareh Zadeh, Kenneth Aldape
Journal: Neuro-Oncology (2018)

Diffuse gliomas are separated based on IDH mutation (mut) status. However, IDH-mut gliomas manifest wide range of clinical outcome that are not explained by the current genomic classification. We aim to identify clinically and biologically relevant subgroups within IDH-mut low grade gliomas to gain a deeper insight and improve classification. We used 412 IDH-mut gliomas profiled by The Cancer Genome Atlas (TCGA) Network, utilising methylation, mRNA and mutation datasets to identify unique molecular signatures. We found that IDH-mut gliomas further subdivide into 2 groups based on mutational rate. High mutation load predicts poor survival in IDH-mut glioma. Analysis of differentially expressed genes in high versus low-mutational rate showed significant enrichment of HOX genes, 24/40 HOX genes were up regulated in this group. Interestingly, both overexpression and hyper-methylation of specific HOX genes were associated with worse survival. We further show that 7 of these HOX genes (HOXA4, HOXA7, HOXA10, HOXA13, HOXD3, HOXD9, and HOXD10) are the most significant in determining survival. Signed average of 7 Hox genes significantly improved survival and hazard ratio (HR) based on high versus low methylation (HR=4.3, p<0.0001) and high versus low mRNA expression (HR=2.8, p=0.00095). Similarly, effect on survival based on high expression and hyper-methylation of HOX genes was not only observed in IDH-mut 1p/19q-codeleted and non-codeleted groups independently, but also in IDH-wild-type low grade glioma. Multivariate analysis adjusted for confounding factors (grade, age and codeletion status) showed prognostic factors associated with survival in high versus low methylated group (HR=3.2, p=0.0036). Interestingly, only the same direction (high-high and low-low groups) of both mRNA and methylation showed significance and increased HR, which challenges the current understanding of methylation of genes and gene expression. We show that IDH-mut gliomas can further be stratified into clinically relevant categories based on high mRNA expression and hyper-methylation of Hox genes.