tbuckley/cabot-search huggingface dataset:
Antibiotic Prophylaxis and Incidence of Endocarditis Before and After the 2007 AHA Recommendations
Authors: Martin H. Thornhill, Teresa B. Gibson, Eli Cutler, Mark J. Dayer, Vivian H. Chu, Peter B. Lockhart, Patrick T. O’Gara, Larry M. Baddour
Journal: Journal of the American College of Cardiology (2018)

The American Heart Association updated its recommendations for antibiotic prophylaxis (AP) to prevent infective endocarditis (IE) in 2007, advising that AP cease for those at moderate risk of IE, but continue for those at high risk. The authors sought to quantify any change in AP prescribing and IE incidence. High-risk, moderate-risk, and unknown/low-risk individuals with linked prescription and Medicare or commercial health care data were identified in the Truven Health MarketScan databases from May 2003 through August 2015 (198,522,665 enrollee-years of data). AP prescribing and IE incidence were evaluated by Poisson model analysis. By August 2015, the 2007 recommendation change was associated with a significant 64% (95% confidence interval [CI]: 59% to 68%) estimated fall in AP prescribing for moderate-risk individuals and a 20% (95% CI: 4% to 32%) estimated fall for those at high risk. Over the same period, there was a barely significant 75% (95% CI: 3% to 200%) estimated increase in IE incidence among moderate-risk individuals and a significant 177% estimated increase (95% CI: 66% to 361%) among those at high risk. In unknown/low-risk individuals, there was a significant 52% (95% CI: 46% to 58%) estimated fall in AP prescribing, but no significant increase in IE incidence. AP prescribing fell among all IE risk groups, particularly those at moderate risk. Concurrently, there was a significant increase in IE incidence among high-risk individuals, a borderline significant increase in moderate-risk individuals, and no change for those at low/unknown risk. Although these data do not establish a cause–effect relationship between AP reduction and IE increase, the fall in AP prescribing in those at high risk is of concern and, coupled with the borderline increase in IE incidence among those at moderate risk, warrants further investigation.
TMOD-31. NOVEL HETEROGENEOUS GLIOBLASTOMA MODELS TO OPTIMIZE HUMAN TUMORICIDAL NEURAL STEM CELL THERAPY
Authors: Andrew Satterlee, Denise Dunn, Shaye Hagler, Donald Lo, Shawn Hingtgen
Journal: Neuro-Oncology (2018)

Tumor-homing neural stem cell (NSC) therapy is a promising new strategy that recently entered human patient testing for glioblastoma (GBM). The success of NSCs in the clinic will depend on their ability to overcome the heterogeneity and invasiveness of patient GBM, and the development of preclinical models that recapitulate these key hurdles is essential to understanding therapeutic strengths and weaknesses. After using live organotypic brain slices to quantify the growth, migration, and drug sensitivities of different GBM lines, we generated a heterogeneous orthotopic tumor model that incorporates three GBM lines displaying significant differences in invasiveness and drug sensitivity, and exhibits spatial heterogeneity in tumor proliferation and CD31, HIF1-α, and CD133 expression. This tumor model has allowed us to begin probing how to most effectively deliver human fibroblast-derived induced NSCs (iNSCs). iNSCs expressing TRAIL or thymidine kinase were used to measure how differences in therapeutic mechanism affect TRAIL-resistant tumor regions, simultaneous solid/invasive tumor growth, and overall survival. Several treatment groups were able to significantly increase survival, depleting the solid tumor mass while decreasing HIF1-α and CD133 expression in the tumor. To further compare therapies in a second heterogeneous GBM model, two distinct tumor populations derived from the same patient tumor were combined, tested, and treated on brain slices and in vivo. Overall, TRAIL and TK treatment each thrived in situations where the other failed, suggesting that treatment durability and combination therapy can be further optimized in these more realistic models by tuning when and how each treatment is delivered.
IMMU-43. RNA-MODIFIED T CELLS AS A NON-INVASIVE AND EFFICACIOUS STRATEGY TO DELIVER THERAPEUTIC MACROMOLECULES LOCALLY TO INTRACRANIAL TUMORS
Authors: Fernanda Pohl-Guimaraes, Changlin Yang, Kyle Dyson, Tyler Wildes, Jeffrey Drake, Jianping Huang, Catherine Flores, Elias Sayour, Duane Mitchell
Journal: Neuro-Oncology (2018)

With the presence of the blood-brain barrier (BBB), successful drug delivery to central nervous system (CNS) malignancies remains a challenge. By inducing tumor regression and potentiating immune responses, cytokines, such as granulocyte macrophage colony-stimulating factor (GM-CSF), have shown promise as a biological agent to enhance anti-tumor efficacy in preclinical studies and cancer immunotherapy trials. However, intravenous cytokine delivery has limited access to CNS, and are often associated with significant systemic side effects. To bypass limitations of systemically administered cytokines, we investigate the HYPOTHESIS that RNA-modified T cells can deliver macromolecules directly to intracranial tumors. Since activated T cells have an inherent ability to cross the BBB and lyse tumor cells, this strategy makes them an attractive biological carrier for cancer cell therapy. Using electroporation to deliver messenger RNA (mRNA) to T cells, we evaluated GM-CSF secretion and the function of GM-CSF RNA-modified T cells. We demonstrated that activated T cells could be modified to secrete GM-CSF protein in vitro, while retaining their inherent effector functions. In a murine intracranial tumor model, GM-CSF RNA-modified T cells effectively delivered GM-CSF to the tumor microenvironment in vivo, and significantly extended median overall survival with long term cures in some treated animals. Importantly, GM-CSF expressing T cells demonstrated a superior anti-tumor efficacy compared to unmodified T cells, and systemic administration of recombinant GM-CSF provided no treatment benefit when co-delivered with unmodified T cells. Such anti-tumor effects were associated with increased interferon gamma secretion locally within tumor microenvironment, and systemic antigen-specific T cell expansion within secondary lymph nodes. This study strongly supports the implementation of a non-invasive and efficacious strategy to deliver therapeutic macromolecules locally to invasive brain tumors, while offers potential widespread applicability for the delivery of biological agents to other CNS conditions, such as neurodegenerative or neuroinflammatory diseases.
MNGI-13. A DNA METHYLATION-BASED CLASSIFIER FOR ASSESSMENT OF RISK OF RECURRENCE IN MENINGIOMA
Authors: Felix Sahm, Daniel Schrimpf, Martin Sill, Damian Stichel, Stefan M Pfister, Andreas von Deimling
Journal: Neuro-Oncology (2018)

The World Health Organization (WHO) classification of brain tumors comprises 15 histological subtypes of meningioma, allotted to three WHO grades. While the current classification and grading approach is of prognostic value, it harbors shortcomings due to the necessarily subjective evaluation of histological criteria and potential sampling bias. In order to devise a molecular approach to meningioma classification, we previously identified six distinct Methylation Classes (MCs) of meningioma by DNA methylation profiling. These six MCs are termed MC benign-1, -2, -3, MC intermediate A, B, and MC malignant. Each MC shows typical mutational, cytogenetic, and gene expression patterns. Importantly, MCs are superior to WHO grading in predicting the risk of recurrence for individual patients. In order to translate these findings into diagnostic practice, we developed a meningioma classifier, assigning novel diagnostic samples to the respective MC of the reference cohort. This classifier is now being used on diagnostic cases for 2 years at the Dept. of Neuropathology Heidelberg and has recently been made available for external users through molecularneuropathology.org, alongside the brain tumor entity classifier. Over 200 diagnostic cases have been evaluated so far. Integrating histology, classifier results, and copy-number alterations provides a more robust basis for grading and the subsequent clinical decision whether to administer radiotherapy or not. In addition, the association of certain subgroups with druggable mutations informs about the potential to identify specific targets by additional sequencing. Collectively, this tool opens the opportunity for an integrated classification of meningioma samples in routine diagnostics.
IMMU-37. VEMURAFENIB ENHANCES THE CYTOTOXICITY OF NY-ESO-1 TCR ENGINEERED T-CELLS FOR BRAF MUTANT BRAIN TUMORS
Authors: Jacob Bethel, Julian Aliche, Joey Orpilla, Horacio Soto, Richard Everson, Tom Davidson, Anthony Wang, Linda Liau, Robert Prins
Journal: Neuro-Oncology (2018)

Missense BRAF mutations are found in a significant portion of pediatric brain tumors, leading to constitutive MAPK pathway activation. By combining immunotherapy with BRAF targeted therapies like vemurafenib, an opportunity might exist to mitigate innate cellular immune escape mechanisms. We hypothesize that vemurafenib is an immunosensitizing agent that induces MAPK pathway de-regulation and sensitizes tumors to T-cell mediated lysis. We treated a human glioma cell line that carries a BRAF V600E mutation (DBTRG-05MG) with decitabine to uncover an antigenic target for NY-ESO-1 transduced T-cells. Tumor cell lysis was assessed using the xCELLigence Real-Time Cell Analyzer system. The Seahorse XF Extracellular Flux Analyzer was used to measure bioenergetic pathway fluctuation with BRAF inhibition. Cytotoxicity data demonstrated a dose-dependent enhancement of tumor cytolysis throughout the 48-hour assay that was not attributable to BRAF inhibition alone. With one effector cell per tumor cell, a 19.95% increase in lysis was found at three hours when cells were treated with the IC20 concentration of vemurafenib versus those untreated (*P= .0028, Student’s t-test). With 2.5 effector cells per tumor cell, cytolysis increased by 25.2% (*P= .0098), and by 40.52% (*P= .0081) with 5 effector cells per tumor cell. Vemurafenib treatment of tumors induced a reduction in the basal, ATP-linked, and maximal oxygen consumption rate (OCR), whereas T-cells co-cultured with vemurafenib treated tumor cells displayed an increase in aerobic and glycolytic metabolism. These results support an innovative, feasible treatment for BRAF mutant tumors. In a competition for metabolic fuel, the cytotoxic advantage for T-cells may be explained by reduced tumor consumption and increased availability of metabolic substrates in the tumor environment. Using the Nanostring Pathways Panel, we are also seeking to identify how vemurafenib induces oncogenic pathway de-regulation, which may provide insight on plausible treatments for metabolically abnormal tumors.
Abstract 10925: The Impact of a Positive Gene Test on Presentation and Disease Progression of Arrhythomogenic Right Ventricular Cardiomyopathy in Childhood
Authors: Paweena Chungsomprasong, Robert Hamilton, Meena Fatah, Cedric Manlhiot, Shi-Joon Yoo, Mike Seed, Bernadette Elders, Brian W McCrindle, Lars Grosse-Wortmann
Journal: Circulation (2015)

Background: The impact of a pathogenic mutation on the presentation and disease progression in arrhythmogenic right ventricular cardiomyopathy (ARVC) during childhood is unknown. The aim of this study was to compare gene-positive (GP) and gene-negative (GN) patients who were evaluated for ARVC. Methods: For this retrospective study, serial clinical data for patients with a known pathogenic mutation for ARVC (GP) were compared to those for GN patients. Magnetic resonance, echocardiography, ECG, signal average ECG (SAECG), Holter, and clinical findings were recorded during each serial evaluation. Patients were classified into possible, borderline or definite ARVC according to the revised Task Force Criteria (rTFC). Patients with ‘no’ ARVC at the last visit were excluded from the follow-up analysis. Results: We included 23 GP and 94 GN patients. GN and GP patients were similar in age at presentation. More patients in the GN group (75% vs. 30%, p=0.001) were symptomatic at presentation. The groups did not differ in their initial rTFC category or in their rate of progression to more severe diagnostic categories . Z-scores for RV end-diastolic volume (EDV) tended to progress faster in the GP group (p=0.06), as did the RV outflow tract diameter by echocardiography (p=0.04). Z-scores for RV ejection fraction deteriorated faster in the GP group (p=0.03) and Z-scores for LV EDV increased more rapidly (p=0.04). Patients who were symptomatic on presentation did not progress more quickly in terms of rTFC grading as compared to asymptomatic patients. During a median follow-up of 3.6 years (0-13.9), 2 patients developed ventricular tachycardia, 3 out of 20 with an implanted defibrillator experienced appropriate shocks, and 2 underwent heart transplantation. There were no deaths. GP did not predict adverse events. Conclusion: Gene negative and gene positive children who undergo a work-up for ARVC are referred at similar ages to a tertiary care centre. GP patients experience a faster growth of LV and RV size and a more rapid deterioration of RV function. However, being GP is not associated with a faster progression to higher rTFC categories , development of symptoms, or adverse outcomes in the pediatric age group.
Abstract 19177: An Orally Administered Small Molecule That Inhibits Hepatic Sulfatase-2 Expression In Vivo: A Novel Strategy to Correct Diabetic Dyslipoproteinemia With Implications for Residual Atherosclerotic Cardiovascular Disease (ASCVD) Risk
Authors: Charles L Bisgaier, Daniela C Oniciu, Kevin Jon Williams
Journal: Circulation (2017)

Introduction: Patients treated with optimal statin therapy and even PCSK9 inhibitors exhibit considerable residual risk for ASCVD events. Residual ASCVD risk may occur, in part, because these medic...
DRES-07. DEFINING THE MECHANISMS OF ACQUIRED RESISTANCE TO TYROSINE KINASE INHIBITORS IN EGFR-DRIVEN GLIOBLASTOMAS USING INTEGRATED KINOME AND TRANSCRIPTOME PROFILING
Authors: Abigail Shelton, Erin Smithberger, Madison Butler, Alex Flores, Ryan Bash, Steven Angus, Noah Sciaky, Harshil Dhruv, Gary Johnson, Michael Berens, Frank Furnari, Ryan Miller
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM), the most common and malignant adult primary brain tumor, has been extensively molecularly characterized. Two mutations occur at particularly high frequency: CDKN2A deletion (50–60%) and EGFR (40–50%), especially EGFRvIII (~35%) in which exons 2–7 are deleted and result in constitutive kinase activation. EGFR is the most attractive therapeutic target due to frequent activating mutations and ready availability of multiple targeted inhibitors. Several EGFR-targeted tyrosine kinase inhibitors (TKI) have failed clinically, due in part to intrinsic and acquired resistance. To examine these mechanisms, we are using genetically-engineered mouse astrocytes harboring homozygous deletions of Cdkn2a, as well as the activating EGFRvIII mutation (CEv3). To model acquired resistance, CEv3 astrocytes were made intrinsically resistant to the EGFR TKI gefitinib or erlotinib via long-term exposure, both in vitro and in vivo. We found that long-term gefitinib or erlotinib exposure confers variable levels of cross resistance to a panel of second- and third-generation EGFR-TKI (ΔIC50 1.12-36.1-fold), relative to non-resistant parent lines. We have previously shown that dynamic kinome reprogramming may be responsible for TKI resistance. Therefore, we are using a chemical proteomics method, multiplexed inhibitor beads and mass spectrometry (MIB-MS), to examine changes in the expressed and functional kinome, in both the presence or absence of one of several EGFR-TKI known to penetrate the blood-brain barrier. Additionally, we are performing RNA sequencing (RNA-seq) to inspect transcriptomic alterations in response to these drugs. Preliminary RNA-seq results showed that resistant CEv3 mouse astrocytes clustered separately from their non-resistant in vitro and in vivo counterparts. Together, data from these experiments will create a framework of transcriptomic and proteomic changes that occur in murine models of GBM with defined mutational profiles. This framework can then be used to help define novel therapeutic targets that could significantly alter the current treatment paradigm of GBM.
Stress-Related Disorders and Autoimmune Disease—Reply
Authors: Huan Song, Fang Fang, Unnur A. Valdimarsdóttir
Journal: JAMA (2018)

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INNV-46. EVALUATING THE DECISIONS OF GLIOMA PATIENTS REGARDING CLINICAL TRIAL PARTICIPATION, A RETROSPECTIVE SINGLE PROVIDER STUDY
Authors: Grant W Jirka, Karl Stessy Bisselou, Dr Lynette Smith, Dr Nicole Shonka
Journal: Neuro-Oncology (2018)

Clinical trial accrual is vital to advancing care. A single study elucidated demographic data correlating with glioma patients’ clinical trial enrollment. However, it did not investigate the underlying decision-making process, a key point to understanding why patients decline clinical trials. All notes for glioma patients seen by a single neuro-oncologist from July 2010-May 2017 were examined. When a trial was declined, the patient’s reasoning was recorded along with the following: diagnosis, KPS, extent of resection, age, gender, race, marital status, religion, trial offered at initial visit vs subsequent, and distance from trial site. Of 92 patients offered a clinical trial, 57 (65%) accepted and 31 (35%) declined. Patients with glioblastoma (GBM) were significantly more likely to accept a trial (44 (72%) vs. 13 (48%), P=0.03). Adjusting for gender and travel distance, GBM was the only significant predictor of clinical trial acceptance, having 3.18 higher odds (95% CI: 1.17, 8.61, P=0.02). Reasons cited for non-participation included: travel distance (39%), lack of interest (39%), visit frequency (16%), and fear of randomization (6%). This study clarified for the first-time individual glioma patient rationale for non-participation and potential areas for improving enrollment. Allowing off-site treatment centers or telemedicine visits may entice rural patients to participate. Visit frequency should be carefully considered and minimized whenever possible. Further prospective study of rationale for non-participation may improve enrollment over time.
DDIS-23. BETULINIC ACID SUPPRESS GLIOBLASTOMA CELLS THROUGH INHIBITION OF UNFOLDED PROTEIN RESPONSE
Authors: Wei-Lun Lo, Jian-Ying Chuang, Ming-Hsiao Wu
Journal: Neuro-Oncology (2018)

The current anti-neoplastic drug for glioblastoma multiforme (GBM) is limited because of insufficient blood-brain-barrier (BBB) penetration and development of resistance. Betulinic acid (BA) is a natural product of plant origin, has been reported to induce Sp1 degradation against temozolomide (TMZ)-resistant GBM and capacity of BBB passage. In this study, we investigated the alternative anti-neoplastic mechanism of BA. MATERIALS AND To explore the mechanism of tumor inhibition by BA in TMZ-resistant cells and uncover novel therapeutic targets for recurrent GBMs, we used high density oligonucleotide microarrays to analyze gene expression during BA treatment. Furthermore, we applied Ingenuity Pathway Analysis (IPA) software performing Canonical Pathways Analysis. We subsequently examined the protein expression of genes identified from the microarray data. We identified the unfolded protein response (UPR), known as a signaling network activated by endoplasmic reticulum (ER) stress functioning to alleviate this stress, appeared most significantly affected by BA. Protein expressions of ER stress-related factors were observed with different concentration of BA. BA is able to inhibit the survival of TMZ-resistant GBM cells via inhibition of unfolded protein response. BA is a good therapeutic strategy to overcome the tumor recurrence after the initial therapy. Key words: Betulinic acid, temozolomide resistance, glioblastoma, unfolded protein response.
TMIC-05. ABSCOPAL IMMUNE RESPONSE IN GLIOBLASTOMA ELICITED BY MIR124-ATTENUATED ONCOLYTIC HERPES SIMPLEX VIRUS 1 ARMED WITH UL16 BINDING PROTEIN 3
Authors: Hans-Georg Wirsching, Huajia Zhang, Paola Grandi, Sonali Arora, Patrick J Cimino, Jean S Campbell, Frank Szulzewsky, Siobhan S Pattwell, Chibawanye Ene, Debrah Kumasaka, Robert H Pierce, Mitchell Finer, Christophe Queva, A McGarry Houghton, Eric Holland
Journal: Neuro-Oncology (2018)

Glioblastoma is a deadly disease with median survival ranging below one year. T-cell-based immunotherapy approaches failed to prolong survival of glioblastoma patients in two phase III clinical trials, thus reflecting the immunologically inert features of glioblastoma. Pre-clinical efficacy of oncolytic virus therapy in combination with immune checkpoint inhibition was demonstrated in syngeneic glioblastoma models. However, given the extensive spreading of glioblastoma cells throughout the brain, we hypothesized that efficacious immunotherapy approaches in patients will need to elicit abscopal responses, i.e. the secondary targeting of tumor cells at sites distant from treated lesions. We addressed this issue in an immune competent RCAS/tv-a-based genetic glioblastoma model that recapitulates the genotype, gene expression, histology and immune phenotype of human glioblastomas. Spatial distance of virus-treated and untreated glioblastoma lesions was modeled by generating two tumors in both hemispheres of N/tv-a;Ink4a/Arf-/-;PTENfl/fl;LucLSL/LSLmice. One tumor was generated by transduction with RCAS-Pdgfb and RCAS-shPTEN. A second, contralateral tumor was generated with RCAS-Pdgfb and RCAS-Cre, thus enabling additional monitoring of tumor growth through luciferase activity. We infected luciferase-negative tumor lesions with a miR-124-attenuated oncolytic herpes simplex virus 1 (oHSV) armed with the NKG2D ligand ULBP3. oHSV-ULBP3 infection slowed the growth of distant, non-infected glioblastoma lesions and prolonged survival. oHSV-ULBP3 led to influx and activation of T-cells in both, treated and untreated glioblastoma lesions. Massive influx of monocytes yielded an increase of mostly PD1+ macrophages in both tumors. Neutrophils were also increased ubiquitously, whereas NK-cells were suppressed. Treatment with an anti-PD1 antibody alone had no effect, but combination with oHSV-ULBP3 counteracted macrophage and neutrophil influx and enhanced abscopal anti-tumor responses. We conclude that oHSV-ULBP3 in combination with anti-PD-1 is a feasible approach to induce abscopal T-cell-mediated immune responses in glioblastoma. Unraveling the role of myeloid components of the tumor microenvironment may be critical to overcome resistance to such treatment.