tbuckley/cabot-search huggingface dataset:
P3.02-062 An EGFR Follow-On Companion Diagnostic for Clinical Care of Patients with NSCLC
Authors: Y. Li, J. Luo, W. Yip, J. Skoletsky, C. Milbury, C. Burns, A. Tsuji, J. Truesdell, E. Peters, H. Gilbert, C. Wu, E. Schleifman, C. Barrett, K. Thress, S. Jenkins, J. Elvin, G. Otto, D. Lipson, J. Ross, V. Miller, P.J. Stephens, M. Doherty, C. Vietz, J. Sun
Journal: Journal of Thoracic Oncology (2017)
METB-14. DOWN-REGULATION OF ACETATE METABOLISM TOWARDS FATTY ACIDS IN IDH1 MUTANT GLIOMA
Authors: Chloe Najac, Marina Radoul, Pavithra Viswanath, Myriam M Chaumeil, Sabrina Ronen
Journal: Neuro-Oncology (2017)

Acetate has recently been identified as a major alternative source of nutrients for glioblastoma and brain metastases. After cellular uptake, acetate is converted to acetyl-CoA, a key metabolic intermediate that fuels the TCA cycle and is an essential building block for the biosynthesis of fatty acids. Interestingly, the potential role of acetate in lower-grade glioma harboring the isocitrate dehydrogenase 1 mutation has not yet been elucidated. The goal of this study was therefore to investigate the role of acetate in fatty acid biosynthesis using a well-characterized genetically-engineered cell model that overexpresses either wild-type IDH1 (IDHwt) or mutant IDH1 (IDHmut): an immortalized normal human astrocyte (NHA)-based model. We used 1H and 13C magnetic resonance spectroscopy to quantify the flux of [1,2-13C]-acetate to 13C fatty acids. Our results indicated that the total levels of fatty acids were not significantly different between IDHmut and IDHwt NHA cells. However, the flux of 13C-labeled acetate towards fatty acids was significantly reduced by ~60% in IDHmut NHA cells relative to IDHwt NHA cells. To investigate this disconnect and understand the underlying biological mechanisms, we performed cell biological assays. Surprisingly, this decrease in acetate metabolism was associated with a drop in fatty acid synthase and ATP citrate lyase expressions, two enzymes involved in fatty acid synthesis from acetyl-CoA, in IDHmut NHA cells, whereas expression of acetyl-CoA synthase (AceS1), the cytosolic enzyme converting acetate to acetyl-CoA, was not altered. A significant drop in lipid droplet accumulation was also observed in IDHmut NHA cells as indicated using a spectrophotometric assay. Taken together, this points to alternate sources for fatty acids (e.g. glucose, glutamine, uptake from serum) in IDH1mut cells and suggests that fatty acids are preferentially directed towards cell membrane assembly. It also highlights the unique metabolic reprogramming of mutant IDH1 cells.
STEM-39. TRANSCRIPTOME ANALYSIS OF GLIOMA STEM-LIKE CELLS REVEALS SOX2 REGULATES miR-425-5p EXPRESSION
Authors: Arlet Maria Acanda de la Rocha, Hernando Lopez-Bertoni, Naiara Martínez-Vélez, Elizabeth Guruceaga, Marisol González-Huarriz, John Laterra, Marta M Alonso Roldán
Journal: Neuro-Oncology (2017)

Glioblastoma is the most common malignant primary brain tumors in adults, and despite established therapeutic approaches, the prognosis remains bleak. Glioblastoma tumors are composed of heterogeneous cell populations, among which the glioma stem-like cells (GSCs) are crucial to tumor self-renewal, growth, and recurrence. The transcription factor sex determining region Y-box 2 (SOX2) is enriched in GSCs where it controls stemness, invasion, and maintenance of tumorigenicity. Therefore, defining the molecular mechanisms governed by SOX2 in GSCs is critical to developing targeted therapies against this recalcitrant population. In this study, we performed a genome-wide analysis of SOX2-regulated coding and non-coding transcripts in GSCs. We identified 2,048 differentially expressed coding transcripts regulated by SOX2. These genes are involved in diverse biological processes, such as cell adhesion, intercellular signal transduction, canonical intracellular signaling cascades (KITLG, GHR, IRS1, HES5, HEY1), and amino-acid metabolism. Additionally, SOX2 was found to differentially regulate 261 non-coding transcripts in GSCs, including miRNAs and lncRNAs. Of particular interest, we identified miR-425-5p as a robust and significant validated candidate for further study. The expression of miR-425-5p was significantly overexpressed in glioblastoma tissue and correlate with SOX2 expression (R2= 0.70; p= 0.01). Using chromatin immunoprecipitation assay followed by qRT-PCR we found that SOX2 activated miR-425-5p expression by directly binding to its promoter. Conversely, inhibition of miR-425-5p expression, using a miRNA sponge lentiviral vector, prevented neurosphere formation, cell proliferation, and promotes apoptosis. Impairing miR-425-5p expression in vivo leads to a significant increase in overall median survival time of nude mice harboring orthotopic glioma xenografts. In summary, this research is the first to identify transcriptional programs controlled by SOX2 in GSCs. In doing so, we defined miR-425-5p as a novel potential onco-miR in GSCs. Taken together, our studies have provided new insights regarding the molecular circuitries governing glioblastoma biology.
Abstract 17353: Effectiveness and Safety of Digoxin in Adults with Incident Systolic Heart Failure
Authors: James V Freeman, Jingrong Yang, Mark A Hlatky, Alan S Go
Journal: Circulation (2011)

Background: Current clinical guidelines endorse digoxin use for patients with symptomatic systolic heart failure (HF) on optimal medical therapy, but this recommendation is based on limited, older clinical trial data. We sought to evaluate the effectiveness and safety of digoxin in a contemporary cohort of patients with incident systolic heart failure and stratified by patient sex and serum digoxin concentration (SDC). Methods: We identified patients with incident systolic HF between 2006 and 2008 in the Kaiser Permanente of Northern California health system. We used multivariable extended Cox regression to examine the association between incident digoxin use and death and hospitalization for HF, controlling for patient medical history, physical exam, diagnostic tests, laboratories, and medications. Longitudinal drug use, patient characteristics and outcomes were identified based on validated algorithms using health plan automated databases. Analyses were also conducted stratifying by sex and SDC. Results: Among 2891 patients with incident systolic HF followed for a mean 2.4 years, digoxin users had higher rates of death (14.2% vs 11.3%) and HF hospitalization (28.2% vs 24.4%). In adjusted analysis, digoxin was associated with excess mortality (odds ratio (OR) 1.60, 95% confidence interval (CI) 1.18-2.17) and HF hospitalization (OR 1.40, 95% CI 1.05-1.86). Compared with non-use, new digoxin use with SDC ≥1.2 ng/mL had higher odds of HF hospitalization and borderline higher odds of death (Table); SDC ≤0.8 ng/mL had higher odds of death. Digoxin use was associated with higher adjusted rates of HF hospitalization and death in men but not in women (Table). Conclusions: Digoxin was associated with a higher risk of death and HF hospitalization, however these risks were dependent on SDC. Digoxin was linked to a higher risk of adverse events in men but not significantly so for women.
OA 18.02 The Landscape of Alteration of DNA Integrity-Related Genes and Their Association with Tumor Mutation Burden in Non-Small Cell Lung Cancer
Authors: M. Sharpnack, J.H. Cho, F. Oezkan, M. Koenig, I. Kim, G. Otterson, K. Huang, D. Carbone, K. He
Journal: Journal of Thoracic Oncology (2017)
Abstract 12799: Hospitalizations and Emergency Consultations Following Generic Antihypertensive Drugs Commercialization in Quebec
Authors: Jacinthe Leclerc, Claudia Blais, Louis Rochette, Denis Hamel, Line Guénette, Paul Poirier
Journal: Circulation (2016)

Introduction: Once patent of a brand-name drug expires, generic drugs are commercialized and substitution may occur. Few studies have assessed clinical impacts of generic drugs commercialization at a population level. Objective: We evaluated the impact for three generic versions of antihypertensive drugs on adverse events: hospitalizations and emergency room consultations. Methods: This is an interrupted time series analysis using the Quebec Integrated Chronic Disease Surveillance System. The rate of adverse events for losartan (brand-name and 8 generics), valsartan (brand-name and 5 generics) and candesartan (brand-name and 3 generics) users aged ≥ 66 years (all: N=121 185 citizens) were calculated monthly, 12 months before and 12 months after generics commercialization. Periods before and after generics commercialization were compared with negative binomial segmented regression models for all users with a specific variable for generic and brand-name users. Results: There was an approximated monthly mean rate of 100 adverse events for 1000 exposed person-months to losartan, valsartan and candesartan. Monthly trend of adverse events was affected by generics commercialization. Generic users of losartan, valsartan and candesartan showed increased rate of adverse events of 11% (p=0.0034), 9% (p=0.0024) and 13% (p=0.0008) respectively right after generics commercialization (Figure 1) which was always higher compared to brand-name users (p&lt;0.05). The monthly trend of hospitalizations was affected for losartan users up to 1 year after generics commercialization (generics: +1.2%, brand-name: -2.2, p=0.0094). Conclusion: Generics commercialization impacted population rates of adverse events. A significant adverse events increase was observed right after generics commercialization for all antihypertensive drugs studied, among generic users. More studies are required to identify differences in drugs or users, which could explain this increase.
PDTM-35. THERAPEUTIC RELEVANCE OF YAP/TAZ ACTIVITY IN PEDIATRIC HIGH-GRADE GLIOMA.
Authors: Se-Yeong Oh, Krishanthan Vigneswaran, Matthew Schniederjan, Craig Horbinski, Dolores Hambardzumyan, Oren Becher, Anna Kenney, Renee Read
Journal: Neuro-Oncology (2017)

High-grade gliomas (HGGs), including glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG), are the most aggressive malignant high-grade gliomas in children, and are incurable with current therapies. The most frequent genetic lesions that drive formation of HGGs include amplification/overexpression, mutation, and/or activation of receptor tyrosine kinases (RTK), such as PDGFRA, and K27M mutations in histone H3 proteins. We have discovered that the Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) transcriptional activators, which encode paralogous transcriptional activators, are frequently overexpressed in RTK-mutant/overexpressing pediatric HGGs. We have also discovered that YAP/TAZ activity is required for to promote stemness and self-renewal in tumor cells. We hypothesize that, because of oncogenic RTK alterations, YAP/TAZ become constitutively activated to drive a gene expression program that promotes uncontrolled expansion of neural stem/progenitor cells to create malignant tumors, and that this can be exacerbated by H3-K27M epigenetic dysregulation. In testing this hypothesis, we have generated compelling preliminary data showing that pharmacologic inhibition of YAP/TAZ activity specifically provokes growth arrest and cell death of RTK-overexpressing HGG cells, particularly in the context of H3-K27M mutations. Our ongoing research is focused on identifying the YAP/TAZ transcriptional program that drives tumorigenesis. Our research indicates that YAP/TAZ inhibition may be a promising therapeutic strategy for pediatric HGGs.
Impacto da vacina conjugada contre o meningococo C em Espanha: uma decisão pertinente ao nivel epidemiológico e microbiológico
Authors: R Cano, A Larrauri, S Mateo, B Alcalá, C Salcedo, J A Vázquez
Journal: Eurosurveillance (2004)

A nova vacina conjugada contre o meningococo C foi licenciada em Espanha em 2000 e introduzida no calendario da vacinacao infantil. Alem disso, foi realizada uma campanha de vacinacao nas criancas de menos de seis anos em todo o pais. Como consequencia, a incidencia da infeccao meningococica de serogrupo C baixou de maneira significativa durante os tres ultimos anos epidemiologicos em Espanha. O risco de sufrir da doenca do serogrupo C baixou de 58%, comparandose com a temporada precedendo a introduccao da vacina. A mortalidade tambem desceu muito. Tres obitos pelo serogrupo C ocorreram nos grupos de idade objectivo da vaccinacao na temporada 2002-2003 comparados com 30 das mesmas idades na temporada precedendo a introduccao da vacina. A cobertura vacinal das campanhas de recuperacao tem sido superior a 92%. Nos programas de rotina dos anos 2001, 2002 e 2003, a cobertura atingiu valores entre 90% e 95%. Nos tres ultimos anos, foram relatados 111 casos de infeccao meningococica por serogrupo C nos grupos de idade objectivos da vaccinacao. As falhas da vacinacao ocorreram principalmente na temporada 2002-2003. Oito (53%) falhas, em criancas vacinadas em rutina, poderiam ser devidas a uma perdida de proteccao com o tempo depois da vacinacao. Foram isoladas varias estirpes B:2a:P1.5 (ST-11) que poderiam ter um potencial epidemico importante. Estas estirpes podem ter a origem em estirpes C:2a:P1.5, depois de ter sofrido uma recombinacao genetica da capsula.
Autologous Hematopoietic Cell Transplantation in Patients with Multiple Myeloma: IMPACT of Age
Authors: Binod Dhakal, Ariel Nelson, Guru Subramanian Guru Murthy, Raphael Fraser, Daniel Eastwood, Mehdi Hamadani, Anita D'Souza, Parameswaran Hari
Journal: Blood (2016)
P1.05-015 Major Pathological Response as a Predictive Value of Survival in Early-Stage NSCLC After Chemotherapy: Cohort of NATCH Phase III Trial
Authors: E. Carcereny, A. Martinez, J.L. Mate, J. Sansano, N. Pardo, A. Estival, A. Navarro, A. Martinez De Castro, J. Zeron-Medina, L. Romero Vielva, T. Morán, S. Cedres, E. Felip
Journal: Journal of Thoracic Oncology (2017)
P3.02-012 Liquid Based Cytology (LBC) Specimens Were Useful for EGFR Mutation Test
Authors: T. Ohira, J. Matsubayashi, S. Maehara, J. Maeda, K. Yoshida, M. Hagiwara, M. Kakihana, T. Okano, N. Kajiwara, T. Nagao, N. Ikeda
Journal: Journal of Thoracic Oncology (2017)
QLIF-25. EFFECT OF TUMOR TREATING FIELDS (TTFIELDS) ON HEALTH-RELATED QUALITY OF LIFE (HRQoL) IN NEWLY DIAGNOSED GLIOBLASTOMA. RESULTS OF THE EF-14 RANDOMIZED PHASE III TRIAL
Authors: Martin J B Taphoorn, Linda Dirven, Sophie Taillibert, Jerôme Honnorat, Thomas Chen, Jan Sroubek, Sun-Ha Paek, Jordi Bruna Escuder, Jacob C Easaw, Carlos A David, Chae-Yong Kim, Rajiv D Desai, Yvonne Kew, Alessandro Olivi, Garth A Nicholas, Gitit Lavy-Shahaf, Eilon D Kirson, Zvi Ram, Roger Stupp
Journal: Neuro-Oncology (2017)

TTFields is a novel treatment modality using a patient-operated device applying alternating electrical fields, interfering with organelle assembly and mitosis in diving cells. Previously, TTFields has shown to improve both progression-free and overall survival in newly diagnosed glioblastoma. To determine the net clinical benefit, results on HRQoL are also important. Patients completed two validated HRQoL questionnaires (EORTC QLQ-C30 + BN20) at baseline, and every 3 months thereafter. HRQoL over time was assessed for 9 preselected scales: global health, physical, cognitive, role, social and emotional functioning, itchy skin, pain, and weakness of legs. Also deterioration-free survival (DFS) and time to deterioration (TTD) were determined. 639/695 (92%) patients completed at least the baseline HRQoL questionnaires, which dropped to 42% (197/473) after 1 year. Baseline scores were balanced. HRQoL over time did not significantly differ between treatment arms, except for itchy skin, which was worse with TTFields. More TTFields patients reported stable or improved scores on global health status (53% vs. 38%, p=.001), pain (57% vs. 36%, p<.0001), physical functioning (54% vs. 38%, p=.001) and leg weakness (59% vs. 42%, p=.001). DFS was significantly longer with TTFields for global health (4.8 vs. 3.3 months), physical (5.1 vs. 3.7 months) and emotional functioning (5.3 vs. 3.9 months), pain (5.6 vs. 3.6 months) and leg weakness (5.6 vs. 3.9 months) (all p<.01). TTD did not differ, except for itchy skin (TTFields worse; 8.2 vs. 14.4 months) and pain (TTFields improved; 13.4 vs. 12.1 months) (both p<.001). TTFields does not negatively impact HRQoL, except for itchy skin, an expected consequence from the electrodes. TTFields did improve DFS of several HRQoL scales, likely related to improved progression-free and overall survival. Excluding progressive disease by considering TTD, TTFields results in less pain, but worse itchy skin. More TTFields patients reported stable/improved HRQoL scores.
METB-11. HYPOXIA INDUCIBLE FACTOR 1α REPROGRAMS CHOLINE AND ETHANOLAMINE PHOSPHOLIPID METABOLISM IN MUTANT IDH1 GLIOMAS
Authors: Pavithra Viswanath, Joanna J Phillips, Russell O Pieper, Sabrina Ronen
Journal: Neuro-Oncology (2017)

Mutations in isocitrate dehydrogenase 1 (IDH1) drive tumorigenesis in low-grade gliomas and result in production of the oncometabolite 2-hydroxyglutarate (2-HG). 2-HG extensively reprograms cell metabolism, often in a manner atypical relative to wild-type IDH1 gliomas. In particular, compared to normal tissue, wild-type IDH1 gliomas are characterized by elevated levels of phosphocholine (PC) and phosphoethanolamine (PE), which are intermediates in the synthesis of the membrane phospholipids phosphatidylcholine and phosphatidylethanolamine. Mutant IDH1 gliomas, however, down-regulate PC and PE levels and we previously linked this effect to 2-HG-mediated down-regulation of choline kinase (CK) and ethanolamine kinase (EK) activity. The goal of this study was to delineate the molecular pathway by which 2-HG down-regulates this activity. Previous studies have linked hypoxia inducible factor-1α (HIF-1α) to modulation of CKα expression. Here, using two genetically-engineered models expressing mutant or wild-type IDH1 (U87-based and immortalized normal human astrocyte-based), we established that HIF-1α levels were higher in mutant IDH1 cells relative to wild-type. Mechanistically, silencing HIF-1α in mutant IDH1 cells restored CKα expression, CK activity, EK activity, PC and PE to levels observed in wild-type IDH1 cells. To further confirm our results, we treated mutant IDH1 cells with KC7F2, a pharmacological inhibitor of HIF-1α synthesis and found that it restored CKα expression, CK activity, EK activity, PC and PE to levels observed in wild-type cells. Importantly, HIF-1α silencing and KC7F2 treatment increased PC, PE, CKα expression, CK activity and EK activity in the clinically relevant BT54 patient-derived mutant IDH1 model. Finally, examination of orthotopic U87 tumors expressing mutant or wild-type IDH1 showed that PC, PE, CKα expression, CK activity and EK activity were reduced in mutant tumors relative to wild-type, an effect associated with higher HIF-1α levels in mutant tumors. Taken together, our study mechanistically links HIF-1α to the unusual down-regulation of phospholipid metabolism in mutant IDH1 gliomas.
P1.03-037 A Phase II Study of Adjuvant Chemotherapy with Docetaxel plus Nedaplatin for Completely Resected Non-Small Cell Lung Cancer
Authors: K. Teramoto, Y. Namura, K. Hayashi, K. Ishida, K. Ueda, K. Okamoto, R. Kaku, T. Hori, Y. Kawaguchi, T. Igarashi, M. Hashimoto, Y. Ohshio, S. Kitamura, M. Motoishi, Y. Suzumura, S. Sawai, J. Hanaoka, Y. Daigo
Journal: Journal of Thoracic Oncology (2017)
P1.01-036 Identifying and Addressing Gaps in Molecular Testing for Patients with Lung Cancer
Authors: J. King, A. Ciupek, T. Perloff, A. Blanchard, K. Mason, E. Blais, D. Halverson, J. Bender, S. Madhavan, E. Petricoin
Journal: Journal of Thoracic Oncology (2017)
NIMG-05. REPEATABILITY OF FET-PET SCANNING AND THE INFLUENCE OF PROTEIN INTAKE IN GLIOMA
Authors: Sarah Chehri, Otto Mølby Henriksen, Lisbeth Marner, Mette Christensen, Aida Muhic, Hans Skovgaard Poulsen, Ian Law
Journal: Neuro-Oncology (2017)

O-(2-18F-fluoroethyl)-L-tyrosine positron-emission-tomography (FET-PET) scanning is used in routine clinical management and evaluation of glioma brain tumours. Clinical guidelines recommend fasting 4-6 hours before a FET-PET scan. Animal studies indicate protein intake prior to the scan does not reduce FET-uptake in tumours. No human studies are published. Critical knowledge of test-retest variation of FET-PET imaging of glioma tumour volume and uptake and the impact of protein intake is sparse. To investigate the repeatability of FET-PET scanning and to assess the impact of protein-intake prior to FET-PET scanning of gliomas. 20 histologically confirmed glioma patients were included in this ongoing prospective study. Subjects were divided into two groups; no protein (NP,n=11) and protein (P,n=9). All subjects underwent two 40min. dynamic FET-PET scans on a Siemens PET/CT scanner with an interval of maximum 7 days between each scan. Group P consumed 24g of protein (Nutricia Nutridrink Compact®) orally an hour before the second scan. Blood samples were drawn before and after protein intake for determining the plasma-amino-acid concentration. None of the patients were in treatment at the time of the scans. Volumes of interest were delineated on the 20-40 min 18F-FET PET acquisition co-registered to contrast enhanced T1-weighted MRI. The two scans were compared by calculating the absolute change between healthy appearing cortex (B), the maximal and the mean tumour uptake normalized to B (Tmax/B; Tmean/B) and by measuring the biological tumour volume (BTV) defined as uptake above 1.6mL of mean in healthy appearing brain. The absolute change in FET tumour metrics, mean (range): Tmax/B: NP=0.12[-0.11;0.52] P=0.16[-0.11;0.82]; Tmean/B: NP=0.20[-0.06;2.00] P=0.06[-0.03;0.22]; BTV(mL): NP=0.76[-1.50;3.30] P=2.59[-0.02;12.0]. All results were non-significant with a p-value>0.05. Tumour day-to-day variation might be greater than first anticipated, and the repeatability of FET-PET scans of gliomas needs to be further investigated. Updated results will be presented.
Is chemotherapy worthwhile in patients with high-risk, lymph node negative, FIGO stage 1, endometrial cancer?
Authors: C. Fontanella, A. Barcellini, M.G. Vitale, S. Lepori, G. Maltese, E. Tripodi, A. Cerrotta, F. Martinelli, C. Andreetta, G. Bogani, A. Ditto, M. Signorelli, C. Scaffa, C. Sacco, F. Raspagliesi, D. Lorusso
Journal: Annals of Oncology (2017)
A single institution twenty-year experience of recurrent or metastatic epithelial non glandular sinonasal cancer
Authors: S. Cavalieri, R. Granata, L. Locati, C. Bergamini, S. Alfieri, C. Resteghini, D. Galbiati, E. Orlandi, N.A. Iacovelli, G. Calareso, M. Guzzo, P. Quattrone, L. Licitra, P. Bossi
Journal: Annals of Oncology (2017)
P3.16-019 Prognostic Factors for Resected Non-Small Cell Lung Cancer in Patients with Type 2 Diabetes Mellitus
Authors: W.S. Yu, J.G. Lee, J.W. Suh, S.Y. Park, C.Y. Lee, D.J. Kim, K.Y. Chung
Journal: Journal of Thoracic Oncology (2017)