tbuckley/cabot-search huggingface dataset:
QLIF-12. HEALTH-RELATED QUALITY OF LIFE RESULTS FROM THE RANDOMIZED PHASE II TAVAREC TRIAL ON TEMOZOLOMIDE WITH OR WITHOUT BEVACIZUMAB IN 1p/19q INTACT FIRS RECURRENCE WHO GRADE II AND III GLIOMA (EORTC 26091)
Authors: Jaap C Reijneveld, Corneel Coens, Martin J B Taphoorn, Peter Sillevis Smitt, Paul M Clement, Ahmed Idbaih, Filip de Vos, Martin Klein, Wolfgang Wick, Paul Mulholland, Joanne Lewis, Vassilis Golfinopoulos, Andrew Bottomley, Martin van den Bent
Journal: Neuro-Oncology (2017)

In an international randomized controlled phase II study of temozolomide (TMZ) vs TMZ in combination with Bevacizumab (BEV) in locally diagnosed non-1p/19q co-deleted grade II or III glioma with a first and contrast-enhancing recurrence after initial radiotherapy, overall survival at 12 months (OS12) was not significantly different (61% in the TMZ arm and 55% in the TMZ+BEV arm). Health-Related Quality of Life (HRQoL) was a key secondary endpoint in this trial, and the main objective was to determine the impact of addition of BEV to TMZ on HRQoL. HRQoL was assessed using the EORTC QLQ-C30 (version 3) and QLQ-BN20 at baseline, and then every 12 weeks until progression of disease. The primary HRQoL endpoint was the QLQ-C30 global health scale, with cognitive functioning and pain selected as secondary HRQoL issues. Analysis was done using linear mixed modeling and complimented with sensitivity analyses using summary statistics and imputation of missing data. A clinical difference of ≥10 points on the 100-point QLQ-C30 scale between the two arms was considered as clinically relevant. Baseline compliance was high at 94%, and remained above 60% until 72 weeks, limiting the analysis to 60 weeks. Compliance was similar in both arms. We found no statically significant or clinically significant differences between the primary HRQoL endpoints of both treatment arms (P=0.2642). The sensitivity analyses confirmed this finding. We observed no statistical or clinical significant differences regarding the selected secondary endpoint scales of cognitive functioning and pain. Among the other scales, social functioning (P=0.0254), physical functioning (P=0.0388) and itchy skin (P=0.0364) were significantly in favor of the TMZ arm, while motor dysfunction (P=0.0285) scores were better in the TMZ+BEV arm. INTERPRETATION: The addition of BEV to TMZ in this patient group neither improves nor negatively impacts HRQoL.
Analysis of miRNAs and their correlation with early malignat melanoma (MM)
Authors: M. Occelli, L.o. Nigro, D. Vivenza, C. Cauchi, G. Sciancalepore, M. Rovera, V. Silvia, C. Varamo, B. Martinoglio, Z. Seia, P. Bosio, F. Errico, F. Lavagna, G. Forte, S. Palazzini, L. Quaranta, D. Basso, S. Gervasio, M.C. Merlano
Journal: Annals of Oncology (2017)
Augmentation significative de la listériose en Allemagne – caractéristiques épidémiologiques, 2001-2005
Authors: J Koch, K Stark
Journal: Eurosurveillance (2006)

En Allemagne, la listeriose est une maladie a declaration obligatoire depuis janvier 2001. Les cas cliniques avec isolement de Listeria monocytogenes a partir de sites steriles ou chez les nouveaux-nes sont rapportes a l’institut Robert Koch. L’incidence de la listeriose a augmente de maniere significative de 0,26 pour 100 000 habitants (217 cas) en 2001 a 0,62 pour 100 000 habitants (519 cas) en 2005. L’augmentation ne concernait que les cas d’infections non materno-neonatales et etait due essentiellement a un accroissement du nombre de cas dans le groupe d’âge ≥60 ans. Les taux d’incidence les plus eleves ont ete detectes chez les nouveau-nes et les personnes âgees de ≥70 ans. Les hommes etaient les plus affectes, a l’exception des cas survenus chez des adultes en âge de procreer. Le taux global de mortalite etait de 9%. Aucun cluster de cas n’a ete identifie dans le temps ou l’espace, ni aucune epidemie avec source d’infection commune. 
Dans 46% des cas, un cancer comme pathologie sous-jacente a ete rapporte comme facteur predisposant. Les raisons de l’augmentation de la listeriose en Allemagne n’ont pas encore ete elucidees. Le nouveau programme de surveillance mis en place ainsi qu’un meilleur diagnostic ne permettent pas d’expliquer l’augmentation particulierement elevee du taux d’incidence de la maladie entre 2004 et 2005. Il est possible que la contamination accrue des denrees alimentaires courantes, l’evolution des pathologies sous-jacentes ou des options therapeutiques aient pu contribuer a cette augmentation. Un programme de surveillance de la listeriose a ete mis en place en 2005 afin de recueillir des informations plus detaillees sur le deroulement clinique, les pathologies sous-jacentes, le traitement medical, la connaissance de la listeriose et les eventuels facteurs de risque alimentaires aupres de tous les cas nouvellement diagnostiques. Pour faciliter la detection des epidemies, la mise en place d’un systeme national de surveillance renforcee pour le sous-typage moleculaire des souches de listeria isolees chez l’homme et dans les produits alimentaires est necessaire. Les recommandations de prevention devraient etre etendues a tous les groupes a risque presentant un terrain predisposant.
Abstract 13086: The Impact of Glycemic Variability on Mortality in Patients With Diabetes Hospitalized With Acute Heart Failure
Authors: Livia Trasca, Roxana Cristina Rimbas, Ileana Nitu, Simona Ionela Calin, Andreea Velcea, Anca Andreea Andronic, Dragos Vinereanu
Journal: Circulation (2016)

Hypothesis: Acute heart failure (AHF) in patients with diabetes is associated with increased mortality, however the impact of glycemic variability is unclear. Methods: We screened our database within 1 year to identify patients with AHF and diabetes. The glucose variables of interest were: hypoglycemia (glucose blood level &lt;70 mg/dl); glycated haemoglobin (HbA1c); admission glycemia; mean glycemia index (MGI), defined as mean of all fasting glucose blood levels measured during hospitalization; and glycemic lability index (GLI), calculated by a validated formula, using successive glucose measurements and times between measurements. All these parameters were added to conventional potential prognostic markers: left ventricular ejection fraction (LVEF), admission systolic/diastolic blood pressure (SBP/DBP) and mean of all measurements during hospitalization (SBPm/DBPm), presence of respiratory failure, mechanical ventilation, atrial arrhythmias, troponin I and NTproBNP values, admission renal function (GRF) and mean of all measurements during hospitalization (GRFm). The outcome was in-hospital mortality. Results: 113 patients (70±10yrs, 56% men) were identified. 13 patients (12%) died. Admission glycemia (341±81 vs 228±105 mg/dl), MGI (287±108 vs 164±38 mg/dl), GLI (18161±24774 vs 6408±18108 mg/dl 2 /h) were higher in non-survivors, whereas LVEF (22±12 vs 34±12%), SBP (102±43 vs 154±43 mmHg), SBPm (92±37vs127±25 mmHg), DBPm (76±11vs.56±24), and GRFm (37±22 vs 57±27 ml/min) were lower (all p&lt;0.01). Presence of atrial arrhythmias, respiratory failure, but not mechanical ventilation was higher in non-survivors; hypoglicemia, HbA1c, troponin I, NTproBNP, and GRF were similar. Only MGI≥188 mg/dl and LVEF≤28% were independently associated with in-hospital mortality (Figure). Conclusions: Parameters of glycemic variability and LVEF are associated with in-hospital mortality in patients with diabetes hospitalized with AHF.
EXTH-35. STEADY STATE BRAIN EXTRACELLULAR FLUID AND PLASMA PHARMACOKINETICS OF LETROZOLE IN SPRAGUE DAWLEY RATS: GENDER DIFFERENCES AND PROJECTIONS FOR TUMORAL DRUG LEVELS
Authors: Priyanka Arora, Courtney Huff, Nimita Dave, Gary Gudelsky, Pankaj Desai
Journal: Neuro-Oncology (2017)

Our recent studies indicate that aromatase, a cytochrome P450 (CYP) enzyme (CYP19A1), which catalyzes the conversion of androgens to estrogens, may be a novel druggable target for the treatment of high-grade gliomas (HGG). Additionally, letrozole, a potent aromatase inhibitor, exhibited marked activity against C6 glioma in Sprague-Dawley rats. Here, we conducted extensive single dose and steady state plasma and brain extracellular fluid (ECF) pharmacokinetics (PK) of letrozole in both female and male rats to facilitate further evaluation of its anti-HGG efficacy. We employed age-matched (65–74 days) adult female (200–225 g; N = 13) and male (300–325 g; N = 12) jugular vein cannulated Sprague-Dawley rats. Letrozole (4mg/kg) was administered intraperitoneally daily for 5–10 days. Serial blood and ECF samples (using intracerebral microdialysis) were collected and letrozole was quantitated employing an HPLC method. Marked gender-dependent difference in letrozole PK were observed with both plasma and brain ECF levels being markedly higher in female rats relative to those in male rats. For instance, the steady state peak plasma and ECF letrozole levels in female rats were 4.8 µg/ml and 2.3 µg/ml, respectively. For male rats, the corresponding values were 1.0 and 0.5 µg/ml. Likewise, the steady state plasma and brain ECF area under the curve (AUC) values were 4–5 fold higher in female rats. The steady state terminal half-life (t1/2) in female rats was markedly higher (36 ± 2 h), relative to that in male rats (13 ± 3 h). A preliminary assessment of the letrozole levels in C6 tumors excised 25 days post implantation indicated that the steady state tumor levels were in the range of 4–10 µg/g of tumor tissue. These results are facilitating dose optimization for further pre-clinical pharmacology and toxicology assessments. In addition, PK-modeling based projections will aid initial dose determination in future clinical studies.
ANGI-09. δ-Catenin Regulates Bevacizumab-Induced Glioma Invasion
Authors: Toshihiko Shimizu, Kazuhiko Kurozumi, Joji Ishida, Tetsuo Oka, Yoshihiro Otani, Yusuke Tomita, Yasuhiko Hattori, Atsuhito Uneda, Yuji Matsumoto, Tomotsugu Ichikawa, Isao Date
Journal: Neuro-Oncology (2017)

Glioblastoma is one of the most aggressive intracranial neoplasms in humans. The addition of bevacizumab to the conventional standard therapy for newly diagnosed glioblastoma prolonged the progression-free survival time, but it failed to extend overall survival time. While bevacizumab potently suppresses angiogenesis, it has also been reported to cause invasive proliferation. We evaluated the effects of bevacizumab on the invasiveness of glioma cells and determined target genes involving in the regulation of bevacizumab-induced invasion. Human glioma U87ΔEGFR cells were stereotactically injected into the brains of animals. Bevacizumab was administered intraperitoneally three times per week. At 18 days after tumor implantation, the brains were removed for histopathology observations and mRNA was extracted from the orthotopic U87ΔEGFR glioma cells. Gene expression was assessed by qRT- PCR arrays, which included factors such as adhesion molecules. Expression of genes-of-interest was compared between the bevacizumab and control groups. In addition, the cytotoxicity of bevacizumab and its effect on U87ΔEGFR, U251MG, A172, and Gli36 invasiveness were investigated. Expression of key factors was targeted by siRNA, and shRNA knockdown, and cell invasiveness was analyzed. In vivo, bevacizumab treatment increased glioma cell invasion, despite reducing angiogenesis. qRT-PCR array analysis revealed upregulation of δ-catenin (CTNND2) and several other factors, and δ-catenin was especially upregulated. Down regulation of δ-catenin by shRNA decreased bevacizumab-induced glioma invasion on murine xenograft models. In vitro experiments showed that a low concentration of bevacizumab was not cytotoxic, but tumor cell motility was increased. And δ-catenin was upregulated by a low dose of bevacizumab treatment. Silencing of δ-catenin decreased the bevacizumab-induced glioma invasion. This study showed that some ECM factors were changed, and glioma cell invasion was induced during bevacizumab therapy. The findings suggest that δ-catenin regulates bevacizumab-induced glioma cell invasion, and may be a novel target for glioma treatment.
ACTR-46. AG-120, A FIRST-IN-class MUTANT IDH1 INHIBITOR IN PATIENTS WITH RECURRENT OR PROGRESSIVE IDH1 MUTANT GLIOMA: UPDATED RESULTS FROM THE PHASE 1 NON-ENHANCING GLIOMA POPULATION
Authors: Ingo K Mellinghoff, Mehdi Touat, Elizabeth Maher, Macarena De La Fuente, Timothy F Cloughesy, Matthias Holdhoff, Gregory M Cote, Howard Burris, Filip Janku, Ray Huang, Robert J Young, Benjamin Ellingson, Tara Nimkar, Liewen Jiang, Yuko Ishii, Sung Choe, Bin Fan, Lori Steelman, Katharine Yen, Chris Bowden, Susan Pandya, Patrick Y Wen
Journal: Neuro-Oncology (2017)

Isocitrate dehydrogenase 1/2 (IDH1/2) mutations occur in >70% of low-grade gliomas (LGG) and lead to an altered metabolic state associated with production of D-2-hydroxyglutarate (2-HG), resulting in genetic/epigenetic dysregulation and oncogenesis. AG-120 is a potent oral inhibitor of mutant IDH1 (mIDH1) under clinical evaluation in an ongoing phase 1 study that treated 66 pretreated (median 2 prior systemic therapies) glioma patients in dose escalation and expansion cohorts. Safety and preliminary results were presented previously (SNO2016). We present updated results from the non-enhancing glioma patient population. Key eligibility: mIDH1 recurrent or progressive disease, ECOG 0–1, no surgery/radiation within 6 months. MRI response was assessed every 8 weeks using RANO and LGG-RANO criteria by local and independent central review. Exploratory analyses: change in tumor growth rate (FLAIR tumor volume, non-enhancing glioma expansion cohort) and pharmacodynamic evaluations of tissue and serum. As of 10March2017, 35 patients with non-enhancing glioma were enrolled in dose escalation (n=11) and expansion (n=24), and 51% (n=18) remain on AG-120. M/F 23/12, median age 38 years, 1p19q intact in 54% (n=19) of patients, 74% reported anticonvulsant use. Frequent (≥5 patients) adverse events (AEs) grade 1–2: diarrhea (26%), headache (26%), nausea (20%), anemia (17%), neutrophil decrease (17%), and vomiting (17%). 7 (20%) patients experienced a grade 3–4 AE (hypophosphatemia most frequent, n=2, unrelated), with no dose reduction due to AEs. 73% and 88% of patients achieved stable disease as best response in the dose escalation (RANO) and expansion (LGG-RANO) cohorts, respectively. Median duration on AG-120 was 14.7 months (range 1.4–25.0); 63% remained on AG-120 for ≥1 year. Updated safety, response, and exploratory imaging analyses will be presented. AG-120 monotherapy is associated with a favorable safety profile and prolonged stable disease in a previously treated non-enhancing mIDH1 glioma patient population, and warrants further clinical evaluation.
TMIC-01. ALERTING THE IMMUNE SYSTEM BY REMOVING EPIGENETIC SILENCING OF TH1 CHEMOKINES
Authors: Heather Sonnemann, Amber Giles, Jinkyu Jung, Caitlin Reid, Marsha-Kay Hutchinson, Deric M Park, Mark Gilbert
Journal: Neuro-Oncology (2017)

Solid tumors employ multiple mechanisms to evade immunologic detection and destruction. However, the potential to enhance the immune response to cancer has been proven in several malignancies and is under investigation in many others, including primary CNS tumors. Brain tumors, in particular, lack robust T-cell infiltration, suggesting poor immune surveillance. Recent studies have found that tumor cells express T-cell attracting chemokines, CXCL9/10, in response to interferon gamma (IFNg). Chemokine expression can be further amplified by drugs that prevent epigenetic silencing, such as histone methyltransferase inhibitors or histone deacetylase (HDAC) inhibitors. This approach increases T-cell trafficking to tumors in vivo and enhances the anti-tumor efficacy of checkpoint blockade. We hypothesized that T-cell trafficking to brain tumors could be increased by epigenetically enhancing CXCL9/10 expression. Assays were performed on human glioma brain tumor cell lines. CXCL9/10 expression were measured by real-time PCR and Western blot. GSK126, a commercially available methyltransferase inhibitor, was utilized to demethylate histone H3 (K9/K27). LB201 (Lixte Biotechnology, Setatuket, NY) was used to inhibit class 1/2 HDAC. Histone methylation and acetylation status were examined using Western blot analysis. T-cell migration was measured using transwell migration assays. expression of CXCL9/10 was induced by IFNg in brain tumor lines. Chemokine expression was further increased when cells were treated with GSK126 and LB201 compared to IFNg alone. Migration assays confirmed that tumor cells treated with GSK126 and LB201 released T-cell chemotactic factors that increased T-cell migration. These studies demonstrate that brain tumors express T-cell attracting chemokines CXCL9/10 in response to IFNg. Further, GSK126 and the combination of GSK126 and LB201 enhanced expression of CXCL9/10, resulting in increased T-cell migration toward tumor cells. Together, these data provide a potential means to enhance the efficacy of immune therapies for brain tumors by promoting T-cell trafficking toward tumor cells.
MA 10.03 3-Year Survival and Duration of Response in Randomized Phase II Study of Atezolizumab vs Docetaxel in 2L/3L NSCLC (POPLAR)
Authors: K. Park, C. Lewanski, S. Gadgeel, L. Fehrenbacher, J. Mazieres, A. Rittmeyer, J. Han, A. Artal-Cortes, F. Braiteh, M. Gandhi, W. Yu, C. Matheny, P. He, A. Sandler, M. Ballinger, J. Vansteenkiste
Journal: Journal of Thoracic Oncology (2017)
P1.04-002 Tolerability of Osimertinib and Its Impact on Quality of Life in Advanced Non-Small Cell Lung Cancer Patients: The ARPA Study
Authors: E. Capelletto, M.V. Pacchiana, E. De Luca, M.L. Reale, M. Gianetta, S. Novello
Journal: Journal of Thoracic Oncology (2017)
Interobserver Variation among Pathologists and Refinement of Criteria in Distinguishing Separate Primary Tumors from Intrapulmonary Metastases in Lung
Authors: Andrew G. Nicholson, Kathleen Torkko, Patrizia Viola, Edwina Duhig, Kim Geisinger, Alain C. Borczuk, Kenzo Hiroshima, Ming S. Tsao, Arne Warth, Sylvie Lantuejoul, Prudence A. Russell, Erik Thunnissen, Alberto Marchevsky, Mari Mino-Kenudson, Mary Beth Beasley, Johan Botling, Sanja Dacic, Yasushi Yatabe, Masayuki Noguchi, William D. Travis, Keith Kerr, Fred R. Hirsch, Lucian R. Chirieac, Ignacio I. Wistuba, Andre Moreira, Jin-Haeng Chung, Teh Ying Chou, Lukas Bubendorf, Gang Chen, Giuseppe Pelosi, Claudia Poleri, Frank C. Detterbeck, Wilbur A. Franklin
Journal: Journal of Thoracic Oncology (2017)
TMIC-31. MLK4 IS REQUIRED FOR METASTASIS INITIATION IN THE BRAIN
Authors: Heba Allah Alsheikh, Mutsuko Minata, Shinobu Yamaguchi, Shuko Harada, Deniz Peker, Rajeev Samant, Bakhos Tannous, Krishna Bhat, Richard Cerione, Shuxing Zhang, Ichiro Nakano
Journal: Neuro-Oncology (2017)

Patients with breast cancer brain metastases (BCBM) suffer from a devastating outcome despite recent progress in a variety of therapeutic modalities. Triple-negative breast cancer (TNBC) and human epidermal growth factor receptor HER-2 positive breast cancer are the two major breast cancer (BC) subtypes that have a higher risk for developing brain metastases compared to Hormone Receptor-positive subtypes. The mechanisms by which the disseminated tumor cells overcome the multistep defense mechanism in the brain, adapt the microenvironment, and subsequently initiate metastasis foci remain elusive. Mixed lineage kinase 4 (MLK4) is a poorly characterized serine/threonine kinase, which we recently identified as a key molecule for initiation of mesenchymal glioblastoma through activation of the NF-kB signaling. In this study, we sought to determine the expression and function of MLK4 in the process of initiation of BCBM. Through analysis of The Cancer Genome Atlas (TCGA) breast cancer exon sequencing data sets, MLK4 was found to be highly expressed in TNBC in comparison to other subtypes. Staining of human BC & BCBM tissues as well showed relatively higher MLK4 expression in TNBC. Expression profiling revealed that TNBC cells exhibit higher MLK4 expression after being primed with Human brain endothelial cells secretory factors. Silencing MLK4 significantly reduced in vitro colony formation ability as well as in vivo brain metastatic capabilities of TNBC cells, while this effect was not evident after direct injection of TNBC cells into the mouse brain, suggesting that MLK4 is required for the transmigration of disseminated BC cells towards brain parenchyma to initiate brain metastases. For the therapeutic development purpose, we performed the structure-based drug design, leading to identification of a small molecule inhibitor of MLK4. We will test its activity on a set of patient-derived breast cancer cells in vitro and their xenografted tumor mouse models in vivo.
Aumento significativo da listeriose na Alemanha – caracteristicas epidemiológicas, 2001-2005
Authors: J Koch, K Stark
Journal: Eurosurveillance (2006)

Na Alemanha, a listeriose e uma doenca de notificacao obligatoria desde janeiro de 2001. Os casos clinicos com isolamento de Listeria monocytogenes provimdo de sitios estereis ou em recem-nascidos foram notificados ao instituto Robert-Koch. A incidencia da listeriose aumentou de forma significativa de 0,26 por 100.000 habitantes (217 casos) em 2001 a 0,62 por 100.000 habitantes (519 casos) em 2005. O aumento so interessava infeccoes nao materno-neonatais e era principalmente devido ao aumento do numero de casos no grupo de idade ≥60 anos. As taxas de incidencia mais altas foram detectadas em recem-nascidos e pessoas de idade ≥70 anos. Os homens eram os mais afectados, excepto para os casos de adultos em idade fertil. A taxa global de mortalidade foi de 9%. Nao foi identificado nenhum cluster de casos no tempo nem no espaco, nem houve surtos com uma fonte de infeccao comun. 
Em 46% dos casos, um cancer como patologia subjacente foi o factor predisponente. O novo programa de vigilância e as melhoria dos diagnosticos nao parecem razoes suficientes para explicar o aumento da incidencia da doenca entre 2004 e 2005. E possivel que a contaminacao crescente dos alimentos mais consumidos, a evolucao das patologias subjacentes ou as opcoes terapeuticas tenham contribuido para este aumento. Um projeto para reforcar a vigilância da listeriose foi implementado em 2005 para recolher informacoes mais detalhadas sobre o desenvolvimento clinico, as patologias subjacentes, os tratamentos medicos, o conhecimento da listeriose e os eventuais factores de risco alimentares de todos os casos recentemente diagnosticados. Para facilitar a deteccao dos surtos e preciso um sistema nacional de sub-tipagem molecular das estirpes de listeria. As recomendacoes de prevencao deveriam ser extendidas a todos os grupos de risco apresentando condicoes predisponentes.