tbuckley/cabot-search huggingface dataset:
TMOD-22. WILD-TYPE p53 DRIVES A MESENCHYMAL PHENOTYPE AFTER TREATMENT OF PRIMARY GLIOBLASTOMA
Authors: Li Li, Vamsidhara Vemireddy, Tomoyuki Mashimo, Paula Huntington, Bruce Mickey, Elizabeth Maher, Robert Bachoo, Sara GM Piccirillo
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is the most common and aggressive adult brain malignancy for which conventional surgery, radiation treatment and chemotherapy based on alkylating agent Temozolomide (TMZ) have limited benefit. Overall survival is variable but less than 10% of GBM patients survive 5 years, making it one of the most aggressive and clinically intractable cancers. The main cause of poor prognosis is the rapid emergence of recurrent disease, despite extensive removal of cancer cells from the primary site. Here, by using patient-derived xenografts we demonstrate that GBM is fueled by a mixture of fast- and slow-cycling cells. In vivo, treatment based on TMZ triggers a transient cell arrest in G2/M and DNA damage but does not promote cell death. In particular, by causing DNA double strand breaks, TMZ induces the autophosphorylation of ataxia telangiectasia mutated (ATM S1981) and the downstream phosphorylation of histone H2AX (YH2AX). In response to TMZ, GBM cells undergo a transient switch to a p53-driven mesenchymal phenotype with significant up-regulation of CD44, Vimentin and Gfap expression. The transient phenotype switch is followed by down-regulation of p53 and the emergence of treatment-resistant GBM. Illumina-based gene expression profiling and marker analysis reveal striking similarities between matched control and treatment-resistant tumors. ChIP-seq experiments are currently ongoing to identify critical nodes of phenotype switch. We are also using genetically-engineered mouse models of gliomas to understand if wild-type p53 drives a mesenchymal phenotype in Nestin-, Gfap-, Glast-, ApoE- and Pla2-derived tumors. Altogether, these results contribute to increase our knowledge of the biology of GBM growth and treatment resistance and identify p53 as a driver of phenotypic plasticity.
HOUT-28. OFF-LABEL USE OF PD-1 BLOCKADE WITH OR WITHOUT BEVACIZUMAB CONFERS ONLY LIMITED CLINICAL BENEFIT IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA
Authors: Sylvia Eisele, Lais Cabrera, David Hastie, David Reardon, Mikael Rinne, Lakshmi Nayak, Eudocia Lee, Patrick Wen
Journal: Neuro-Oncology (2017)

The PD-1 targeting antibodies nivolumab and pembrolizumab are intensely investigated as promising therapies for newly-diagnosed and recurrent high-grade gliomas. Outside of clinical trials, these agents are also offered off-label to patients who have exhausted conventional chemotherapies or are not eligible to participate in a clinical study. If such practice confers any clinical benefit has been insufficiently studied. We performed a single-institution retrospective observational study in 25 adult patients who received nivolumab (n=7) or pembrolizumab (n=18) off-label for recurrent high-grade glioma (IDH-1 mutant n=7, IDH-1 wild-type n=18). All patients had previously undergone tumor resection, radiation and temozolomide. At time of recurrence patients received various therapies including bevacizumab (n=18). Clinical and radiological (RANO) assessments were performed every two and eight weeks, respectively, or as clinically indicated. Patients received a median of four (range 1-20) doses of nivolumab or pembrolizumab. Twenty-one patients (84%) developed disease progression, two patients (8%) had mixed response, one patient (4%) had stable disease and one patient was lost to follow-up. Median progression free-survival and median survival from initiation of PD-1 blockade was 2.3 month (95% CI 0.8 3.6) and 4.9 months (95% CI, 2.4-7.25). No dose-limiting toxicites were observed. There was no significant difference in median survival of patients receiving PD-1 blockade for early (1st and 2nd, n=16) vs. late (≥3rd, n=9) recurrence (4.9 months, 95% CI 1.1-12.4 vs. 4.5 months 95% CI 3.5-7.3; p=0.7). There was also no significant difference in survival of patients that were bevacizumab naïve (2.4 months, 95% CI 0.75-not reached) compared to patients who had received bevacizumab (5.1 months, 95% CI 3.5-7.6) prior to initiation of PD-1 blockade (p=0.5). Eighteen patients were deceased at time of last follow-up. The median time to death from the last dose of PD-1 blockade was only two (range 0-6.5) months (95% CI 0.8-2.7).
CBIO-11. UPREGULATION OF THE TGF-β PATHWAY DRIVES TRANSFORMATION OF GLIOBLASTOMA INTO GLIOSARCOMA AND OSTEOSARCOMA
Authors: Aiguo Li, Surabhi Ranjan, Susie Ahn, Orieta Celiku, Sun A Kim, Martha Quezado, Edjah Nduom, Mark R Gilbert, Deric M Park
Journal: Neuro-Oncology (2017)

Gliosarcoma, a histopathological variant of glioblastoma, is defined by clonal biphasic differentiation into gliomatous and sarcomatous components. The underlying molecular mechanisms driving the transformation of glioblastoma to gliosarcoma are unclear. We observed a patient with glioblastoma that transformed to gliosarcoma at disease recurrence, and further evolved to an osteosarcoma at second disease relapse. Our objectives were to characterize the molecular mechanisms of tumor progression associated with phenotypic transformations. Tumor samples were collected at all three stages, and RNA sequencing was performed to capture the transcriptomic profiles. Sequential clonal evolution was confirmed by maintenance of identical PTEN mutation throughout the transformations. Applying EdgeR, DEseq2 and limma/voom to the data, we derived approximately 7,000 differentially-expressed genes by mutual comparisons between disease stages. Functional analysis identified TGFB1 as a key regulator driving the tumor transformation -- a signature of 600 TGFB target genes and TGFB signaling pathways were upregulated. An active mesenchymal signature and significant increase in expression of mesenchymal transcriptional regulators (SNAI2, TWIST1) was observed at gliosarcoma stage. In addition, cellular migratory and angiogenic signatures were enhanced in the gliosarcoma stage. During transformation to gliosarcoma, neuronal developmental pathways, notch signaling, and PDGF signaling decreased. These results were validated via an independent external GBM and gliosarcoma dataset. The third stage of the tumor transformation was additionally characterized by upregulation of RUNX2 transcriptional regulator and an osteosarcoma network. These findings will be confirmed by examining additional primary and secondary gliosarcomas, and de novo osteosarcoma. This unusual clinical case provides an opportunity to explore the modulators of sarcomatous transformation. Improved understanding of the underlying molecular mechanisms may contribute to identification of novel therapeutic targets in this disease.
Actualización de los datos sobre la enfermedad asociada a Clostridium difficile debida al ribotipo 027 de RCP en Europa
Authors: E J Kuijper, B Coignard, J S Brazier, C Suetens, D Drudy, C Wiuff, H Pituch, P Reichert, F Schneider, A F Widmer, K Ep Olsen, F Allerberger, D W Notermans, F Barbut, M Delmée, M Wilcox, A Pearson, B Patel, D J Brown, R Frei, T Akerlund, I R Poxton, Peet Tüll
Journal: Eurosurveillance (2007)

Los recientes brotes epidemicos de diarrea asociada a Clostridium difficile (DACD), de mayor intensidad y con una elevada tasa de recidivas y una mortalidad importante, han sido relacionados con la aparicion de una nueva cepa hipervirulenta de C. difficile en Norteamerica, Japon y Europa.
Vers une meilleure surveillance de la résistance aux antituberculeux en Europe
Authors: M. C. Raviglione, M A Espinal
Journal: Eurosurveillance (2000)

Au cours des dix dernieres annees, le renforcement de la surveillance de la tuberculose (TB) est devenu une priorite de sante publique en Europe. Alors qu’en Europe de l’Ouest, la precedente tendance a la baisse de l’incidence de la tuberculose s’est attenuee, les taux de declaration en Europe de l’Est ont fortement augmente, allant souvent jusqu’a doubler (1). Cette situation a pousse les epidemiologistes et les experts de sante publique a revoir la meilleure facon de controler l’epidemie. Il fut rapidement evident qu’il n’existait pas de standard de surveillance clairement defini. Les definitions et les systemes d’information variaient considerablement d’un pays a l’autre, rendant les comparaisons internationales au niveau regional tres difficiles.
MNGI-02. PREOPERATIVE EMBOLIZATION OF MENINGIOMA: INFERIOR NEUROLOGICAL OUTCOME, INCREASED RISK OF CARDIOVASCULAR COMPLICATIONS AND SHORTER TIME TO RECURRENCE?
Authors: Hans-Georg Wirsching, Johannes Konstantin Richter, Felix Sahm, Corinne Morel, Niklaus Krayenbuehl, Elisabeth Jane Rushing, Andreas von Deimling, Antonios Valavanis, Michael Weller
Journal: Neuro-Oncology (2017)

Preoperative embolization of radiographically suspected meningiomas is often performed to facilitate subsequent tumor resection. Its effects on the post-operative course have not been studied in detail and randomized trials are lacking. To gain insight into the role of tumor embolization, we conducted a retrospective study in all patients undergoing resection of an intracranial meningioma at the University Hospital Zurich 2000-2013 with a post-operative follow-up of at least 3 months (N=741). Patients were reviewed for the inclusion of pre-operative embolization in the management strategy. Annotations included demographics, radiographic, surgical, histological and hematological parameters, cardiovascular risk factors, pre- and postoperative neurological function and genome-wide methylation-based classification. Binary regression and Cox proportional hazards models were applied to determine factors associated with outcome. Pre-operative embolization was performed in 337 patients (42%). The decision for embolization was associated with larger tumor size and presence of peritumoral edema. On multivariate analyses controlling for established prognostic factors, pre-operative embolization was associated with inferior post-operative neurological outcome (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.30-2.63), whereas gross total resection was associated with better neurological outcome (OR 0.59, 95% CI 0.39-0.87). Cardiovascular events after surgery comprised mostly deep vein thrombosis (N=39) and pulmonary embolisms (N=64). There were also associations with embolization (OR 2.38, 95% CI 1.37-4.00) and female gender (OR 2.18, 95% CI 1.17-4.08). Recurrence-free survival (RFS) of embolized patients was less favorable among patients with WHO grade II or grade III meningiomas (median RFS: 4.3 versus 7.0 years, multivariate hazard ratio [HR] 1.92, 95% CI 0.97-3.79, p=0.062) or in patients with intermediate or malignant gene methylation subtype meningiomas (median RFS: 2.0 versus 8.2 years, multivariate HR 8.66, 95% CI 3.00-25.05, p<0.001). Pre-operative meningioma embolization may cause adverse surgical outcomes. Randomized trials to determine benefit-risk ratios are warranted to clarify the role of pre-operative embolization for meningioma surgery.
Emergence d'une nouvelle souche de SARM communautaires en Allemagne
Authors: W Witte, C Cuny, B Strommenger, C Braulke, D Heuck
Journal: Eurosurveillance (2004)

L'analyse des Staphylococcus aureus resistants a la methicilline communautaires (co-SARM) produisant la leucocidine de Panton-Valentine en Allemagne montre un profil de macrorestriction unique, different des souches epidemiques nosocomiales. Ce profil moleculaire correspond a celui de souches de co-SARM isolees dans d'autres pays de l'Union europeenne. Tous les isolats montraient une resistance a l'acide fusidique, code par le gene far-1. D'apres les donnees sur la dissemination geographique et la periode d'apparition de cette souche, elle serait apparue en Allemagne dans la seconde moitie de 2002, ce qui laisse supposer une dissemination plus large. L'emergence de SARM resistants a l'acide fusidique est le premier signe de l'emergence d'un clone de SARM PVL-positif.
NIMG-61. USE OF TEXTURAL RADIOMIC MAPS IN A 3D CONVOLUTIONAL NEURAL NETWORK FRAMEWORK CAN AUGMENT GLIOMA LESION SEGMENTATION
Authors: Ayush Karnawat, Prateek Prasanna, Anant Madabhushi, Pallavi Tiwari
Journal: Neuro-Oncology (2017)

Gliomas, one of the most common primary brain malignancies, exhibit phenotypically heterogeneous histological sub-regions (edema ED, necrotic core N, enhancing E, non-enhancing NE), each containing relevant diagnostic and prognostic information. Segmentation of these sub-regions in multimodal MRI is a major challenge, and usually performed manually. In this work, we hypothesize that radiomic features capturing sub-visual heterogeneity information on routine MRI (T1c, T2w, FLAIR), in conjunction with a Convolutional Neural Network (CNN) classifier will improve identification of lesion boundaries and hence improve segmentation, as compared to using intensity alone. 221 high grade glioma studies were acquired from the BraTS 2016 challenge. After sequence co-registration, all cases were skull-stripped and normalized to correct for intensity inhomogeneity. Ground truth sub-compartment delineations were obtained from clinical experts. Four gray-level co-occurrence features were extracted from each MRI protocol. A 3D CNN was trained on N=154, validated on N=33, and tested on N=34 using original intensities and extracted feature maps. The architecture comprised eleven layers: eight convolutional-pooling layers followed by two fully connected layers and one classification layer. Both fully connected layers had 150 neurons connected to the two final neurons to determine voxel sub-type. We compared the performance of our model against a standard intensity-trained model and other similar intensity-trained pipelines from the challenge. Dice Similarity Coefficient (DSC) scores were used to evaluate segmentation performance. Using radiomic-CNN, there was an improvement in the DSC scores (0.82 and 0.80) for non-enhancing and enhancing tumor respectively as compared to the intensity-only CNN (0.79 and 0.79). In comparison to 18 segmentation methods, our method performed better (0.90 vs. 0.84-0.87) in segmenting tumor core (N+E+NE) and enhancing region (0.80 vs. 0.72-0.76), and comparable in segmenting whole tumor (ED+N+E+NE). Our results suggest that radiomic features in conjunction with 3D CNNs can augment lesion segmentation performance.
STEM-01. INVESTIGATING ASPM FUNCTION IN REGULATION OF CELL DIVISION MODE OF OLIGODENDROCYTE PROGENITOR CELLS
Authors: Malek Chouchane, Claudia Petritsch
Journal: Neuro-Oncology (2017)

Our past studies in mouse models of glioma have shown that the switch from asymmetric, self-sustaining to symmetric, self-renewing divisions is a critical step in the neoplastic transformation of oligodendrocyte progenitor cells (OPC). Just how the asymmetric-to-symmetric cell division mode switch is regulated is not known and yet the development of therapies specifically interfering with aberrant symmetric cell divisions will depend on defining the effect of glioma-associated genetic alterations on cell division mode. The objective of the presented work is to test if active receptor tyrosine kinases, in particular PDGFRa and EGFR, which are frequently altered in glioma, promote symmetric OPC divisions through activation of abnormal spindle microcephaly-associated, Aspm. The central hypothesis to be tested is that Aspm mRNA expression is upregulated by constitutive-active receptor tyrosine kinase and that elevated levels of Aspm protein, as frequently found in glioma cells, positively regulates symmetric divisions of OPC and thereby promotes tumor growth. We will achieve our objective by determining the subcellular localization of Aspm protein using immunocytochemistry. Aspm transcript levels will be measured by real-time PCR in OPC with Cre-inducible, constitutive-active PDGFRalpha signaling isolated from transgenic mice. We will conduct time lapse imaging of mutant OPC to determine if increased PDGFRalpha signaling and elevated Aspm levels positively regulate symmetric cell division mode and increases proliferation rate and decrease differentiation. Preliminary data to be discussed at the meeting have identified that Aspm is expressed in proliferative cells and localizes to microtubules. We have preliminary evidence showing that Aspm expression is upregulated by PDGFA activation of PDGFRalpha signaling. We expect to demonstrate that the switch of cell division mode is regulated by an extrinsic signal through modulation of Aspm levels.
CBIO-13. MicroRNA-93 REGULATES TUMORGENICITY AND RESPONSES TO THERAPIES OF GLIOBLASTOMA THROUGH AUTOPHAGY PATHWAY
Authors: Tianzhi Huang, Xuechao Wan, Ichiro Nakano, Erik Sulman, Bo Hu, Shiyuan Cheng
Journal: Neuro-Oncology (2017)

Macroautophagy (autophagy) is an evolutionarily conserved process that degrades damaged proteins and organelles in a lysosome-dependent manner. It is established that autophagic activity is critical for aggressive growth of tumors and contribute to tumor survival when challenged by targeted therapies. Previous studies also indicate that the first line clinical treatments for glioblastoma (GBM), the most malignant brain cancer such as radiation therapy (RT) and temozolomide (TMZ) also induce autophagy, thereby resulting in tumor resistance to these therapies. MicroRNAs (miRNAs) are small RNAs that act as post-transcriptional regulators of gene expression and dysregulated miR expression plays an important role in cancer. The objective of this study is to whether miRNAs regulate tumorigenic behaviors and therapy response of GBM through modulating autophagic activity. Here, we determined miRNA expression profiles in patient-derived glioma stem cells (GSCs), and GBM tumors using The Cancer Genome Atlas (TCGA) data. We found that miR-93 was expressed at low levels in mesenchymal (MES) subtype tumors compared with proneural (PN) GBM. Lower levels of miR-93 expression are associated with poorer prognosis of GBM. Overexpression of miR-93 in MES GSCs reduced self-renewal and tumorigenicity in immune-compromised mice, whereas antagonizing miR-93 function in PN GSCs promoted cell growth in vitro and tumor growth in the brain of animals. By in silico prediction following experimental validation, we show that miR-93 has a suppression effect on autophagic activity in GSCs through simultaneously targeting multiple autophagy regulators, namely, BECN1, ATG5, ATG4B and SQSTM1. Moreover, RT and TMZ induce autophagy by decreasing miR-93 expression that in turn up-regulate activities of autophagy in GSCs. Inhibition of autophagy by miR-93 overexpression or suppression of autophagy enhanced therapeutic efficacy on GBM by treatments with RT and TMZ. Collectively, our findings provide novel insights for understanding miR regulation of autophagy that modulates tumorigenicity and therapy responses of GBM.
ACTR-05. THE RANDOMIZED PHASE II ARTE TRIAL: BEVACIZUMAB PLUS HYPOFRACTIONATED RADIOTHERAPY VERSUS RADIOTHERAPY ALONE IN ELDERLY PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Michael Weller, Ghazaleh Tabatabai, Ulrich Roelcke, Andreas Hottinger, Francisca Joerger, Andrea Schmid, Ludwig Plasswilm, Daniel Schrimpf, Christoph Mancao, David Capper, Katrin Conen, Thomas Hundsberger, Francesca Caparrotti, Roger von Moos, Christian Riklin, Jörg Felsberg, Patrick Roth, David Jones, Stefan M Pfister, Elisabeth Jane Rushing, Lauren Abrey, Guido Reifenberger, Leonhard Held, Andreas von Deimling, Adrian Ochsenbein, Hans-Georg Wirsching
Journal: Neuro-Oncology (2017)

The addition of bevacizumab to temozolomide-based chemoradiotherapy (TMZ/RT→TMZ) prolonged progression-free survival (PFS), but not overall survival (OS) in patients with newly diagnosed glioblastoma in two double-blind phase III trials. Elderly and frail patients are underrepresented in most clinical trials, but early reports of bevacizumab in glioblastoma suggested preferential benefit in this population. ARTE was a 2:1 randomized, multi-center, open-label trial of hypofractionated RT (40 Gy in 15 fractions) in combination with bevacizumab (10 mg/kg x 14 days) (arm A, N=50) versus RT alone (arm B, N=25) in patients with newly diagnosed glioblastoma aged >65 years. The primary endpoint was median OS. Quality of life (QoL) was monitored by the EORTC QLQ-C30/BN20 modules. Response was assessed by RANO criteria. Exploratory studies included 18F-fluoro-ethyltyrosine positron emission tomography (FET-PET, N=34), as well as whole methylome (N=57) and nanostring gene expression (N=54) analyses. Median PFS was longer in arm A versus arm B (7.6 vs. 4.8 months, p=0.003), but OS was similar (12.1 vs 12.2 months, p=0.8). Clinical deterioration was delayed and more patients came off steroids in arm A versus arm B. Longer PFS in arm A versus arm B was confined to the receptor tyrosine kinase (RTK) I methylation subtype and to the proneural gene expression subtype, but was not observed for patients with RTK II, classical or mesenchymal subtype glioblastoma. Applying a Cox model to OS that controlled for established prognostic factors, we detected an association with age and KPS. Exploration of imaging predictors of OS in this model identified the presence of non-enhancing tumor detected by FET-PET (HR 0.31, p=0.02) as an important prognostic factor. Efficacy outcomes and exploratory analyses of ARTE do not support the notion that bevacizumab generally prolongs survival in elderly glioblastoma patients. However, novel molecular and imaging biomarkers may identify patients with preferential benefit from bevacizumab.
TMIC-08. EXOSOMES AND ACQUIRED TREATMENT RESISTANCE IN CANCER
Authors: Oliver Mrowczynski, A B Madhankumar, Christine Mau, Russell Payne, Becky Slagle-Webb, Elias Rizk, Brad Zacharia, James Connor
Journal: Neuro-Oncology (2017)

Glioblastoma Multiforme (GBM) is the most common CNS malignancy in adults, and even with multimodal therapies, carries a poor prognosis. These tumors are heterogeneous and modify their environment, promoting tumor growth, invasion, and therapeutic resistance. The intratumoral heterogeneity of GBM is accentuated during treatment. Even in the face of surgical resection and adjuvant chemoradiation, the unfortunate but inevitable recurrence and progression of GBM is nearly universal. This mechanism of acquired radiation resistance is not understood. We believe that acquired resistance of GBM is due to exosomes secreted from radiated GBM cells conferring resistance to the local cell population. Exosomes are nanometer cell-derived vesicles containing RNAs and proteins. Growing evidence demonstrates exosomes are instrumental to a cell’s interaction with its microenvironment, and have the ability to transfer information to recipient cells contributing to tumorigenicity. We utilized nanoparticle tracking analysis to analyze characteristics of exosome secretion after exposure to radiation. We used cell proliferation assays and cell survival assays to interrogate radiation derived exosome effects on the local cancer cell population. We assessed the potential of exosome blocking agents as a possible avenue for therapeutic manipulation to abrogate this oncogenic effect. We demonstrate that resistance and proliferative factors in GBM derived exosomes change after radiation exposure. Moreover, radiation derived exosomes have functional impact on tumor cell proliferation and radiation resistance. We also demonstrate the therapeutic potential of exosome blocking agents to inhibit acquired resistance, which develops in nearly all GBM patients. Radiation-derived exosomes cause increases in cellular proliferation and survival in the local cancer cell population and may be the hidden mediators of an ultimately radiation resistant tumor recurrence and the dire prognosis that follows. Adjuvant therapy with exosome blocking agents may be used to inhibit these oncogenic effects, leading to optimal patient outcomes.
P3.02-060 EGFR Mutation Status by Three Sequencing Platforms in 704 Non-Small Cell Lung Cancer (NSCLC) Brazilian Patients
Authors: M. Corassa, V. De Sa, I. Werneck, V. Lima, A. Saito, G. Dal Molin, M. De Macedo, E. Ferreira, D. Carraro, H. Freitas
Journal: Journal of Thoracic Oncology (2017)