tbuckley/cabot-search huggingface dataset:
CSIG-26. HETEROGENEITY OF EGFRvIII-POSITIVE GLIOBLASTOMA STEM CELLS: IMPLICATIONS FOR PERSONALIZED DRUG DEVELOPMENT
Authors: Madan Kwatra, Cory Nanni, Callie Roberts, Shawn Kwatra, Glenn J Lesser, Mark R Gilbert
Journal: Neuro-Oncology (2017)

EGFRvIII, a constitutively active mutant of EGFR, is present in over 20% of glioblastoma patients. To develop pre-clinical models for developing therapies against EGFRvIII-expressing GBMs, we isolated four different EGFRvIII-positive (EGFRvIII+) glioblastoma stem cell lines (GSCs). Molecular characterization of these GSCs revealed that they express different levels of several genes (such as CD133, OLIG2, SOX2, NOTCH1, and transferrin receptor) that are considered as stem cell markers. These molecular differences (or heterogeneity) between EGFRvIII+ GSCs are likely to result in a differential response of these cells to drugs. Additionally, we have identified an EGFRvIII+ GSC line that lacks the wild-type EGFR (wtEGFR) i.e. EGFRvIII+/wtEGFR-. This is a novel finding because it is believed that GBMs that express EGFRvIII also co-express the wtEGFR. In fact, it was shown recently that EGFRvIII activation in GBM is caused by its phosphorylation by the wtEGFR. To begin to understand how EGFRvIII is activated in the setting of GSCs that lack wtEGFR, we used reverse phase protein arrays to compare proteomic profiles of EGFRvIII+/wtEGFR- and EGFRvIII+/wtEGFR+ GSCs. Of the 301 proteins and phosphoproteins examined, sixteen proteins showed significantly different expression. These sixteen proteins are known mediators of EGFR-signaling. Thus, we have shown that EGFR signaling in EGFRvIII+ /wtEGFR+ and EGFRvIII+/wtEGFR- GSCs differs. These difference in EGFR signaling between the two sets of GSCs are likely to result in a differential response to anti-EGFR drugs. Thus, future clinical studies targeting EGFRvIII with EGFR-tyrosine kinase inhibitors would be strengthened by further stratifying EGFRvIII-positive GBM patients.
RARE-06. CANADIAN PATTERNS OF PRACTICE FOR INTRACRANIAL GERM CELL TUMOURS IN ADOLESCENTS AND YOUNG ADULTS
Authors: Andrea Lo, Normand Laperriere, David Hodgson, Eric Bouffet, James Nicholson, Michael McKenzie, Juliette Hukin, Karen Goddard
Journal: Neuro-Oncology (2017)

To describe Canadian patterns of practice for intracranial germ cell tumours (IGCT) in adolescents and young adults (AYA), and to determine factors associated with treatment approaches in this disease. A survey was written containing questions on the management of two 17-year old males, one with localized pineal germinoma and the other with localized pineal non-germinoma germ cell tumor (NGGCT). An invitation to participate anonymously in the survey was e-mailed to 119 oncologists who treat brain tumors across Canada. Seventy-two (61%) of the 119 oncologists participated in the study. For the germinoma case, the most common treatment approaches were whole ventricular radiotherapy (WVRT) and chemotherapy (CH) (57%), WVRT without CH (15%), and craniospinal radiotherapy (CSRT) without CH (10%); of those who recommended WVRT+CH, 57% recommended 24Gy, 20% recommended 18Gy, 9% recommended 36Gy, and 9% stated that the radiation dose would depend on tumour response to chemotherapy. Chemotherapy was included in the treatment of germinoma by 96% of pediatric physicians vs. 54% of adult physicians (P=0.001). The most common treatment approaches for NGGCT were CSRT+CH (38%), WVRT+CH (18%), and pineal gland radiotherapy and CH (13%); of those who chose CSRT+CH, 74% recommended 36Gy, 15% recommended 24Gy, and 4% recommended 18Gy. The selection of craniospinal vs. smaller-volume radiotherapy was not associated with the physicians’ specialty, percentage of practice treating brain tumours, number of IGCT seen in the past 5 years, or size of institution. There is wide variation in the management of IGCT in AYA across Canada. A 17-year old male with a localized pineal germinoma is highly likely to receive chemotherapy if managed by a pediatric physician, while the same patient is much less likely to receive chemotherapy if managed by an adult physician. Future efforts should focus on improving consistency in the management of IGCT in AYA.
P3.07-007 Blockade of the Complement C5a/C5aR1 Axis Impairs Lung Cancer Bone Metastasis
Authors: D. Ajona, C. Zandueta, L. Corrales, H. Moreno, M. Pajares, S. Ortiz-Espinosa, E. Martinez-Terroba, N. Perurena, F. De Miguel, S. Vicent, J. Agorreta, L. Montuenga, F. Lecanda, R. Pio
Journal: Journal of Thoracic Oncology (2017)
Un nuovo rilassamento dei comportamenti preventivi negli omosessuali maschi: ruolo dei progressi terapeutici?
Authors: A Laporte
Journal: Eurosurveillance (2002)

Gli articoli pubblicati in questo numero di Eurosurveillance sull'andamento recente dei comportamenti preventivi negli omosessuali maschi in Spagna, Svizzera e Paesi Bassi, concludono tutti che e in declino la pratica del sesso sicuro. Mettono in evidenza un aumento della pratica della penetrazione anale (quel che sia il tipo di partner), un aumento dei rapporti anali non protetti e dell'eiaculazione nella bocca, in particolare tra partner occasionali. L'aumento delle diagnosi di malattie sessualmente trasmesse acute (gonorrea, sifilide) in diversi paesi europei, illustrato in questo numero dai dati provenienti dai Paesi Bassi, e la prima conseguenza tangibile di questo declino.
P2.08-006 Immunological Biomarkers Characterization in Locally Advanced Non-Small Cell Lung Cancer Treated with Concurrent Chemo-Radiotherapy
Authors: M. Saigi, N. Baixeras, A. Rullan, M. Bergamino Sirvén, A. Navarro-Martin, M. Arnaiz, J.C. Ruffinelli, C. Mesia, R. Palmero, S. Padrones, F. Cardenal, M. Sanchez-Cespedes, E. Nadal
Journal: Journal of Thoracic Oncology (2017)
P1.03-051 Medically Underserved and Geographically Remote Individuals May Be Underrepresented in Current Lung Cancer Screening Programs
Authors: Candice Wilshire, Bretta Mccall, Hannah Modin, Joelle Fathi, Christopher Gilbert, Brian Louie, Ralph Aye, Alexander Farivar, Eric Vallieres, Jed Gorden
Journal: Journal of Thoracic Oncology (2017)
P1.06-013 Latent Tuberculosis in Newly Diagnosed Lung Cancer Patients. An Spanish Prospective Study
Authors: E. Martinez Moreno, C. Esteban Esteban, A. Irigoyen, E. Muñoz Platón, R. Alvarez Cabellos, J. Andrade Santiago, I. Burgueño Lorenzo, J.D. Cardenas, K. Martinez Barroso, A.K. Santos, M. Borregon Rivilla, B. Trujillo Alba, J.I. Chacon Lopez-Muñiz
Journal: Journal of Thoracic Oncology (2017)
Persistent Long-Term Structural, Functional, and Metabolic Changes After Stress-Induced (Takotsubo) Cardiomyopathy
Authors: Caroline Scally, Amelia Rudd, Alice Mezincescu, Heather Wilson, Janaki Srivanasan, Graham Horgan, Paul Broadhurst, David E. Newby, Anke Henning, Dana K. Dawson
Journal: Circulation (2017)

Takotsubo cardiomyopathy is an increasingly recognized acute heart failure syndrome precipitated by intense emotional stress. Although there is an apparent rapid and spontaneous recovery of left ventricular ejection fraction, the long-term clinical and functional consequences of takotsubo cardiomyopathy are ill-defined.In an observational case-control study, we recruited 37 patients with prior (>12-month) takotsubo cardiomyopathy, and 37 age-, sex-, and comorbidity-matched control subjects. Patients completed the Minnesota Living with Heart Failure Questionnaire. All participants underwent detailed clinical phenotypic characterization, including serum biomarker analysis, cardiopulmonary exercise testing, echocardiography, and cardiac magnetic resonance including cardiac 31P-spectroscopy.Participants were predominantly middle-age (64±11 years) women (97%). Although takotsubo cardiomyopathy occurred 20 (range 13-39) months before the study, the majority (88%) of patients had persisting symptoms compatible with heart failure (median of 13 [range 0-76] in the Minnesota Living with Heart Failure Questionnaire) and cardiac limitation on exercise testing (reduced peak oxygen consumption, 24±1.3 versus 31±1.3 mL/kg/min, P<0.001; increased VE/Vco2 slope, 31±1 versus 26±1, P=0.002). Despite normal left ventricular ejection fraction and serum biomarkers, patients with prior takotsubo cardiomyopathy had impaired cardiac deformation indices (reduced apical circumferential strain, -16±1.0 versus -23±1.5%, P<0.001; global longitudinal strain, -17±1 versus -20±1%, P=0.006), increased native T1 mapping values (1264±10 versus 1184±10 ms, P<0.001), and impaired cardiac energetic status (phosphocreatine/γ-adenosine triphosphate ratio, 1.3±0.1 versus 1.9±0.1, P<0.001).In contrast to previous perceptions, takotsubo cardiomyopathy has long-lasting clinical consequences, including demonstrable symptomatic and functional impairment associated with persistent subclinical cardiac dysfunction. Taken together our findings demonstrate that after takotsubo cardiomyopathy, patients develop a persistent, long-term heart failure phenotype.URL: https://clinicaltrials.gov. Unique identifier: NCT02989454.
SURG-08. RESECTION OF CONTRAST ENHANCING TISSUE PROLONGS OVERALL SURVIVAL IN GLIOMAS – SECONDARY ENDPOINT ANALYSIS OF A RANDOMIZED CONTROLLED TRIAL ON INTRAOPERATIVE MRI USE
Authors: Florian Gessler, Peter Baumgarten, Patrick Harter, Oliver Baehr, Kea Franz, Marie-Therese Forster, Andrea Bink, Volker Seifert, Christian Senft
Journal: Neuro-Oncology (2017)

There is a lack of high-class evidence to promote surgical treatment of gliomas. In a previosly published randomized controlled trial (RCT) the use of an intraoperative MRI (iMRI) led to improved rates of complete tumor removal (GTR) in glioma surgery. In this study, GTR was associated with longer progression-free survival. Here, we report on the overall survival (OS) of trial participants as a prespecified secondary study endpoint. In an RCT (registered with ClinicalTrials.gov, number NCT01394692), we enrolled adults (≥18 years) with contrast enhancing gliomas amenable to radiologically complete resection who presented to our institution. We randomly assigned patients (1:1) to undergo iMRI-guided surgery or conventional microsurgery (control group). Surgeons and patients were unmasked to treatment group allocation, but an independent neuroradiologist was masked during analysis of all pre- and postoperative imaging data. Analysis was done per protocol. At 5-year follow-up, we performed an analysis of OS data. We enrolled 58 patients with contrast enhancing gliomas between Oct 1, 2007, and July 1, 2010. 24 (83%) of 29 patients randomly allocated to the iMRI group and 21 (72.4%) of 29 controls were eligible for analysis of OS. Median OS was 18.9 months. The use of iMRI itself did not affect outcome (560 vs. 624 days, p=0.53). GTR (724 vs. 437 days, p=0.024), MGMT promotor methylation status (641 vs. 500 days, p=0.026) and tumor recurrence (576 vs. 560 days, p=0.038) were associated with OS in a multivariate analysis. Also for the subgroup of patients with IDH1_R132H-wt untreated glioblastomas, a multivariate analyis identified MGMT promotor methylation status (HR 1.81, p=0.036) and GTR (HR 2.42, p=0.024) as parameters independently associated with OS. Our data provide evidence that GTR is an independent prognostic factor in high grade gliomas. Intraoperative resection control is warranted to optimize surgical treatment.
P3.02-061 An ALK Follow-On Companion Diagnostic Using CGP for Clinical Care of Patients with NSCLC
Authors: Y. Li, W. Yip, J. Luo, J. Skoletsky, C. Milbury, C. Burns, A. Tsuji, J. Truesdell, E. Peters, H. Gilbert, C. Wu, E. Schleifman, J. Noe, 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)
NIMG-43. GLIOMA PATIENT OUTCOME AND TUMOR BIOLOGY CORRELATE WITH INTRAOPERATIVE MRI FLAIR AND T2 TUMOR VOLUMES COMPARED WITH IMMEDIATE AND 3 MONTH POSTOPERATIVE VOLUMES
Authors: Randy Jensen
Journal: Neuro-Oncology (2017)

Intraoperative MRI is a useful tool in the operative management of human gliomas. T2 and FLAIR signals are often used as resection margins. We hypothesized that intraoperatively obtained MRI T2 and FLAIR signal volumes might not reflect corresponding post-operative volumes due to tumor edema after resection and brain manipulation. We examined 160 patients, average age 48.0 (range 16-82) 71 females and 89 males, who underwent intraoperative imaging during glioma surgery. We excluded patients with a new vascular injury identified on diffusion-weighted imaging. Volumetric assessment of T2 and FLAIR signals were made with OSRIX image analysis program and ratios calculated for intraoperative, immediate and 3 month post-operative images for each patient. This was correlated with tumor histology and various molecular markers including IDH-1 mutation and MGMT methylation status as well a patient progression-free and overall survival. We examined 13 grade I gliomas (DNET, ganglioglioma, JPA) with postop/intraop FLAIR and T2 ratios of roughly 3. In a similar fashion we found that ratios of FLAIR and T2 images for grade 2 tumors (29 LGA, 16 oligo) averaged around 3-4 times larger for immediate and 3 months post op images. A similar ratio was found for high-grade gliomas, (17 AA, 10 AO and 75 GBM). Molecular markers did not predict imaging volume ratios. Postoperative FLAIR and T2 signal volumes are significantly higher than intraoperatively obtained corresponding volumes for most gliomas studied. Further work will be required but this study questions the validity of T2 and FLAIR images obtained intraoperatively.
NIMG-53. POST-SURGICAL, RESIDUAL ENHANCING TUMOR VOLUME IS PROGNOSTIC FOR OVERALL SURVIVAL IN NEWLY DIAGNOSED GLIOBLASTOMA: EVIDENCE FROM 1,458 PATIENTS POOLED FROM INTERNATIONAL TRIALS, SINGLE INSTITUTION DATABASES, AND MULTICENTER CONSORTIUMS
Authors: Benjamin Ellingson, Lauren Abrey, Sarah Nelson, Josep Garcia, Olivier Chinot, Frank Saran, Ryo Nishikawa, Roger Henriksson, Warren Mason, Wolfgang Wick, Nicholas Butowski, Keith Ligon, Elizabeth Gerstner, Howard Colman, John de Groot, Susan Chang, Ingo K Mellinghoff, Robert J Young, Rivka Colen, Jennie Taylor, Isabel Arrillaga-Romany, Ray Huang, Whitney Pope, David Reardon, Tracy Batchelor, Patrick Wen, Michael Prados, Timothy F Cloughesy
Journal: Neuro-Oncology (2017)

The prognostic significance of residual contrast enhancing tumor volume after initial surgery to predict OS in newly diagnosed GBM remains poorly understood and not controlled for in prospective clinical trials. In the current study we pooled imaging data in >1,400 newly diagnosed GBM patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums identify relationships between clinical parameters, MGMT methylation status, treatment, and residual enhancing tumor volume on OS. Data from 1,458 newly diagnosed GBM patients from 3 sources (2 for training and 1 for validation) were included in our imaging database: 1) a single institution database from UCLA (N=398; Training Set 1); 2) patients treated within the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Consortium (N=262 from 8 centers; Training Set 2); and 3) AVAglio – an international phase III trial comparing chemoradiation plus bevacizumab (N=404) vs. placebo (N=394) used as a validation set. Post-surgical, residual enhancing disease was isolated from blood products and quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, MGMT status, and residual tumor volume on OS. Results confirmed that post-surgical, residual enhancing tumor volume is a strong prognostic factor for OS (P<0.0001), regardless of therapy, age, and MGMT status. Pre-surgical tumor volume and extent of resection as continuous variables were not significant prognostic factors, but patients with an extent of resection greater than 98% had a significant survival advantage (P<0.01). Influence of residual non-enhancing disease and other imaging factors will also be discussed. Results support the hypotheses that post-surgical, residual contrast-enhancing disease significantly influences survival in patients with newly diagnosed glioblastoma, regardless of treatment.
EXTH-83. TARGETING DNA REPAIR AND SURVIVAL PATHWAYS THROUGH HEAT SHOCK PROTEIN INHIBITION USING AT13387 TO SENSITIZE GLIOMA TO CHEMORADIATION THERAPY
Authors: Jasmine P J Wu, Alessandro Canella, Jihong Xu, Tzung-Huei Lai, Alessandra M Welker, Christine E Beattie, Vijay Nadella, Cynthia Timmers, Balveen Kaur, Naduparambil Jacob, Deepa Sampath, Vinay K Puduvalli
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is the most lethal of adult primary brain tumors. Resistance to the standard chemoradiation therapy with temozolomide (TMZ) emerges due to increased expression of DNA-alkylating proteins and potent DNA repair. This is in part through activation of the heat-shock response, an evolutionally conserved defense mechanism mediated by heat-shock proteins (HSP). We recently reported that AT13387, an orally-bioavailable second generation HSP90 inhibitor, efficiently crosses the blood brain barrier (BBB) and is effective preclinically against gliomas as a single agent and in combination with TMZ. To test whether its potent effects on DNA-repair pathways could sensitize GBM to chemoRT, we examined the effects of AT13387 in glioma cell lines and patient-derived glioma stem-like cells. AT13387 potently induced apoptosis, inhibited key oncogenic pathways and inhibited proliferation and migration of glioma cells. RPPA and RNAseq analysis revealed reduced expression of several key DNA-repair proteins and genes. AT13387-treated glioma cells exposed to radiation showed impaired ability to repair DNA in NHEJ/HR DNA-repair assays and increased DNA damage in a Comet assay. The combination of AT13387 with TMZ and RT showed in vivo efficacy with significant improvement in survival in intracranial GBM-xenotransplanted zebrafish and in an intracranial glioma PDX nude mouse model compared with radiotherapy alone or chemoRT. Lastly, AT13387-treated ex vivo human glioma slice cultures showed reduced levels of DNA repair and survival pathway proteins and increased g-H2AX levels indicating DNA damage compared with untreated controls. The oral bioavailability, ability to cross the BBB and multi-target pathway inhibition by AT13387 makes it a promising agent for therapeutic targeting of GBM. Our results also strongly support the potential for Hsp90 inhibition with AT13387 as a therapeutic strategy against gliomas in combination with chemoradiation therapy. A phase I/II trial of the combination in newly-diagnosed GBM patients is currently under planning.
TMOD-16. MODELING GLIOBLASTOMA THROUGH CANCER STEM CELL ORGANOIDS
Authors: Christopher Hubert, Maricruz Rivera, Lisa C Wallace, Qiulian Wu, Stephen Mack, Briana Prager, Tyler E Miller, Marta Couce, Roger McLendon, Andrew Sloan, Jeremy Rich
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) therapeutic resistance is driven in part by tumor-initiating, cancer stem cells (CSCs) which rely on complex interactions with the tumor microenvironment. Standard cell culture conditions fail to recapitulate the original tumor architecture or microenvironmental gradients, and are not designed to retain tumor cellular heterogeneity. We demonstrate a 3D culture system that supports long-term growth and expansion of tumor organoids derived directly from GBM specimens.1 Tumor organoids grow for months and display regional heterogeneity with a rapidly dividing outer region of SOX2+, OLIG2+, and TLX+ cells surrounding a hypoxic core of primarily non-stem senescent cells and diffuse, heterogeneous, and rare quiescent CSCs. Unlike patient-matched sphere cultures, orthotopic transplantation of patient-derived organoids resulted in tumors strikingly similar to the parental tumor. Non-stem cells within organoids are sensitive to radiation therapy whereas directly adjacent CSCs are radioresistant, an example of granular therapeutic response previously only demonstrable in whole tumors. We have further developed and leveraged a method of 3D region-specific labeling of live CSCs within organoids to perform high-throughput functional screens for genes essential to glioblastoma survival within distinct niches. These niche-essential genes better reflect glioblastoma-lethal gene targets in vivo.2 Our novel ex-vivo systems preserve phenotypically diverse stem and non-stem cell populations side-by-side amidst varying microenvironmental gradients similar to patient tumors, allowing exploration of new CSC biology. These methods and screening techniques are further applicable to a wide range of disease models that require a complex microenvironment to maintain physiologic relevance. 1Hubert et. al. Cancer Research 2016, 2Miller et. al. Nature 2017
ATIM-25. IMMUNOLOGICAL ACTIVATION IN RESPONDING PATIENTS WITH RECURRENT HGG AFTER TREATMENT WITH TOCA 511 &amp; TOCA FC: RESULTS FROM A PHASE 1 TRIAL
Authors: Derek Ostertag, William Accomando, Daniel Hogan, Oscar Diago, Dawn Gammon, Ali Haghighi, Leah Mitchell, Maria Rodriguez-Aquirre, Timothy Cloughesy, Steven Kalkanis, Tom Mikkelsen, Joseph Landolfi, Clark Chen, Michael Vogelbaum, Harry Gruber, Asha Das, Douglas Jolly
Journal: Neuro-Oncology (2017)
P3.17-003 A Selective Small Molecule Inhibitor of C-Met Kinase, BPI-9016M, Has Synergistic Effects with Radiation on Esophageal Squamous Cell Carcinoma
Authors: Y. Xu, C. Jiang, S. Han, G. Lin, F. Gu, Q. Lin, J. Feng
Journal: Journal of Thoracic Oncology (2017)
P2.14-015 Outcomes for Stereotactic Ablative Body Radiotherapy (SABR) for Early Primary Lung Cancers: Cyberknife Versus VMAT Platform
Authors: B. Allos, S. Mascall, M. Vreugdenhil, S. Watkins, R. Stevenson, Q. Ghafoor
Journal: Journal of Thoracic Oncology (2017)