tbuckley/cabot-search huggingface dataset:
RTHP-02. CHARACTERIZATION AND EVOLUTION OF RADIOTHERAPY-INDUCED VASCULAR INJURY AND CORRESPONDING CHANGES IN WHITE MATTER STRUCTURE: AN INVESTIGATIVE STUDY IN 125 PATIENTS WITH GLIOMAS
Authors: Melanie Morrison, Angela Jakary, Wei Bian, Qiuting Wen, Christopher Hess, Jennifer Clarke, Nicholas Butowski, Susan Chang, Sarah Nelson, Janine Lupo
Journal: Neuro-Oncology (2017)

While radiation therapy (RT) remains a standard practice in the upfront treatment of high-grade gliomas and low-grade gliomas at the time of recurrence, it is often associated with long-term effects including vascular injury and cognitive decline. The former typically manifests as size-varying hemosiderin deposits in the brain called cerebral microbleeds (CMBs), and can be accompanied by changes in the surrounding white-matter (WM) microstructure. As the median survival of lower grade gliomas can be 10 years or longer with current treatment strategies, minimizing the deficits incurred through treatment becomes especially important. Prior studies have shown increases in CMB formation over time that were dependent on RT dose and were not observed in patients treated only with chemotherapy. The goal of this study was to characterize the evolution of CMBs in a much larger cohort with serial scans and relate their changes over time to alterations in WM structure. 125 patients (age:46 ± 12) were scanned on a 7-Tesla GE scanner either once or serially for 2-8 scans. The cohort included patients treated with RT for a glioma 2 months to 27 years prior, and a subset of nonirradiated control patients. Susceptibility-weighted vascular imaging and multi-directional, multi-shell diffusion-tensor imaging were acquired. Characteristics of RT-induced CMBs were evaluated within- and across patients, correlated with clinical and treatment parameters, and related to global and local WM changes. Total CMB burden increased over time and was more severe for larger irradiated volumes and frontal lobe tumors. WM fractional anisotropy and diffusivity changes initially decreased as a function of CMB burden before improving approximately 6 years post-treatment. Although there was initially a direct relationship between RT-induced vasculature injury and degradation of WM microstructure, changes in WM structure appeared to be reversible over time, whereas CMBs, potential markers of vascular injury, persisted.
P1.03-015 The Relationship between the UGT1A1*27 and UGT1A1*7 Genetic Polymorphisms and Irinotecan-Related Toxicities in Patients with Lung Cancer
Authors: M. Fukuda, M. Okumura, K. Arimori, A. Takahira, M. Mori, D. Nakamura, M. Shimada, H. Taniguchi, H. Gyotoku, H. Senju, T. Ikeda, H. Yamaguchi, K. Nakatomi, T. Tsuchiya, H. Mukae, K. Ashizawa
Journal: Journal of Thoracic Oncology (2017)
P3.14-014 Lung Stereotactic Body Radiotherapy (SBRT): Patient's Outcome and Prognostic Factors
Authors: N. Farré, E. Acosta, J. Balart, G. Sancho, K. Majercakova, P. Carrasco, A. Fernández, M.D.V. Camacho, M. Majem, A. Giménez, E. Martínez, J.C. Trujillo, A. Torrego, V. Pajares, J. Craven-Bartle
Journal: Journal of Thoracic Oncology (2017)
Local production of tenascin-C acts as a trigger for monocyte/macrophage recruitment that provokes cardiac dysfunction
Authors: Dounia Abbadi, Fanny Laroumanie, Mathilde Bizou, Joffrey Pozzo, Danièle Daviaud, Christine Delage, Denis Calise, Fréderique Gaits-Iacovoni, Marianne Dutaur, Florence Tortosa, Edith Renaud-Gabardos, Victorine Douin-Echinard, Anne-Catherine Prats, Jerome Roncalli, Angelo Parini, Nathalie Pizzinat
Journal: Cardiovascular Research (2017)

Abstract Aims Tenascin-C (TNC) is an endogenous danger signal molecule strongly associated with inflammatory diseases and with poor outcome in patients with cardiomyopathies. Its function within pathological cardiac tissue during pressure overload remains poorly understood. Methods and results We showed that TNC accumulates after 1 week of transverse aortic constriction (TAC) in the heart of 12-week-old male mice. By cross bone marrow transplantation experiments, we determined that TNC deposition relied on cardiac cells and not on haematopoietic cells. The expression of TNC induced by TAC, or by administration of a recombinant lentivector coding for TNC, triggered a pro-inflammatory cardiac microenvironment, monocyte/macrophage (MO/MΦ) accumulation, and systolic dysfunction. TNC modified macrophage polarization towards the pro-inflammatory phenotype and stimulated RhoA/Rho-associated protein kinase (ROCK) pathways to promote mesenchymal to amoeboid transition that enhanced macrophage migration into fibrillar collagen matrices. The amplification of inflammation and MO/MΦ recruitment by TNC was abrogated by genetic invalidation of TNC in knockout mice. These mice showed less ventricular remodelling and an improved cardiac function after TAC as compared with wild-type mice. Conclusions By promoting a pro-inflammatory microenvironment and macrophage migration, TNC appears to be a key factor to enable the MO/MΦ accumulation within fibrotic hearts leading to cardiac dysfunction. As TNC is highly expressed during inflammation and sparsely during the steady state, its inhibition could be a promising therapeutic strategy to control inflammation and immune cell infiltration in heart disease.
CSIG-11. ONCOSTREAMS: NOVEL STRUCTURES THAT SPECIFY GLIOMAS’ SELF-ORGANIZATION, ARE ANATOMICALLY DISCRETE, FUNCTIONALLY UNIQUE, AND MOLECULARLY DISTINCT
Authors: Andrea Comba, Dan Zamler, Anna E Argento, Carl Koschmann, Felipe J Nunez, Marta Edwards, Padma Kadiyala, Neha Kamran, Viveka Nand Yadav, Sebastien Motsch, Maria G Castro, Pedro R Lowenstein
Journal: Neuro-Oncology (2017)

Whether tumors in general and gliomas in particular are self-organized has not been determined. Brain tumor self-organization would be revealed through individual recognizable structures. Here we demonstrate that brain tumors are indeed self-organized. Brain tumor self-organization is evidenced by the existence of oncostreams, multicellular structures composed of elongated glioma cells. Oncostream structure, function and molecular makeup was studied in several glioma models. In experimental mouse models, and in human GBM tumors, oncostreams were demarcated anatomically as multicellular arrangements of fusiform cells, 10–20 cells wide, of various lengths and distributed throughout the tumors. Using genetically engineered glioma models we found a negative correlation between oncostream density and survival, suggesting that oncostreams contribute to tumor aggressiveness. As oncostreams also reached tumor borders, it is likely that they participate in glioma invasion. Further, by placing slow moving glioma stem cells into oncostreams we detected that these function as streams that distribute glioma cells throughout the tumors. Importantly, we performed the molecular analysis of oncostreams using a Laser Microdissection Microscope to dissect oncostreams from surrounding tumor. The transcriptome landscape was analyzed by next generation sequencing using RNA-Seq and advanced bioinformatics algorithms. The molecular analysis showed that oncostreams are defined by a distinctive transcriptome landscape. We hereby show that oncostreams: (i) are anatomically discrete structures that reveal the existence of glioma self-organization, (ii) are functionally unique as they regulate glioma growth, invasion and spread, and (iii) molecularly distinct, their genetic landscape and associated gene networks differentiate oncostreams from surrounding glioma. Understanding glioma self-organization and its molecular basis will contribute to uncover novel targets for future translational development.
STEM-36. A TRANSLATIONAL REPRESSION PROGRAM IS ASSOCIATED WITH THE STEM CELL STATE IN GLIOBLASTOMA
Authors: Christine Lee, Yunku Yeu, Ulf-peter Guenther, Tae Hyun Hwang, Eckhard Jankowsky, Jeremy Rich
Journal: Neuro-Oncology (2017)

Glioblastoma is the most prevalent and lethal brain tumor. Within glioblastoma, stem-like glioma stem cells (GSCs) contribute to the heterogeneous and highly aggressive nature of the tumor. It is critical to decipher the changes in the regulation of gene expression that accompany the differentiation from GSCs to differentiated glioma cells (DGCs). To date, such changes have only been investigated on the transcriptional and proteomic levels but not on the translational level, despite the key role that the regulation of protein production plays in all aspects of cellular function. Here, we interrogated changes in the translational landscape during the differentiation of patient-derived GSCs into DGCs. We utilized ribosome profiling to assess translation on a transcriptome wide level in both GSCs and DGCs. We identified a translational repression program in GSCs wherein a significant subset of transcripts (>1,600) is translationally repressed. Roughly 80% of these transcripts are de-repressed upon differentiation in DGCs, including genes with roles in Wnt-signaling and ribosome structure and function. Most notably, we find that the poly(A) binding protein interacting protein 2B (PAIP2B) is most preferentially translated gene in GSCs when compared to DGCs. PAIP2B is a broad yet transcript-specific repressor of translation that antagonizes poly(A) binding proteins (PABPs), which are broad activators of translation. Interestingly, PABPs are preferentially translated in DGCs. Our results suggest that glioblastoma cells utilize the PAIP2B-PABP axis to exert translational control over the transcriptome in order to maintain the cancer stem cell state and to drive the differentiation of GSCs.
PATH-52. TIME-VARYING EFFECT OF MGMT METHYLATION LEVEL ON SURVIVAL OF GLIOBLASTOMA MULTIFORME
Authors: Rikke H Dahlrot, Pia V Larsen, Henning Boldt, Melissa S Kreutzfeldt, Jacob v B Hjelmborg, Steinbjørn Hansen, Bjarne W Kristensen
Journal: Neuro-Oncology (2017)

Standard treatment for patients with glioblastoma multiforme (GBM) consists of surgery, radiotherapy and concomitant and adjuvant treatment with the alkylating agent temozolomide (TMZ). The repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) removes the alkyl groups thereby preventing DNA damage and apoptosis. However, methylation of the MGMT promoter gene causes MGMT protein deficiency and a better response towards TMZ, which may affect patient survival. In a population-based cohort of 508 patients with primary GBMs diagnosed between 2005 and 2014 we identified 226 patients receiving the Stupp regime and with enough viable tissue for analyzing MGMT methylation status. The MGMT methylation level was obtained by pyrosequencing; all analyses were performed using mean methylation percentage of four CpG sites. The association of the MGMT methylation level and survival was investigated using Cox proportional hazards model and Aalen’s additive hazard model. Our results suggest that beneficial effects of MGMT methylation level on overall survival start 9-12 months after the diagnosis, with no effect regardless of MGMT methylation level before that. For patients surviving at least nine months the mortality hazard is decreased by 3% for each percentage increase in MGMT methylation level (HR=0.97, 95% CI=(0.96,0.98)) with Harrel’s C of 68%. Progression-free survival is strongly related to MGMT methylation levels (HR=0.97, 95% CI=(0.96,0.98)) from time of diagnosis. Similar effects on overall survival and progression-free survival are seen in patients across age-groups below and above 70 years of age. We conclude that the MGMT methylation level is strongly associated with progression-free survival from time of diagnosis, and long term overall survival, but only for patients surviving beyond nine months. Future evaluation of the validity of cut-points of MGMT methylation levels and promoter site selection should take into account the time-varying effect on overall survival.
OA 07.05 Serial Biopsies in Patients with EGFR-Mutant NSCLC Highlight the Spatial and Temporal Heterogeneity of Resistance Mechanisms
Authors: Z. Piotrowska, K. Stirling, R. Heist, M. Mooradian, C. Rizzo, S. Digumarthy, M. Lanuti, F. Fintelmann, I. Lennes, A. Farago, J. Gainor, C. Azzoli, J. Temel, M. Mino-Kenudson, D. Dias-Santagata, R. Corcoran, A. Shaw, A. Hata, L. Sequist
Journal: Journal of Thoracic Oncology (2017)
Une grande épidémie de rubéole en Roumanie, 2003
Authors: A Rafila, M Marin, A Pistol, D Nicolaiciuc, E Lupulescu, A Uzicanin, S Reef
Journal: Eurosurveillance (2004)

Entre 2002 et 2003, une epidemie importante de rubeole s'est declaree en Roumanie avec plus de 115 000 cas notifies dans le pays, et une incidence de 531 cas pour 100 000 habitants. L'incidence la plus elevee concernait les enfants d'âge scolaire. Les cohortes d'adolescentes vaccinees en 1998 et en 2002 (lorsqu'un vaccin anti-rubeoleux etait disponible) presentaient des incidences significativement plus basses (pl0,001) que celles de garcons du meme âge non vaccines. En 2003, sur les 150 cas suspects de syndrome de rubeole congenitale (SRC), sept (4,6%) ont ete confirmes par la presence d'anticorps IgM anti-rubeole. En l'absence de vaccin pour lutter contre l'epidemie, un plan de reponse a l'alerte a ete mis en place pour ameliorer la detection des cas et limiter la transmission du virus de la rubeole. Les activites suivantes ont ete mises en œuvre : surveillance des femmes enceintes avec une suspicion de rubeole ou des antecedents d'exposition au virus de la rubeole et suivi des issues de grossesses, renforcement de la surveillance des SRC ainsi que des recommandations existantes relatives au controle de l'infection pour prevenir la transmission de la maladie dans les etablissements de soins, et mise en place d'une campagne grand public. Le vaccin combine Rougeole-Oreillons-Rubeole sera introduit en mai 2004 en Roumanie pour la vaccination en routine des enfants de 12 a 15 mois, tandis que la vaccination des jeunes filles de 13-14 ans avec un vaccin monovalent contre la rubeole sera maintenue.
RADI-13. EXPERIENCE WITH 18F-FET PET/MRI FOR CNS-TUMORS IN CHILDREN AND ADOLESCENTS
Authors: Lisbeth Marner, Karsten Nysom, Astrid Sehested, Lise Borgwardt, René Mathiasen, Peder Skov Wehner, Otto Mølby Henriksen, Michael Lundemann, Carsten Thomsen, Lars Bøgeskov, Jane Skjøth-Rasmussen, Helle Broholm, David Scheie, Marianne Juhler, Liselotte Højgaard, Ian Law
Journal: Neuro-Oncology (2018)

18F-fluoro-ethyltyrosine (18F-FET) positron emission tomography (PET) in addition to MRI improves accuracy in adult patients with gliomas. We aimed to 1) collect a material of various pediatric brain tumors 2) determine sensitivity and specificity for tumor using 18F-FET PET versus MRI alone 3) test the clinical impact of the scans. Ninety-seven patients with primary pediatric CNS-tumors were included consecutively and prospectively, and a total of 151 hybrid 18F-FET PET/MRI or PET/CT scans were performed. A high 18F-FET uptake was seen in pilocytic astrocytoma, gangliogliomas and in high grade gliomas, while moderate uptake was seen in ependymomas and germinomas. Atypical teratoid/rhabdoid tumors (AT/RT) showed varying uptake. The addition of 18F-FET PET to MRI added extra relevant information in 28% of all scans and influenced the clinical management in 8%. Of the 30 18F-FET PET scans that beforehand were rated desirable for a clinical decision (e.g. due to equivocal MRI), 40% added new information and 33% influenced clinical management. A subset consisting of 27 early postoperative 18F-FET PET scans showed one case of influenced clinical management and a lesion-based sensitivity/specificity for diagnosing residual tumor of 0.80/0.75 for MRI alone and 0.73/1.00 for PET/MRI. The addition of 18F-FET PET to MRI for imaging of pediatric CNS-tumors influenced clinical management in 8% of all scans and in 33% of the clinically indicated scans. Early postoperative 18F-FET PET is not recommended routinely but supplementary 18F-FET PET could be relevant when re-operation for residual tumor is considered based on early postoperative MRI.
The activated conformation of integrin β7 is a novel multiple myeloma–specific target for CAR T cell therapy
Authors: Naoki Hosen, Yukiko Matsunaga, Kana Hasegawa, Hiroshi Matsuno, Yuki Nakamura, Mio Makita, Kouki Watanabe, Mikako Yoshida, Kei Satoh, Soyoko Morimoto, Fumihiro Fujiki, Hiroko Nakajima, Jun Nakata, Sumiyuki Nishida, Akihiro Tsuboi, Yoshihiro Oka, Masahiro Manabe, Hiroyoshi Ichihara, Yasutaka Aoyama, Atsuko Mugitani, Takafumi Nakao, Masayuki Hino, Ryosuke Uchibori, Keiya Ozawa, Yoshihiro Baba, Seitaro Terakura, Naoki Wada, Eiichi Morii, Junichi Nishimura, Kiyoshi Takeda, Yusuke Oji, Haruo Sugiyama, Junichi Takagi, Atsushi Kumanogoh
Journal: Nature Medicine (2017)
EPID-19. RISK OF GLIOMA AMONG PEOPLE WITH ASTHMA: A POPULATION-BASED CASE-CONTROL STUDY USING DIFFERENT CONTROL GROUPS
Authors: Daniel Lachance, Harsheen Kaur, Conor Ryan, Youn Ho Sheen, Hee Yun Seol, Chung-Il Wi, Katherine King, Euijung Ryu, Young Juhn
Journal: Neuro-Oncology (2017)

Several previous studies suggested inconsistent associations between asthma and risk of glioma, while inverse association with allergy is consistently affirmed. Variation in sampling frame, control selection, and asthma and/or glioma ascertainment are likely responsible. To address these inconsistent results, we conducted a retrospective population-based case-control study, which enrolled all eligible biopsy-proven incident glioma cases (1995–2014) and 2 sets of controls among Olmsted County, Minnesota residents matched to birth-year and gender (1st set: community controls without ICD9 codes for glioma; 2nd set: MRI (brain)-negative controls from the same community). To ascertain asthma status, predetermined validated asthma criteria were applied instead of ICD-code or self-report to minimize detection and misclassification bias. Conditional logistic regression models were used to compare frequency of history of asthma prior to index date between cases and their matched controls. There were 135 glioma incident cases (14%, age <18 years) and 270 controls. The median ages (IQR) at the index date were 52 years (32–67) for glioma cases. Of the glioma cases, 21 (16%) had a history of asthma, compared to 17 of community controls (13%) and 36 of MRI controls (27%) (OR [95%CI]: 1.28 [0.63–2.58], p=.48 for community control vs. 0.48 [0.25–0.91], p=.02 for MRI control). As a measure of health care access, cases and MRI controls had similar flu vaccine rates, but dissimilar rates with community controls. Epidemiologic assessment of glioma risks requires specific attention to case ascertainment and control selection. Different control groups draw different conclusions. Community controls appear susceptible to detection bias. Using a more stringent control group, our study findings uphold prior reports of inverse association between asthma and the risk of glioma.
Donor age determines outcome in acute leukemia patients over 40 undergoing haploidentical hematopoietic cell transplantation
Authors: Jonathan Canaani, Bipin N. Savani, Myriam Labopin, Xiao‐Jun Huang, Fabio Ciceri, William Arcese, Yener Koc, Johanna Tischer, Didier Blaise, Zafer Gülbas, Maria Teresa Van Lint, Benedetto Bruno, Mohamad Mohty, Arnon Nagler
Journal: American Journal of Hematology (2017)

Abstract Haploidentical hematopoietic cell transplantation (haplo‐HCT) is being increasingly used in acute leukemia patients as an alternative transplant modality when matched sibling or matched unrelated donors are unavailable. As several potential haploidentical relative donors are typically available for a given patient, optimizing donor selection to improve clinical outcome is crucial. The impact of donor age and kinship on the outcome of acute leukemia patients is not clearly established in this setting. Using the multinational registry of the acute leukemia working party of the European society for blood and marrow transplantation we retrospective analyzed the clinical outcome of 1270 acute myeloid leukemia and acute lymphoblastic leukemia patients who underwent haplo‐HCT between 2005 and 2015. Patients over the age of 40 were significantly affected by increasing donor age resulting in higher non‐relapse mortality (NRM) [Hazard ratio (HR)=1.86, confidence interval (CI) 95%, 1.18‐2.94; P = .007], inferior leukemia‐free survival (LFS) (HR = 1.59, CI 95%, 1.13‐2.24; P = .007), and overall survival (OS) (HR = 1.74, CI 95%, 1.22‐2.47; P = .002) when donors were over the age of 40. Additionally, kinship was found to be prognostically significant as patients transplanted from children donors over the age of 35 experienced an increased rate of NRM (HR = 1.82, CI 95%, 1.13‐2.9; P = .01), inferior LFS (HR = 1.5, CI 95%, 1.05‐2.13; P = .03), and OS (HR = 1.5, CI 95%, 1.04‐2.15; P = .03). For patients younger than 40 years, donor age and kinship were mostly not clinically impactful. Our data establish donor age and kinship as significant determinants of outcome following haplo‐HCT for acute leukemia patients.
ANGI-05. CYTOMEGALOVIRUS INFECTION STIMULATES TUMOR CELL–PERICYTE CROSSTALK TO FACILITATE ANGIOGENESIS AND TUMOR GROWTH IN GLIOBLASTOMA
Authors: Harald Krenzlin
Journal: Neuro-Oncology (2017)

Cytomegalovirus (CMV) has been linked to glioblastoma for over a decade. However there is a lack of understanding of the mechanisms by which CMV affects tumor growth in vivo. Here, we have identified novel regulatory mechanisms involving cross-talk between GBM cells and vascular pericytes in the context of CMV infection, increasing angiogenesis and tumour growth in a mouse syngeneic glioblastoma model. This study investigates CMV expression in human glioblastoma samples, and establishes and characterizes a new CMV latent, orthotopic glioblastoma mouse model. RNAseq, and in vitro functional assays were used to investigate mechanisms. Immunostaining of patient samples identified viral antigens expressed in multiple cellular compartments including the novel observation of co-localization with pericytes. RNAseq of human brain vascular pericytes (HBVPs) and glioblastoma stem-like cells (GSCs) revealed upregulation of proangiogenic cytokines after CMV infection. Conditioned medium derived from CMV infected GSCs/HBVPs led to the establishment of larger (160%, p<0.0001) and more complex (number of junctions 9.5 (control) vs. 21 (CMV), p<0.0001) tube formation in human brain microvascular endothelial cells (HBMEC) cultured on Matrigel in vitro. Also, PDGF-DD, secreted by GSCs after CMV infection, was identified as a driver of angiogenesis and HBVP migration in vitro. Orthotopic injection of Gl261fluc murine glioblastoma cells in C57BL/6 mice harboring latent CMV infection caused intratumoral virus reactivation and shortened survival rates (30d vs 43d, p=0.0004). Increased area (p=0.0004) and length (p=0.001) of tumor vessels was found in CMV latent mice. Furthermore, CMV infected tumours showed significantly higher numbers of infiltrating- and blood vessel-associated pericytes. In patient-derived tumor samples CMV partially co-localizes with perivascular pericytes. Tumor growth is faster in a murine glioblastoma model in the context of latent CMV infection, and this is in part driven by paracrine effects mediated by PDGF-DD which are associated with increased pericyte recruitment and angiogenesis.