tbuckley/cabot-search huggingface dataset:
TMIC-18. MICROENVIRONMENT-DERIVED MITOCHONDRIA PRIME GLIOMA CHEMO-RESISTANCE BY POTENTIATED NAD METABOLISM AND BASE EXCISION DNA REPAIR
Authors: Yang Liu, Mark Gilbert, Chunzhang Yang
Journal: Neuro-Oncology (2017)

Cancer cells take advantage of microenvironmental factors to meet their increasing demands for fast proliferation and macromolecule synthesis. Exchange of mitochondria between cells is a recently defined model of cell-cell signaling among microenvironment, which supports energy metabolism and physiology in recipient cells. However, the biologic impact of microenvironmently-derived mitochondria on cancer biology has been largely elusive. We developed fluorescence-based in vitro and in vivo models that visualize intercellular mitochondria translocation. Metabolic reprogramming in recipient glioma cells, as well as their respond to chemotherapy were then investigated. Our studies demonstrated that mitochondria are actively released from glial cells into extracellular space through microvesicles. Excreted mitochondria maintained their metabolic potential, and are internalized by glioma cells that share the same microenvironment. In recipient glioma cells, transferred mitochondria support energy metabolism and synthetic pathways, as evidenced by an increase in ATP and NAD+ generation by 32.3% and 28.1%, respectively. Mitochondria-derived metabolic support enhances tumor cell resistance to temozolomide chemotherapy by potentiating PARP-associated base excision repair. Mitochondria transfer reduced DNA damage burden by 66.68% and cellular apoptosis by 47.8% in the presence of therapeutic dose of chemo agent. Further, suppression of mitochondria release from glial cells sensitized intracranial glioma xenografts, limited tumor progression and improved the efficacy of chemotherapy. Diminished mitochondrial transfer in glioma xenografts prolonged overall survival by 28.6% when combined with chemotherapy. These findings suggest a novel mitochondria-based mechanism of tumor-microenvironment crosstalk that may be involved in tumor formation, metabolic reprogramming, and resistance to chemotherapy.
ACTR-42. INITIAL EXPERIENCE OF BLOOD-BRAIN BARRIER OPENING FOR CHEMOTHERAPEUTIC-DRUG DELIVERY TO BRAIN TUMOURS BY MR-GUIDED FOCUSED ULTRASOUND
Authors: Nir Lipsman, Sarah Ironside, Ryan Alkins, Allison Bethune, Yuexi Huang, James Perry, Arjun Sahgal, Maureen Trudeau, Kullervo Hynynen, Todd Mainprize
Journal: Neuro-Oncology (2017)

Magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly open the blood-brain barrier (BBB) for targeted drug delivery. Animal models have shown the feasibility of BBB opening for delivery of a broad range of compounds. We describe the first experience of focused ultrasound mediated BBB opening in malignant brain tumours. This phase-one clinical trial was approved by Health Canada and our Research Ethics Board. A modified clinical MRgFUS brain system was used with a 3T MR scanner. Prior to BBB opening patients received a single dose of IV liposomal doxorubicin (N=1) or temozolomide (N=2). Patients were positioned in the FUS array with a stereotactic frame. Two targets close to the posterior margin of the tumor were chosen based on T2 images. A bolus injection of Definity microbubbles was applied simultaneously with each sonication. Post sonication, Gd-enhanced images were acquired to verify BBB openings, and T2*-weighted GRE images were collected to detect hemorrhage. All patients tolerated FUS procedures and BBB opening well, with no adverse events. T2* images demonstrated a small degree of RBC extravasation, with no overt hemorrhage on standard T1, no edema on T2 or DWI changes on treatment or follow-up scans. BBB was successfully opened in all patients at each targeted location, with clear Gd enhancement. All patients underwent safe maximal surgical resection at 24 hours post-sonication. Our initial experience of FUS-mediated BBB opening in high-grade glioma demonstrates the safety and feasibility of this emerging adjuvant modality. We were able to open the BBB, as demonstrated with Gd enhancement, in several discrete brain regions surrounding the tumour, without adverse events. Patients tolerated the procedure well. Next steps will include sonication of larger tumour volumes, done in conjunction with standard of care prescriptions of chemotherapeutic agents, for which the BBB is a major challenge.
GENE-04. COMPREHENSIVE GENOMIC CHARACTERIZATION OF AGGRESSIVE MENINGIOMAS IDENTIFIES MOLECULAR SIGNATURES THAT PREDICT CLINICAL OUTCOMES
Authors: Harish Vasudevan, Steve Braunstein, Joanna J Phillips, Melike Pekmezci, Ashley Wu, Gerald Reis, Stephen Magill, Susan Chang, Penny Sneed, Michael McDermott, Arie Perry, David Raleigh
Journal: Neuro-Oncology (2017)

Current pathological grading schemes do not fully predict meningioma behavior, and the molecular basis for meningioma is incompletely understood. Here, we perform whole exome sequencing (WES), DNA methylation arrays, RNA-seq, NanoString (NS), and immunohistochemistry using tissue microarrays (TMAs) on meningiomas to elucidate molecular drivers of aggressive behavior and identify clinically relevant biomarkers. We constructed a database containing clinical data and tissue from 283 patients who underwent resection of meningioma between 1990 and 2015. Histology was re-evaluated using current grading criteria. We conducted WES (n=24), methylation arrays (n=26), and RNA-seq (n=42) in a discovery cohort composed of 14 grade I, 23 grade II and 5 grade III meningiomas. We further carried out NS profiling of 282 cancer-associated transcripts (n=96), and TMAs (n=241) in an independent validation cohort composed of 132 grade I, 87 grade II and 22 grade III meningiomas. WES data was analyzed via the bcbio pipeline with the ensemble method and CNVkit, methylation data was processed in the minfi Bioconductor package, and RNA-seq data was analyzed with the DESeq2 Bioconductor package. Hierarchical clustering and statistics were performed in R. WES demonstrated increased somatic mutation burden was associated with decreased overall survival (OS) (p=0.005). Unsupervised hierarchical clustering of methylation arrays segregated meningioma samples into three groups with significant differences in OS (p=0.0465) and age (p=0.0123). RNA-seq showed enrichment of a FOXM1 mediated transcriptional network with an overrepresentation of cell division genes. High FOXM1 mRNA expression was associated with decreased local recurrence free survival (LRFS) (p=0.004). Consistently, high FOXM1 mRNA expression in NS samples was associated with decreased LRFS (p=0.001) and OS (p=0.006), and high FOXM1 protein expression was associated with decreased LRFS in TMA samples (p=0.049). Comprehensive genomic characterization of aggressive meningiomas identifies molecular signatures associated with poor outcomes, suggesting novel prognostic markers and therapeutic targets.
P2.07-056 SAKK 16/14 – Perioperative Anti-PD-L1 Antibody Durvalumab in Patients with Stage IIIA(N2) Non-Small Cell Lung Cancer (NSCLC)
Authors: S. Rothschild, A. Zippelius, S. Savic, M. Gonzalez, W. Weder, A. Xyrafas, C. Rusterholz, M. Pless
Journal: Journal of Thoracic Oncology (2017)
GENE-10. CHARACTERISTIC MOLECULAR PROFILE CHANGES IN PRIMARY AND RECURRENT GLIOMAS DEPENDING ON THEIR HISTOPATHOLOGY
Authors: Akitake Mukasa, Masashi Nomura, Kuniaki Saito, Koki Aihara, Genta Nagae, Takahide Nejo, Shota Tanaka, Shunsaku Takayanagi, Satoshi Takahashi, Mayu Omata, Taishi Nakamura, Yoshitaka Narita, Yoshihiro Muragaki, Motoo Nagane, Keisuke Ueki, Ryo Nishikawa, Hiroyuki Aburatani, Nobuhito Saito
Journal: Neuro-Oncology (2017)

Diffuse gliomas are typically characterized by intratumoral heterogeneity, and further clonal changes often occur during their treatment, with such plasticity being one cause of their resistance to therapy. In this study, we sought an appropriate therapeutic strategy, as well as to identify novel targeted molecules, by revealing molecular genetic changes that occur during the course of treatment, through comparative molecular analysis of primary and recurrent gliomas. We collected 55 sets of primary and recurrent gliomas, and performed multi-omics analysis with exome sequencing and RNA-sequencing using Illumina HiSeq, as well as epigenomic profile analysis using an Illumina Infinium 450K methylation chip. Then, integrated comparative bioinformatics analysis was performed. Most gliomas showed a complex and remarkable form of clonal evolution, called branched evolution, at tumor recurrence. After temozolomide chemotherapy, some diffuse astrocytomas recurred, with numerous acquired de novo mutations accompanying mutations in mismatch repair genes, and showed a hypermutator phenotype. In contrast, acquisition of potent driver mutations was infrequent in oligodendrogliomas at recurrence, and no emergence of a hypermutator phenotype was observed after temozolomide or PAV chemotherapy. At recurrence of diffuse astrocytomas, which initially showed the glioma CpG island methylator phenotype (G-CIMP), characteristic and remarkable DNA demethylation was observed; however, such dramatic DNA methylation change was not typical for recurrent oligodendrogliomas. Integrated multi-omics analysis demonstrated that recurrent malignant astrocytomas frequently include disruption of cell cycle-related genes such as RB. In oligodendrogliomas, deletion of chromosome 9p (CDKN2A), and mutations in FUBP1, TP53, or TCF12, were commonly observed in recurrent tumors, but acquisition of crucial driver genes and malignant transformation were not. Features of clonal evolution due to treatment may differ depending on their histopathology; therefore, treatment strategies including chemotherapy must be optimized based on such differences.
SCDT-05. LIMITATION OF RADICAL RESECTION OF GLIOBLASTOMA INFILTRATING FROM AMYGDALA TO GLOBUS PALLIDUS: EFFECTIVENESS OF CARMUSTINE WAFERS FOR RESIDUAL TUMOR CONTROL
Authors: Toshihiro Kumabe, Mitsuto Hanihara, Ichiyo Shibahara, Sumito Sato, Ryuta Saito, Masayuki Kanamori, Yukihiko Sonoda, Teiji Tominaga
Journal: Neuro-Oncology (2017)

The concept of surgery for glioblastoma is maximizing tumor resection and minimizing surgical morbidities. The most critical surgical morbidity must be motor deficit. However, if perforating arteries are involved within the hypervascular glioblastoma, preservation of these fine arteries is difficult, thus the risk of motor deficit is still high. From this reason, the tumor infiltrating from amygdala to globus pallidus is difficult to be removed completely without motor disturbance. In this report, we want to discuss about the surgical strategy for removal of glioblastoma infiltrating from amygdala to globus pallidus, and also the benefit of carmustine wafers implantation to the stump of amygdala for local control of the residual tumor. Radically resected 18 consecutive glioblastomas infiltrating from amygdala to globus pallidus were reviewed. Carmustine wafers were implanted around the resection cavity including the stump of amygdala in recent 6 cases. Preoperatively, three-dimensional 3-Tesla time-of-flight (TOF) MR angiography was performed to identify the lenticulostriate artery (LSA). It is still difficult to resect all the tumor infiltrating from amygdala to globus pallidus, excepting in the cases such as, 1) having to accept risk of sacrifice of the LSA resulted hemiparesis, or 2) LSA could be visualized outside of the tumor on preoperative 3-Tesla TOF MR angiography because the tumor infiltration into globus pallidus was a lesser extent. Recent 6 cases using carmustine wafers showed better local tumor control and relatively longer survival. The risk of removal all the tumor infiltrating from amygdala to globus pallidus is still high because the separation all LSAs from highly vascular glioblastoma is difficult. Under the existing conditions, in order to obtain the better local tumor control, we should shave off the amygdala until the level of optic tract and implant carmustine wafers onto its stump.
Bone pain control in Castration resistant prostate cancer (CRPC): retrospective analysis of first patients trated with Radium 223
Authors: I. Toma, F. Lancia, D. Scapoli, A. Frassoldati, S. Panareo, I. Santi, C. Cittanti, M. Bartolomei, F. Daniel, A. Moretti, L.R. Martella, L. Belluomini, G. Mentrasti
Journal: Annals of Oncology (2017)
Maternal β-Blocker Use and Fetal Cardiac Anomalies—Reply
Authors: Ming-Sum Lee, Lewei Duan
Journal: JAMA Internal Medicine (2017)

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SCDT-13. PHASE I CLINICAL TRIAL ON SYSTEMIC PD-1 BLOCKADE IN COMBINATION WITH DIRECT INTRA-TUMORAL INJECTION OF CTLA-4/PD-1 IMMUNE CHECKPOINT INHIBITION FOLLOWING RESECTION OF RECURRENT GLIOBLASTOMA
Authors: Johnny Duerinck, Stephanie Du Four, Lailia Ben Salama, Jennifer De Cremer, Anne Van Binst, Hendrik Everaert, Pieter Theuns, Anne Rogiers, Bart Neyns
Journal: Neuro-Oncology (2017)

Recurrent glioblastoma is a devastating disease for which no treatment has demonstrated to improve overall survival in a randomized clinical trial. Anti-tumor Cytolytic T-cell (CTL) activity is suppressed by the CTLA4 and PD-1 immune-checkpoint receptors. Nivolumab(NIVO) is an IgG-4 mAb that blocks PD-1, and ipilimumab(IPI) an IgG-1 mAb that blocks CTLA-4. In a clinical trial for recurrent glioblastoma (BMS CheckMate143), combination of NIVO and IPI administered IV caused unacceptable toxicity. Animal models showed that intratumoral administration of CTLA-4-blocking mAb at a ratio of [1:100] compared to IV-dosing had equivalent anti-tumor effect and was associated with improved tolerability. An ongoing phase I clinical trial for patients with recurrent glioblastoma (rGB) has currently recruited 5 patients: 2M, 3F, median age 60 (range 38-72). Study treatment consists of surgical resection of rGB with injection of IPI (10mg:2ml) (cohort 1 = first 3 patients) or IPI (5mg:1ml) plus NIVO (10mg:1ml) (cohort 2 = 2 patients at present) in the walls of the resection cavity, concomitant with biweekly IV-administration of 10 mg of NIVO x6. Grade 3 AE consisted of epileptic seizures (1pt in cohort 2) and hemiplegia due to accumulation of serosanguinous fluid in the resection cavity (1pt in cohort 2). Additionally, 4/5 patients developed transient grade 1 pyrexia during the postoperative period. Lymphopenia gr 3 was seen in 4/5 patients. All patients have persisting rim-contrast enhancement on MRI. After median follow-up of 22weeks, two patients have progression of disease (after respectively 13 and 19 weeks). All patients are alive. We conclude from these early results that surgical resection of rGB combined with direct intracerebral injection of IPI alone/with NIVO followed by IV administration of NIVO at the doses administered in this trial is feasible and safe. Updated results of this ongoing clinical trial will be presented at the meeting.
P1.02-047 Mutational Features and Prognosis of Non-Small-Cell Lung Cancer Harboring RAS Mutations
Authors: Y. Zhu, C. Xu, W. Wang, X. Liao, W. Zhuang, Z. Song, Y. Chen, R. Chen, Y. Guan, X. Yi, G. Chen, M. Fang, T. Lv, Y. Song
Journal: Journal of Thoracic Oncology (2017)
Paludismo y turismo: análisis retrospectivo de los casos de paludismo importado de la República Dominicana en Alemania
Authors: J Richter, A Sagir, A. Schöneberg, K Alpers, D Häussinger
Journal: Eurosurveillance (2001)

Este articulo resume los casos de paludismo contraido por turistas alemanes entre julio de 1999 y marzo de 2000 en una zona calificada anteriormente de no endemica en la Republica Dominicana. El paludismo por P. falciparum es endemico en las provincias occidentales y en el interior de la Republica Dominicana. Sin embargo, el riesgo de contraer paludismo en los principales complejos turisticos de la region oriental del pais siempre se ha considerado tan bajo que nunca se ha recomendado quimioprofilaxis antipaludica (1).
ANGI-01. FIBROBLAST GROWTH FACTOR 13 REGULATES GLIOMA CELL INVASION
Authors: Yoshihiro Otani, Tomotsugu Ichikawa, Kazuhiko Kurozumi, Satoshi Inoue, Joji Ishida, Tetsuo Oka, Toshihiko Shimizu, Yusuke Tomita, Yasuhiko Hattori, Atsuhito Uneda, Yuji Matsumoto, Hiroyuki Michiue, Isao Date
Journal: Neuro-Oncology (2017)

Glioblastoma has a poor prognosis, and its aggressive nature including excessive invasion and angiogenesis. To reveal the invasive mechanisms, we previously established two glioma cell lines (J3T-1 and J3T-2) with different invasive phenotypes. J3T-1 exhibited abundant angiogenesis and tumor cell invasion around neovasculature, while J3T-2 exhibited diffuse cell invasion into surrounding normal parenchyma. Invasion-related genes in J3T-2 cells were identified using microarray analyses of both cell lines, and their intracellular and intratumoral distribution patterns were evaluated in J3T-2 cell lines, human glioma cell lines, human glioblastoma stem cells, and human glioblastoma specimens. In addition, we revealed the role of the invasion-related genes in vitro and in vivo. Fibroblast growth factor 13 (FGF13) was up-regulated in J3T-2 cells compared to J3T-1 cells. The expression level of FGF13 was also overexpressed in human glioma cell lines, human glioblastoma stem cells, and human glioblastoma specimens, when compared to that of normal human astrocytes. The RNA-seq data from the IVY Glioblastoma Atlas Project and immunohistochemical staining of glioblastoma specimens showed FGF13 expression in glioma cells in the invasive edges. The intracellular distribution was mainly in the cytoplasm of tumor cells and colocalized with tubulin. Overexpression of FGF13 stabilized tubulin dynamics in vitro and knockdown of FGF13 inhibited glioma invasion both in vitro and in vivo. Moreover, silencing of FGF13 also decreased bevacizumab-induced glioma invasion in vitro and in vivo. FGF13 regulated glioma cell invasion. Our results suggested that FGF13 could be a promising new target to treat and prevent glioma invasion.
Concomitant versus sequential Fotemustine and Bevacizumab in recurrent malignant gliomas: treatment response and survival outcomes in a retrospective analysis
Authors: A. Prelaj, S.E. Rebuzzi, J.R. Giròn Berrìos, S. Pecorari, C. Fusto, C. Ferrara, M. Salvati, S. Tomao, V. Bianco
Journal: Annals of Oncology (2017)
P1.08-009 Neutrophilia as Prognostic Biomarker in Locally Advanced Stage III Lung Cancer
Authors: A. Schernberg, L. Mezquita, A. Boros, C. Caramella, B. Besse, A. Botticella, A. Escande, D. Planchard, C. Le Pechoux, E. Deutsch
Journal: Journal of Thoracic Oncology (2017)
Aumento del número de enterococos resistentes a la vancomicina (VRE) aislados en Helsinki, Finlandia
Authors: J Vuopio-Varkila, J Suppola, N Klinger, E Tarkka, E Kolho
Journal: Eurosurveillance (1997)

La aparicion de infecciones nosocomiales causadas por bacterias resistentes a agentes antimicrobianos, como los enterococos resistentes a la vancomicina (VRE) se ha convertido en un motivo de preocupacion a nivel internacional. En hospitales de los EE UU, los VRE se han propagado rapidamente y en la actualidad son la causa de una de cada diez infecciones nosocomiales por enterococos declaradas al 'National Nosocomial Infections Surveillance Program of the Centers for Disease Control and Prevention' (Programa Nacional de Vigilancia de Infecciones Nosocomiales de los Centros para el Control y Prevencion de Enfermedades) (CDC) (1).
Long-term Sustainability of Diabetes Prevention Approaches
Authors: J. Sonya Haw, Karla I. Galaviz, Audrey N. Straus, Alysse J. Kowalski, Matthew J. Magee, Mary Beth Weber, Jingkai Wei, K. M. Venkat Narayan, Mohammed K. Ali
Journal: JAMA Internal Medicine (2017)

Diabetes prevention is imperative to slow worldwide growth of diabetes-related morbidity and mortality. Yet the long-term efficacy of prevention strategies remains unknown.To estimate aggregate long-term effects of different diabetes prevention strategies on diabetes incidence.Systematic searches of MEDLINE, EMBASE, Cochrane Library, and Web of Science databases. The initial search was conducted on January 14, 2014, and was updated on February 20, 2015. Search terms included prediabetes, primary prevention, and risk reduction.Eligible randomized clinical trials evaluated lifestyle modification (LSM) and medication interventions (>6 months) for diabetes prevention in adults (age ≥18 years) at risk for diabetes, reporting between-group differences in diabetes incidence, published between January 1, 1990, and January 1, 2015. Studies testing alternative therapies and bariatric surgery, as well as those involving participants with gestational diabetes, type 1 or 2 diabetes, and metabolic syndrome, were excluded.Reviewers extracted the number of diabetes cases at the end of active intervention in treatment and control groups. Random-effects meta-analyses were used to obtain pooled relative risks (RRs), and reported incidence rates were used to compute pooled risk differences (RDs).The main outcome was aggregate RRs of diabetes in treatment vs control participants. Treatment subtypes (ie, LSM components, medication classes) were stratified. To estimate sustainability, post-washout and follow-up RRs for medications and LSM interventions, respectively, were examined.Forty-three studies were included and pooled in meta-analysis (49 029 participants; mean [SD] age, 57.3 [8.7] years; 48.0% [n = 23 549] men): 19 tested medications; 19 evaluated LSM, and 5 tested combined medications and LSM. At the end of the active intervention (range, 0.5-6.3 years), LSM was associated with an RR reduction of 39% (RR, 0.61; 95% CI, 0.54-0.68), and medications were associated with an RR reduction of 36% (RR, 0.64; 95% CI, 0.54-0.76). The observed RD for LSM and medication studies was 4.0 (95% CI, 1.8-6.3) cases per 100 person-years or a number-needed-to-treat of 25. At the end of the washout or follow-up periods, LSM studies (mean follow-up, 7.2 years; range, 5.7-9.4 years) achieved an RR reduction of 28% (RR, 0.72; 95% CI, 0.60-0.86); medication studies (mean follow-up, 17 weeks; range, 2-52 weeks) showed no sustained RR reduction (RR, 0.95; 95% CI, 0.79-1.14).In adults at risk for diabetes, LSM and medications (weight loss and insulin-sensitizing agents) successfully reduced diabetes incidence. Medication effects were short lived. The LSM interventions were sustained for several years; however, their effects declined with time, suggesting that interventions to preserve effects are needed.
P2.01-011 The Efficiency and Safety of Apatinib plus S-1 as Second-Line or Laterline Chemotherapy for Advanced Squamous Cell Lung Carcinoma
Authors: Q. Shi, X. Guo, Z. Wang, X. Cheng, L. Xia, X. Li, W. Hu, F. Zhao, Y. Liu, J. Wang, F. Wang
Journal: Journal of Thoracic Oncology (2017)