tbuckley/cabot-search huggingface dataset:
P07.05 Intravenous delivery of oncolytic reovirus to brain tumours in patients to immunologically prime for sequential checkpoint blockade
Authors: A. Samson, K. Scott, D. Taggart, E. West, E. Wilson, G. Nuovo, S. Thomson, L. Stead, S. Short, A. Melcher
Journal: Neuro-Oncology (2017)

Introduction: Therapies targeting T-cell inhibitory checkpoint signalling pathways are redefining cancer survival in many solid malignancies. Unfortunately only a minority of patients respond, with mounting evidence that tumour response and patient survival are significantly associated with the presence of tumour PD-L1 expression, which prevents immune activation in situ within the tumour. We hypothesised that pre-conditioning of the tumour immune microenvironment using targeted, virus-mediated interferon stimulation, would upregulate PD-L1 protein expression and improve the efficacy of sequential checkpoint blockade. Oncolytic viruses (OV) stimulate anti-tumour immunity, and represent a promising novel form of cancer immunotherapy. However almost all brain tumour studies to date administer OV via intra-lesion injection, following a largely untested belief that intra-venous (IV) administration will not deliver virus to this site, due to exclusion by the blood brain barrier. Materials and Methods: In this window-of-opportunity clinical study 9 patients were injected IV once with 1x1010 TCID50 of oncolytic human Orthoreovirus (reovirus) ahead of planned surgical resection of their brain tumour. Following resection, tumour tissue was analysed by RNAseq and virus presence assayed by IHC, in-situ-hybridisation, electron microscopy and qPCR. Virus regulated expression of PD1/PDL1 axis was determined in ex vivo brain tumour culture, and intracranial tumour models were used to assess combination treatment of OV and checkpoint therapy. Results: Here we show that IV injection of reovirus leads to infection of tumour cells both in high grade glioma and brain metastases. Reovirus σ3 protein and RNA were detected in all tumour samples by at least one detection method. RNAseq analysis indicated reovirus upregulates interferon-regulated gene expression in tumours, and we further show in stem-like cell lines and ex vivo primary human tumour cultures that the PD-1/PD-L1 axis is altered across both target tumour and immune effector cells via an IFN-mediated mechanism. Finally, in a pre-clinical glioma model we demonstrate significantly enhanced clinical therapy using combination treatment of PD-1 blockade and reovirus. CONCLUSION: These results support the development of novel combination, systemic immuno-virotherapy strategies for the treatment of both primary and secondary tumours in the brain.
Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: a randomised, double-blind, placebo-controlled phase 2 trial
Authors: Enrico Bertini, Eric Dessaud, Eugenio Mercuri, Francesco Muntoni, Janbernd Kirschner, Carol Reid, Anna Lusakowska, Giacomo P Comi, Jean-Marie Cuisset, Jean-Louis Abitbol, Bruno Scherrer, Patricia Sanwald Ducray, Jeppe Buchbjerg, Eduardo Vianna, W Ludo van der Pol, Carole Vuillerot, Thomas Blaettler, Paulo Fontoura, Carole André, Claudio Bruno, Brigitte Chabrol, Nicolas Deconinck, Brigitte Estournet, Stephanie Fontaine-Carbonnel, Nathalie Goemans, Ksenija Gorni, Alessandra Govoni, Michela Guglieri, Hanns Lochmuller, Francesca Magri, Michele Mayer, Wolfgang Müller-Felber, François Rivier, Helen Roper, Ulrike Schara, Mariacristina Scoto, Leonard van den Berg, Giuseppe Vita, Maggie C Walter
Journal: The Lancet Neurology (2017)
PathOS: a decision support system for reporting high throughput sequencing of cancers in clinical diagnostic laboratories
Authors: Kenneth D. Doig, Andrew Fellowes, Anthony H. Bell, Andrei Seleznev, David Ma, Jason Ellul, Jason Li, Maria A. Doyle, Ella R. Thompson, Amit Kumar, Luis Lara, Ravikiran Vedururu, Gareth Reid, Thomas Conway, Anthony T. Papenfuss, Stephen B. Fox
Journal: Genome Medicine (2017)

The increasing affordability of DNA sequencing has allowed it to be widely deployed in pathology laboratories. However, this has exposed many issues with the analysis and reporting of variants for clinical diagnostic use. Implementing a high-throughput sequencing (NGS) clinical reporting system requires a diverse combination of capabilities, statistical methods to identify variants, global variant databases, a validated bioinformatics pipeline, an auditable laboratory workflow, reproducible clinical assays and quality control monitoring throughout. These capabilities must be packaged in software that integrates the disparate components into a useable system. To meet these needs, we developed a web-based application, PathOS, which takes variant data from a patient sample through to a clinical report. PathOS has been used operationally in the Peter MacCallum Cancer Centre for two years for the analysis, curation and reporting of genetic tests for cancer patients, as well as the curation of large-scale research studies. PathOS has also been deployed in cloud environments allowing multiple institutions to use separate, secure and customisable instances of the system. Increasingly, the bottleneck of variant curation is limiting the adoption of clinical sequencing for molecular diagnostics. PathOS is focused on providing clinical variant curators and pathology laboratories with a decision support system needed for personalised medicine. While the genesis of PathOS has been within cancer molecular diagnostics, the system is applicable to NGS clinical reporting generally. The widespread availability of genomic sequencers has highlighted the limited availability of software to support clinical decision-making in molecular pathology. PathOS is a system that has been developed and refined in a hospital laboratory context to meet the needs of clinical diagnostics. The software is available as a set of Docker images and source code at https://github.com/PapenfussLab/PathOS .
OS01.4 Induction of differential macrophage and microglial glioblastoma phagocytosis by anti CD47 treatment - implication of tumor subtypes
Authors: G. Hutter, J. L. Theruvath, S. A. Kahn, C. M. Graef, M. K. Schoen, S. Gholamin, E. M. Manz, I. L. Weissman, S. S. Mitra, S. H. Cheshier
Journal: Neuro-Oncology (2017)

Introduction: Modulation of macrophages and microglia (tumor associated macrophages, TAMs) in glioblastoma (GBM) poses a strategy against the disease. But little is known about the composition of the TAM-pool and the role of GBM subtypes in shaping their microenvironment. Thus, we sought to decipher the contribution of peripheral macrophages and microglia to the GBM-TAM-pool and their response to myeloid modulation such as CD47-Sirpa disruption with CD47 blocking antibodies. Methods: We generated immunodeficient mice with genetically color-coded macrophages and microglia. B6 Ccr2Rfp/+Cx3cr1Gfp/+ mice were crossed to NSG (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ)-mice, and termed Ccr2Rfp/+Cx3cr1Gfp/+NSG-mice. Further, Ccr2Rfp/RfpCx3cr1Gfp/+NSG-mice devoid of macrophage influx to the brain were generated. Mice were grafted with patient-derived GBM cell lines transduced with EBFP2-luciferase, and treated with anti-CD47 Mab. At endpoint, tumors were analyzed by flow cytometry to assess TAM composition, polarization and phagocytosis, and both microglial and macrophage TAMs sorted for RNAseq analysis. Plasma cytokines were assessed. Further, brain tumors were imaged through cranial windows using in vivo confocal and 2-photon microscopy to monitor macrophage and microglial phagocytosis and behavior upon anti-CD47 treatment in real time. Results: The composition of the TAM pool was highly variable depending on the xenografted cell line. While TAMs in diffuse, slow growing tumors almost exclusively consisted of microglia, high-passage mesenchymal and classical GBM lines induced significant peripheral macrophage influx. In contrast, TAMs of proneural tumors only had a minor macrophage component. Anti-CD47 treatment induced macrophage and microglial phagocytosis and a marked microglial morphology change assessed by intracranial in vivo imaging and flow-cytometry. Furthermore, anti-CD47 treatment led to modest peripheral macrophage recruitment to the tumor site in the absence of Ccr2. Anti-CD47 treatment in absence of Ccr2 was accompanied by a stronger proinflammatory cytokine profile compared to wildtype, and significantly improved survival of tumor burdened mice in presence or absence of Ccr2. RNAseq analysis of sorted macrophages and microglia after anti-CD47 treatment revealed a transcriptional change towards a proinflammatory and M1-polarized signature in macrophages, whereas microglia displayed a distinct loss of M2-related genes. Conclusion: The GBM TAM pool is dynamic and dependent on tumor- specific characteristics. Resident microglia by themselves are able to respond to anti-CD47 treatment and act as phagocytic effector cells that reduce GBM growth and improve survival. Additional recruitment and reprogramming of peripheral macrophages by CD47-blockade boosts the therapeutic response and points towards macrophage-microglial cooperativity.
Combined Targeting of STAT3 and STAT5: A Novel Approach to Overcome Drug Resistance in Ph+ Cml
Authors: Karoline V Gleixner, Mathias A Schneeweiss, Harald Herrmann, Katharina Blatt, Daniela Berger, Gregor Eisenwort, Georg Greiner, Konstantin Byrgazov, Gregor Hoermann, Marina Konopleva, Islam Waliul, Patrick T Gunning, Hiroshi Maeda, Richard Moriggl, Michael W. Deininger, Thomas Lion, Michael Andreeff, Peter Valent
Journal: Blood (2016)
P10.04 Anti-angiogenetic Therapy with Bevacizumab for Gliomas with a Gliomatosis Cerebri Growth Pattern
Authors: M. C. Burger, I. C. Mildenberger, M. Wagner, M. Mittelbronn, J. P. Steinbach
Journal: Neuro-Oncology (2017)

Anti-angiogenetic therapy is widely used in patients with glioma in the relapse situation. In glioblastoma and glioma, bevacizumab has been shown to have an impact on progression-free survival and neurologic function, but not on overall survival. However, its use on patients with gliomas showing a gliomatosis cerebri growth pattern is still more controversial. Due to the mainly diffuse infiltrative growth of these tumors, it may appear questionable whether bevacizumab can have a therapeutic effect in patients with these tumors. However, the development of nodular, necrotic and/or contrast-enhancing lesions in patients with a gliomatosis cerebri pattern is not uncommon and may indicate active neo-angiogenesis. Therefore, control of growth of these lesions as well as control of edema and reduction of steroid use may be viewed as rationales for the use of bevacizumab in these patients. In this patient series, we report on seventeen patients with primary brain tumors and a gliomatosis cerebri growth pattern (seven glioblastoma WHO°IV, two anaplastic astrocytoma WHO°III, one anaplastic oligodendroglioma WHO°III, seven astrocytoma WHO°II) treated with bevacizumab alone or in combination with lomustine or irinotecan. We found bevacizumab to be active with response rates, progression-free survival and overall survival intervals comparable to a control cohort of patients with gliomas of a less infiltrative phenotype. Based on these results, anti-angiogenic therapy with bevacizumab should also be considered in patients suffering from gliomas of a mainly infiltrative phenotype.
Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition
Authors: Jane Goodall, Joaquin Mateo, Wei Yuan, Helen Mossop, Nuria Porta, Susana Miranda, Raquel Perez-Lopez, David Dolling, Dan R. Robinson, Shahneen Sandhu, Gemma Fowler, Berni Ebbs, Penny Flohr, George Seed, Daniel Nava Rodrigues, Gunther Boysen, Claudia Bertan, Mark Atkin, Matthew Clarke, Mateus Crespo, Ines Figueiredo, Ruth Riisnaes, Semini Sumanasuriya, Pasquale Rescigno, Zafeiris Zafeiriou, Adam Sharp, Nina Tunariu, Diletta Bianchini, Alexa Gillman, Christopher J. Lord, Emma Hall, Arul M. Chinnaiyan, Suzanne Carreira, Johann S. de Bono
Journal: Cancer Discovery (2017)

Abstract Biomarkers for more precise patient care are needed in metastatic prostate cancer. We have reported a phase II trial (TOPARP-A) of the PARP inhibitor olaparib in metastatic prostate cancer, demonstrating antitumor activity associating with homologous recombination DNA repair defects. We now report targeted and whole-exome sequencing of serial circulating cell-free DNA (cfDNA) samples collected during this trial. Decreases in cfDNA concentration independently associated with outcome in multivariable analyses (HR for overall survival at week 8: 0.19; 95% CI, 0.06–0.56; P = 0.003). All tumor tissue somatic DNA repair mutations were detectable in cfDNA; allele frequency of somatic mutations decreased selectively in responding patients (χ2 P &amp;lt; 0.001). At disease progression, following response to olaparib, multiple subclonal aberrations reverting germline and somatic DNA repair mutations (BRCA2, PALB2) back in frame emerged as mechanisms of resistance. These data support the role of liquid biopsies as a predictive, prognostic, response, and resistance biomarker in metastatic prostate cancer. Significance: We report prospectively planned, serial, cfDNA analyses from patients with metastatic prostate cancer treated on an investigator-initiated phase II trial of olaparib. These analyses provide predictive, prognostic, response, and resistance data with “second hit” mutations first detectable at disease progression, suggesting clonal evolution from treatment-selective pressure and platinum resistance. Cancer Discov; 7(9); 1006–17. ©2017 AACR. See related commentary by Domchek, p. 937. See related article by Kondrashova et al., p. 984. See related article by Quigley et al., p. 999. This article is highlighted in the In This Issue feature, p. 920
30-second chair-stand test is a valuable evaluation in chronic respiratory diseases
Authors: Daigo Kato, Makoto Fueki, Yasuhiro Endo, Daisuke Uga, Kunio Dobashi, Rie Nakazawa, Masaaki Sakamoto
Journal: European Respiratory Journal (2014)

[Introduction] 6-Minute Walk Test (6MWT) is a valuable tool for measuring exercise tolerance in patients with chronic respiratory diseases (CRD). However, severe CRD patients often show marked depression in SpO2 during or after walking that leads to interruption of 6MWT. Therefore we tried to evaluate their exercise tolerance by 30-second Chair-Stand Test (CS-30). CS-30 used to be performed for evaluating physical fitness in elderly who were instructed to stand up and sit down on the chair as fast as possible during a 30-second period. This study is aimed at confirming usefulness of CS-30 as one of safe assessments for exercise tolerance in CRD.  [Methods] 33 patients with CRD (18 COPD / 15 IPF. Age73.7±9.6 yrs) performed 6MWT and CS-30. SpO2 was recorded before and after the tests. In COPD, muscle strength of quadriceps was measured by hand-held dynamometer.  [Results] Significant correlation between 6-minute walking distance (383.0±99.6m) and frequency of standing-up (13.9±4.4times) was found (p  [Conclusion] CS-30 can evaluate exercise tolerance in patients with CRD like 6MWT. This study suggests that CS-30 is a valuable method to evaluate exercise tolerance in CRD patients who show SpO2 depression with exercise.
Smoking History Predicts Sensitivity to PARP Inhibitor Veliparib in Patients with Advanced Non–Small Cell Lung Cancer
Authors: Martin Reck, Normand Blais, Erzsebet Juhasz, Vera Gorbunova, C. Michael Jones, Laszlo Urban, Sergey Orlov, Fabrice Barlesi, Ebenezer Kio, Ulrich Keilholz, Qin Qin, Jiang Qian, Caroline Nickner, Juliann Dziubinski, Hao Xiong, Rajendar K. Mittapalli, Martin Dunbar, Peter Ansell, Lei He, Mark McKee, Vincent Giranda, Suresh S. Ramalingam
Journal: Journal of Thoracic Oncology (2017)

IntroductionTobacco-related NSCLC is associated with reduced survival and greater genomic instability. Veliparib, a potent poly(adenosine diphosphate–ribose) polymerase inhibitor, augments platinum-induced DNA damage. A phase 2 trial of untreated advanced NSCLC showed a trend for improved outcomes (hazard ratio [HR] = 0.80, 95% confidence interval: 0.54–1.18, p = 0.27 for overall survival and HR = 0.72, 95% CI: 0.45–1.15, p = 0.17 for progression-free survival) when veliparib was added to carboplatin/paclitaxel. Here we report an exploratory analysis by smoking history.MethodsPatients were randomized 2:1 to receive carboplatin/paclitaxel with veliparib, 120 mg (n = 105), or placebo (n = 53). Patients were stratified by histologic subtype and smoking history (recent smokers [n = 95], former smokers [n = 42], and never-smokers [n = 21]). Plasma cotinine level was measured as a chemical index of smoking. Mutation status was assessed by whole exome sequencing (n = 38).ResultsSmoking history, histologic subtype, age, Eastern Cooperative Oncology Group performance status, sex, and geographic region predicted veliparib benefit in univariate analyses. In multivariate analysis, history of recent smoking was most predictive for veliparib benefit. Recent smokers treated with veliparib derived significantly greater progression-free survival and overall survival benefits (HR = 0.38 [p < 0.01] and HR = 0.43 [p < 0.01]) than former smokers (HR = 2.098 [p = 0 0208] and HR = 1.62 [p = 0.236]) and never-smokers (HR = 1.025 [p = 0.971] and HR = 1.33 [p = 0.638]). Sequencing data revealed that mutational burden was not associated with veliparib benefit. The rate of grade 3 or 4 adverse events was higher in recent smokers with veliparib treatment; all-grade and serious adverse events were similar in both treatment arms.ConclusionsSmoking history predicted for efficacy with a veliparib-chemotherapy combination; toxicity was acceptable regardless of smoking history. A prespecified analysis of recent smokers is planned for ongoing phase 3 studies of veliparib in NSCLC.
P08.21 Discovery of CT-179--a small molecule inhibitor of the transcription factor OLIG2 with potent anti-tumour activity in high-grade glioma
Authors: S. Chen, S. A. Greenall, G. Beaton, G. Stein, G. Alton, T. G. Johns
Journal: Neuro-Oncology (2017)

OLIG2 is a protein transcription factor that is expressed exclusively in progenitor cells in the brain and spinal cord during development. Typically, OLIG2 is not active in the adult brain and is not found outside the central nervous system; however, it is re-expressed in most patients with high-grade glioma (HGG). The expression of OLIG2 potentially drives the growth, invasiveness, and resistance to radiation of HGG cells and tumours in animal models. CT-179 is a small molecule (M.W. 397) that, on the basis of homology modelling studies, is a putative disruptor of OLIG2 homodimerization. We found that, at low nanomolar concentrations, CT-179 profoundly inhibited the growth of, and induced apoptosis in, a range of patient-derived HGG cell lines. Approximately half of the HGG cell lines showed substantial degradation of OLIG2 protein, and this was associated with arrest of the cells in the G2/M phase of the cell cycle. We are currently exploring whether this leads to mitotic catastrophe. Additionally, CT-179 caused significant downregulation of receptor tyrosine kinases that are associated with HGG tumorigenicity, including epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR). Orally administered CT-179 (20 mg/kg) crossed the blood-brain barrier of intact mice and reached levels sufficient to inhibit HGG cells. Indeed, the growth of established orthotopic HGG xenografts in mice was significantly inhibited by orally or intraperitoneally administered CT-179, leading to increased survival. CT-179 is one of the few small molecules that has been identified to directly inhibit the function of a transcription factor. Our experiments showing the profound anti-tumour activity of CT-179 in HGG models provide the impetus needed for moving this molecule into the clinic as a novel therapy for patients with HGG.
Epidemiology of injuries in judo: a cross-sectional survey of severe injuries based on time loss and reduction in sporting level
Authors: Ralph Akoto, Christophe Lambert, Maurice Balke, Bertil Bouillon, Karl-Heinz Frosch, Jürgen Höher
Journal: British Journal of Sports Medicine (2017)

Sport injury severity can be detected by duration of time loss and reduction of sporting performance.To detect injury type-specific time loss duration and sporting performance reduction in judo.An online survey of active and former judo athletes was conducted (exclusion criterion: incomplete questionnaire). Only injuries causing more than 3 weeks' time loss were recorded. Athletes classified themselves into performance classes. Injury type-specific frequencies were recorded according to gender, age and performance level. Injury severity was assessed by time loss duration and performance reduction.The study included 4659 athletes (65% male, 38% competitive sports). The most commonly injured body regions were the upper extremity (41%) and the lower extremity (39%). Anterior cruciate ligament (ACL) ruptures were the most severe injury type (time loss: 4% of cases 3-6 weeks, 6% 6-12 weeks, 26% 3-6 months, 32% 6-9 months, 18% 9-12 months, 14%>12 months; performance reduction: 32% same level, 39% slightly reduced, 24% strongly reduced, 5% stopped judo). The second most severe type of injury was a vertebral disc prolapse (time loss: 26% 3-6 weeks, 31% 6-12 weeks, 20% 3-6 months, 7% 6-9 months, 3% 9-12 months 13%>12 months; reduction of sporting performance: 39% same level, 34% slightly reduced, 20% strongly reduced, 8% stopped judo).Across genders and performance levels, ACL ruptures and vertebral disc prolapses were the most severe injuries with respect to time loss and sporting performance reduction.