tbuckley/cabot-search huggingface dataset:
Irinotecan plus platinum analog (IP) compared to etoposide plus platinum analog (EP) in extensive stage small cell lung cancer (ED-SCLC): Systematic review with meta-analysis
Authors: E. C. Sasse, J. P. Lima, L. V. Santos, A. D. Sasse
Journal: Journal of Clinical Oncology (2009)

8105 Background: Superiority of irinotecan/cisplatin over etoposide/cisplatin in ED-SCLC has been a matter of debate with contradictory findings in randomized trials. Methods: PUBMED, EMBASE, CENTRAL databases, ClinicalTrials.gov, ASCO, IASLC, ESMO Meeting sites were searched. Eligible studies were randomized trials comparing first-line IP versus EP in ED-SCLC patients. The primary outcome measure was overall survival (OS); secondary endpoints of interest were progression-free survival (PFS), response rate (RR), and toxicity. Two reviewers independently assessed eligibility, quality, and time-to-event (TTE) outcomes. Hazard ratios (HR) were derived from reported TTE outcomes or extracted using Parmar methods with 95% confidence intervals (CI). Odds Ratio (OR) was used to compare dichotomous data. A fixed effect model was used for meta-analysis. Results: Six studies were identified. Four of them had sufficient data to be included (four for OS and three for PFS). The data coming from 1,365 patients showed a HR for OS favoring IP, with significant heterogeneity (I 2 =50%). Sensitivity analysis identified one trial with exclusively Japanese population (144 patients). The exclusion of this trial in the meta-analysis resulted in a HR for OS of 0.86 (95% CI=0.76 - 0.97, p=0.01) still favoring IP, with no heterogeneity (I 2 =3%). For PFS, there was also significant heterogeneity between trials. After excluding the Japanese trial the HR for PFS was of 0.96 (95% CI=0.85 - 1.09, p=0.54) with acceptable heterogeneity. The ITT RRs were 60% for IP and 49% for EP (p&lt;0.0001). Grade 3/4 diarrhea was more frequent in IP group while anemia, leucopenia and thrombocytopenia were more frequent in EP. Conclusions: The present meta-analysis demonstrates statistically significant OS benefit of IP over EP in westerns patients. Specific characteristics in safety profile should be taken into account when administrating IP. No significant financial relationships to disclose.
Mutant p53 Enhances the Development and Sustained Growth of MYC-Driven Lymphoma and Exerts a Dominant Negative Effect Preferentially Deregulating Pathways for Metabolism and DNA Repair
Authors: Brandon J Aubrey, Ana Janic, Yunshun Chen, Gordon K Smyth, Andrew J Kueh, Stephen Wilcox, Margs S Brennan, Lin Tai, Daniel HD Gray, Charis Teh, Ann Lin, Catherine Chang, Lorraine A O'Reilly, Marco J Herold, Andreas Strasser, Gemma L Kelly
Journal: Blood (2016)
Identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis
Authors: L D Bos, L R Schouten, L A van Vught, M A Wiewel, D S Y Ong, O Cremer, A Artigas, I Martin-Loeches, A J Hoogendijk, T van der Poll, J Horn, N Juffermans, C S Calfee, M J Schultz
Journal: Thorax (2017)

<h3>Rationale</h3> We hypothesised that patients with acute respiratory distress syndrome (ARDS) can be clustered based on concentrations of plasma biomarkers and that the thereby identified biological phenotypes are associated with mortality. <h3>Methods</h3> Consecutive patients with ARDS were included in this prospective observational cohort study. Cluster analysis of 20 biomarkers of inflammation, coagulation and endothelial activation provided the phenotypes in a training cohort, not taking any outcome data into account. Logistic regression with backward selection was used to select the most predictive biomarkers, and these predicted phenotypes were validated in a separate cohort. Multivariable logistic regression was used to quantify the independent association with mortality. <h3>Results</h3> Two phenotypes were identified in 454 patients, which we named 'uninflamed' (N=218) and 'reactive' (N=236). A selection of four biomarkers (interleukin-6, interferon gamma, angiopoietin 1/2 and plasminogen activator inhibitor-1) could be used to accurately predict the phenotype in the training cohort (area under the receiver operating characteristics curve: 0.98, 95% CI 0.97 to 0.99). Mortality rates were 15.6% and 36.4% (p&lt;0.001) in the training cohort and 13.6% and 37.5% (p&lt;0.001) in the validation cohort (N=207). The 'reactive phenotype' was independent from confounders associated with intensive care unit mortality (training cohort: OR 1.13, 95% CI 1.04 to 1.23; validation cohort: OR 1.18, 95% CI 1.06 to 1.31). <h3>Conclusions</h3> Patients with ARDS can be clustered into two biological phenotypes, with different mortality rates. Four biomarkers can be used to predict the phenotype with high accuracy. The phenotypes were very similar to those found in cohorts derived from randomised controlled trials, and these results may improve patient selection for future clinical trials targeting host response in patients with ARDS.
Is it time to loosen the restrictions on athletes with cardiac disorders competing in sport?
Authors: Rui Providência, Carina Teixeira, Oliver Segal, Augustus Ullstein, Kim T Mueser, Pier Lambiase
Journal: British Journal of Sports Medicine (2017)

Sudden cardiac death (SCD) in young athletes is a rare and dramatic event.Initial consensus guidelines from 2005 recommend restriction from competitive sports for all athletes with hereditary cardiomyopathies and channelopathies, with very minor exceptions. 1
OS02.2 Functional investigation of recurrent genetic aberrations in newly identified pediatric brain tumor entities
Authors: S. van Rijn, M. Kool
Journal: Neuro-Oncology (2017)

Primitive neuroectodermal tumors of the central nervous system (CNS-PNET) are aggressive tumors that predominantly occur in children and adolescents. The current treatment options include surgery, radiotherapy and chemotherapy and while ~50% of the patients survive, the treatment results in a variety of developmental and cognitive problems at a later age. CNS-PNET is a designation of a molecularly heterogeneous group of embryonal tumors characterized by poor cellular differentiation, histopathological overlap with other high-grade neuronal tumors and a lack of defining molecular markers. The inability to adequately classify these tumors hampers our understanding of the underlying molecular mechanisms and may result in aberrant treatment of patients. Recently our lab identified four novel pediatric CNS tumor entities derived from the molecular classification of histopathologically diagnosed primitive neuroectodermal tumors. These tumor entities differ in histopathology and clinical presentation and can be classified by a single recurrent genomic aberration. We have consequently renamed them CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2), CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC), CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) and CNS neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR). We have attempted to model these tumors by overexpression of aforementioned genetic aberrations in mouse brain by in utero electroporation and ex vivo transfection of neural stem cells and subsequent intracranial injection. In several instances this resulted in tumor growth and further analysis should reveal the nature of these tumors. We aim use the models to perform gene expression arrays and co-immunoprecipitations to identify underlying tumorigenic mechanisms and explore novel strategies to effectively combat these rare but destructive tumors.
P01.16 Cell-free circulating tumor DNA(CfTDNA) in patients with high grade glioma as diagnostic and prognostic biomarker- a guide for future direction.
Authors: H. B. Govardhan, I. A. Khaleel, S. Shubha, T. Arun, T. Naveen, P. Siddanna, P. Satyajit, P. Sridhar
Journal: Neuro-Oncology (2017)

Back ground: High grade gliomas are most aggressive primary brain lesions with limited survival with limited therapeutic option. Many diagnostic and therapeutic trials to improve these issues were in process. Thus in this study we are aiming weather CfTDNA as diagnostic, tool to detect early minimal residual or recurrent disease and to guide for genomically matched therapy. Methods and Material: A total of 27 patients with high grade gliomas who are undergone biopsy or upto near total excision were tested prospectively with 50 gene tumor panel in a NABL accredited laboratory. 4 ml serum was collected, CfTDNA was isolated and they were checked for single nucleotide variants (SNVs) genes/ copy number variants (CNVs) by using NGS and tumor ffpe blocks were again rechecked by NGS or PCR for the same genetic alterations. Results: Average patient age was 32.5 (range 24–60) and 87.5% % were male. In 24/27(88.8%) patients CfTDNA was detected and sufficient to carry under NGS. Out of 50 genes, only 12 genes were detected. In 6/24 (25%) patients had one genomic alteration detected, 25% patients had 3 genetic alteration, another 25% patients had 4 genetic alteration and 3/24(12.5%) patients had 5 and 6 genetic alteration each. SNVs detected included TP53 -21/24(87.5%) patients, PIK3CA and EGFR-50% patients each, PTEN-37.5%, KIT and VHL -25% patents each, RB1, NF 2, MET, ATRX, CDK2A,CTNNB1- in 2–4 patients (8.3–16.6%) each. On combination of these genetic alterations - EGFR, KIT,PTEN, PIK3CA,TP 53, VHL are the main alterations and combination of these gene(Diagostic GENETIC MODULE), at least one genetic alteration among combination was found in 100% patients at any point of time. Further follow up data regarding correlation of these genetic alteration with prognosis will follows. Conclusions: CfTDNA can be easily demonstrable and can be used as non invasive diagnostic tool in brain tumor. Further, to create proper genetic module as diagnostic and prognostic marker- continuation of the study in large scale with different race, ethnicity and country required.
P09.62 Towards individualized survival prediction in glioblastoma patients using machine learning methods
Authors: L. Vera, J. Pérez-Beteta, D. Molina, J. M. Borrás, M. Benavides, J. A. Barcia, C. Velásquez, D. Albillo, P. Lara, V. M. Pérez-García
Journal: Neuro-Oncology (2017)
P02.02 Treatment and Outcomes in Glioblastoma Multiforme: A multi-country chart review study
Authors: A. Shillington, C. Macahilig, J. Shaw, H. Dastani
Journal: Neuro-Oncology (2017)

Background: There is an existing unmet need in glioblastoma multiforme (GBM) due lack of effective treatment options. To understand the treatment landscape as newer agents are in development, it was the objective of this study to gain a better understanding of the current treatment of second line (2L) GBM therapy with related outcomes in a “real-world” setting in Canada, France and Germany. Methods: A retrospective, chart-review study was conducted in each country; 72 oncologists were recruited to contribute patients ≥18 years of age, newly diagnosed with GBM between January 1, 2013 - June 30, 2015 with a minimum of 12 months follow-up or until death. Excluded were those treated with investigational agents. Patients were followed through August 2016. Enrollment was in 2 cohorts, Cohort 1 comprising a random selection of 337 patients irrespective of line of the therapy (LOT). Cohort 2 included 136 patients who received more than one LOT for a total N = 473 (146 each in France and Germany, and 181 in Canada). Demographics and treatment data were analyzed descriptively. Survival was determined using Kaplan-Meier analysis censoring for date of chart abstraction in surviving patients. Results: Patients were 61% male with mean (SD) age of 61.4 (12.0) years at initial diagnosis. Overall, most patients (92%) were treated 1L with temozolomide (TMZ) monotherap and 88% received radiation. In the 337 patient random sample, 97 (29%) received 2L treatment. A total of 233 patients in both cohorts were analyzed for 2L treatment and outcomes. Of all 2L-treated patients the majority were Eastern Cooperative Oncology Group (ECOG) performance grade 1 (38%) or 2 (49%) at the time of 2L start. In 2L, 27% were retreated with TMZ monotherapy, 7% received TMZ in combination with other agents, 40% received bevacizumab either as monotherapy 22%, or combination therapy (18%). In all patients receiving a 2L therapy, complete response following 2L was achieved by 5%, 23% partial response and 29%, stable disease. Median overall survival from start of 2L was 7.5 months (95% CI 6.5 – 8.5) in all patients, (7.0 [95% CI 6–8.1] in France; 6.0 [95% CI 4.5–7.4] in Germany; 10.5 [95% CI 8.6–12.5] in Canada). Conclusions: Most GBM patients received TMZ during 1L and bevacizumab monotherapy or combination therapy during 2L treatment with some regional differences. Survival following initiation of 2L treatment was poor. Prognosis remains grim under current treatment paradigms.
FIRST STEPS TOWARDS PREVENTION OF MUSCULOSKELETAL INJURIES IN SPEED SKATING
Authors: Alexander T.M. van de Water, Matthias Hendricks
Journal: British Journal of Sports Medicine (2017)

Background Musculoskeletal injuries are commonly seen by medical staff of speed skating teams, but lack of injury registration underreports the incidence and prevalence of these injuries. Systematic injury prevention research in speed skating has not been undertaken. Objective Initiating injury prevention research following the 6-step TRIPP framework. Design Qualitative research including literature review and survey amongst medical staff involved with elite level speed skating teams and development of a logbook and risk factor testing battery for musculoskeletal injuries in speed skaters. Setting N/A. Participants Doctors and specialised physiotherapists in sports medicine involved with elite level speed skaters. Assessment of risk factors/methods A qualitative study aimed to initiate the first steps of the TRIPP framework: injury surveillance, aetiology and mechanisms of injury and development of preventative measures. A review for epidemiological studies in speed skaters was conducted. Musculoskeletal injuries and related factors were further explored by interview and expert survey. Measurements Literature review for epidemiological studies, interview and survey. Results Four epidemiological studies reported on musculoskeletal injury prevalence (one season) between 24 to 60%. The expert survey (n=5, mean experience in sport=10.4 years) identified the lower back (100%), gluteal/pelvic area (80%) and the hip/groin, knee and lower leg (60%) as most commonly injured. The specific speed skating position and technique, kinetic chain instability, reduced joint mobility and falls were identified as risk factors for musculoskeletal injuries. Based on these results, an injury registration system, logbook, physical tests screening battery were created for pilot testing. Conclusions This study described the first steps towards injury prevention using the TRIPP framework. Limitations are the small scale study and work at preliminary stages. However, there is underreporting of injuries in speed skaters and potential underestimation of the problem. Future research continues to focus on injury surveillance, aetiology and mechanisms of injury and development of preventative measures.
P10.17 Predicting isocitrate dehydrogenase genotype in malignant glioma using FET PET radiomics
Authors: P. Lohmann, C. Lerche, E. Bauer, J. Steger, G. Stoffels, C. P. Filss, C. Stegmayr, B. Neumaier, N. J. Shah, K. Langen, N. Galldiks
Journal: Neuro-Oncology (2017)

Introduction: Accurately determining isocitrate dehydrogenase (IDH) genotype pre-operatively may have both prognostic and diagnostic value that contributes to treatment decision-making. Here, we investigated the potential of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET textural features in comparison with standard static and dynamic FET PET parameters for differentiation of IDH-mutated anaplastic astrocytoma (mut-AA) from IDH-wildtype glioblastoma (wt-GBM). Materials and Methods: Thirty-six patients with histologically confirmed malignant glioma (26 wt-GBM, 10 mut-AA) based on the updated WHO classification 2016 underwent a dynamic FET PET. Volumes-of-interest were defined on summed images from 20-40 min post-injection (p.i.) by a 3-dimensional auto-contouring process using a tumor-to-brain ratio (TBR) of 1.6 or more. For each lesion, TBRs and the time-activity curves (TACs) of the FET uptake were determined. The TACs were used to evaluate the dynamic FET PET parameters time-to-peak (TTP), slope (slope of linear regression line 20-50 min p.i.) and intercept (intercept of linear regression line with y-axis). Additionally, 39 textural parameters were calculated using the software LifeX (lifexsoft.org). The diagnostic accuracy of TBRs, TTP, slope, intercept, and textural parameters for prediction of IDH genotype was evaluated using ROC analyses. In order to further increase the diagnostic accuracy, parameters were combined using linear logistic regression. Results: The standard static FET PET parameters TBRmean and TBRmax showed a diagnostic accuracy to discriminate between IDH genotypes of 78% and 75%, respectively. The dynamic FET PET parameters TTP, slope, and intercept yielded an accuracy of 69%, 81% and 72%, respectively. The best five textural parameters showed a diagnostic accuracy of 81%. Parameter combinations could not further increase the diagnostic accuracy. Conclusions: Textural feature analysis may have the potential to predict the IDH genotype of malignant gliomas without the need for acquiring a more time consuming dynamic FET PET acquisition. Textural parameters might yield additional valuable information about tumor heterogeneity and should be further evaluated prospectively in larger cohort of patients.
How to Monitor Immune Reconstitution Following Allogeneic Hematopoietic Stem Cell Transplantation: A Survey from the EBMT- Cellular Therapy &amp; Immunobiology Working Party
Authors: Raffaella Greco, Fabio Ciceri, Maddalena Noviello, Attilio Bondanza, Luca Vago, Giacomo Oliveira, Jacopo Peccatori, Nicoletta Cieri, Annalisa Ruggeri, Ulrike Koehl, Katharina Fleischhauer, Vanderson Rocha, Francesco Dazzi, Steffie Maria van der Werf, Sofie Rosanne Terwel, Antoine Toubert, Christian Chabannon, Chiara Bonini
Journal: Blood (2016)
Abstract 239: Nitric Oxide Suppresses the Angiogeneic Potential of Mesenchymal Stem Cells
Authors: Samirah A Gomes, Erika B Rangel, Courtney Premer, Raul Dulce, Yenong Cao, Claudia O Rodrigues, Wayne Balkan, Joshua M Hare
Journal: Circulation Research (2012)

Introduction: Mesenchymal stem cells (MSCs) participate in blood vessel formation which is crucial for tissue regeneration. However, the mechanism involved in regulating MSC angiogenesis remains elusive. We examined the role of Nitric Oxide (NO) in this process by comparing angiogenesis by MSCs derived from wild type mice and mice lacking S-nitrosoglutathione reductase (GSNOR-/-), an enzyme that increases intracellular GSNO and enhances endogenous S-nitrosylation (a ubiquitous redox-related modification of cysteine thiol by NO) Hypothesis: Nitric oxide signaling pathways are mediated via small molecular thiols that regulate MSC angiogenesis. Method: Bone marrow-derived MSCs were isolated from wild type and GSNOR-/- mice and grown for 7 days in endothelial growth media followed by 24h in Matrigel (in vitro angiogenesis assay) in the presence of either vehicle, 15µM L-NAME (a nitric oxide synthase (NOS) inhibitor) or 500µM SNAP (a nitric oxide donor). Human (h)MSCs were similarly treated with vehicle, 15µM L-NAME and 100µM SNAP. MSC NO production and NOS expression were assessed. Results: Both types of MSCs exhibited similar levels of NO production and NOS expression, however, in the Matrigel Assay, MSCs from GSNOR-/- mice formed fewer (29.9±12.0 vs.. 50.0±15.4, p&lt;0.001) and shorter (62.8 ± 34.6 µm vs. 105.9±57.0 µm, p&lt;0.001) tubes than MSCs derived from wild type mice. L-NAME treatment normalized GSNOR-/- tube number (49.9 ± 14.8, p&lt;0.001) and length (82.8±42.5 µm, p&lt;0.001). Treatment of wild type MSCs with SNAP impaired tube formation (15.6±9.0, p&lt;0.001) and length (57.1±24.9 µm, p&lt;0.001). Similarly, hMSCs treated with SNAP exhibited impaired tube formation, both in number (25.0±4.9 vs. 49.2±8.1, p&lt;0.001) and length (81±29.1 vs. 128.0±52.5 µm, p&lt;0.001) compared to vehicle treated MSCs. L-NAME had no effect on hMSCs . Conclusion: These findings are consistent with a paradoxical negative influence of NO/GSNO on vascular formation by MSCs and reveal a novel mechanism whereby NO/GSNO inhibits MSC dependent angiogenesis. These findings have implications for disease states characterized by excessive or dysregulated angiogenesis; moreover NO deficient environments may trigger MSC mediated angiogenesis.
Abstract 340: Single Nucleotide Polymorphism of MLX Gene Plays a Crucial Role in the Pathogenesis of Takayasu Arteritis Through Facilitating Inflammasome Formation of the Aorta
Authors: Yasuhiro Maejima, Natsuko Tamura, Yusuke Ito, Mitsuaki Isobe
Journal: Circulation Research (2015)

We have identified that single nucleotide polymorphisms (SNPs) of both IL12B gene which encodes IL-12p40 and MLX gene, which encodes a basic helix-loop-helix leucine zipper transcription factor, were significantly associated with clinical manifestations of Takayasu arteritis (TA), an autoimmune systemic arteritis, by genome-wide association study (GWAS). Recently, we reported that SNP of IL12B plays an important role in mediating the development of TA through modulating the level of IL-12p40-related cytokines, including IL-12 and IL-23. However, it remains unknown whether MLX mutation is associated with the pathogenesis of TA. Here, we elucidate that whether SNP of the MLX (rs665268), a missense mutation of MLX that alters the 139 th glutamine to arginine (Q139R), upregulates the factor(s) associated with the development of TA. Pull-down assays with recombinant proteins demonstrated that mutation of Q139R on MLX protein enhanced the heterodimer formation of MLX with MondoA, a binding partner of MLX that promotes thioredoxin-interacting protein (TXNIP) expression. As Gln is a neutral amino acid, we speculated that alteration from Gln 139 to Arg 139 , which confers a positive charge to the DNA binding site of MLX, should enhance formation of the MLX-MondoA-DNA complex. Consistent with our hypothesis, luciferase reporter gene assays showed that the TXNIP promoter activity of human aortic smooth muscle cells (hASMCs) co-transfected with TXNIP promoter-containing reporter, MondoA and MLX-Q139R plasmids was significantly higher than those with the wild type MLX (MLX-WT) (MLX-Q139R: 63138 ± 2557 RLU* vs. MLX-WT: 31263 ± 3433 RLU, * p &lt; 0.05). The protein levels of both NLRP3 and procaspase-1, major components of inflammasome upregulated by TXNIP, was significantly increased in hASMCs transfected with MLX-Q139R than compared to those in transfected with MLX-WT. Immunohistochemical analyses of the human aortas revealed that NLRP3 in the SMCs accumulated more prominently in the aortas of TA than those in normal ones. In conclusion, Q139R mutation on MLX plays a crucial role in the pathogenesis of TA through facilitating NLRP3 accumulation, which in turn facilitating inflammasome formation in the aorta.
Macrolide Antibiotics By Modulating the Autophagic Flux Exert an Antileukemic Effect through the Involvement of hERG1 Potassium Channel
Authors: Serena Pillozzi, Massimo D'Amico, Giulia Petroni, Marinella Veltroni, Claudio Favre, Andrea Becchetti, Giuseppe Basso, Annarosa Arcangeli
Journal: Blood (2016)
Quantifying Postdonation Risk of ESRD in Living Kidney Donors
Authors: Allan B. Massie, Abimereki D. Muzaale, Xun Luo, Eric K.H. Chow, Jayme E. Locke, Anh Q. Nguyen, Macey L. Henderson, Jon J. Snyder, Dorry L. Segev
Journal: Journal of the American Society of Nephrology (2017)

Studies have estimated the average risk of postdonation ESRD for living kidney donors in the United States, but personalized estimation on the basis of donor characteristics remains unavailable. We studied 133,824 living kidney donors from 1987 to 2015, as reported to the Organ Procurement and Transplantation Network, with ESRD ascertainment