tbuckley/cabot-search huggingface dataset:
Prolonged shedding of rhinovirus and re-infection in adults with respiratory tract illness (European Respiratory Journal (2014) 44, (169-177))
Authors: K T Zlateva, De Vries Jjc., Coenjaerts Fej., A M Van Loon, T Verheij, P Little, C C Butler, H Goossens, M Ieven, Claas Ecj.
Journal: European Respiratory Journal (2014)
NIMG-17. UTILIZING MACHINE LEARNING FOR PREDICTIVE MODELING OF SEIZURE PRESENTATION IN GLIOMA PATIENTS
Authors: Aditya Khurana, Sara Ranjbar, Sandra Johnston, Leland Hu, Paula Whitmire, Akanksha Sharma, Kristin Swanson
Journal: Neuro-Oncology (2018)

PURPOSE: Seizures are frequent symptoms of gliomas. Predicting which patients are more likely to seize and in turn require anti-epileptic management has been a challenge. Correctly identifying these patients could help optimize care and minimize side effects. To provide guidance for clinicians, we used machine learning techniques to predict seizure presentation in this population. We used volumetric data of pre-treatment MR images (T1Gd and T2-FLAIR sequences), patient demographics (age; sex), and measurements of tumor proliferation (log()), invasiveness (log(D)) and their relative ratio (log(/D)). We compared the performance of 5 machine learning models in predicting seizure status, using Artificial Neural Network, Naive Bayes (NB), Linear Discriminant Analysis (LDA), Random Forest, and Support Vector Machine. Correlations between probability of seizure presentation (p(SP)) and continuous variables were also analyzed. Our cohort consisted of 59 seizure-presenting and 77 non-seizure-presenting patients. All models consistently demonstrated significant correlations (p < 0.05) between (p(SP)) and the following variables: T1Gd radius (-0.781 to -0.674), T2-FLAIR (-0.674 to -0.611), and log(/D) (0.169 to 0.294). Age was significant (p < 0.05) in 4 of the 5 models (-0.211 to -0.175). Mean performance measures for the models (and the best performer) were: 0.726 for Area under the ROC curve (0.75 with NB), 0.6202 for sensitivity (0.661 with NB), 0.74 for specificity (0.766 with LDA). The 5 features ranked as most important were: T1Gd, T2-FLAIR, log(/D), age, log(). CONCLUSIONS: We found an association in seizure-presenting patients with smaller, more proliferative tumors and younger age. Machine learning predictive modeling can potentially be informative in the clinical arena. Further validation studies, to determine the degree of data overfitting, model versatility, as well as performance on test data, are warranted.
THU0218 The efficacy and drug survival of the biosimilar infliximab (CT-P13) compared to the original reference infliximab in inflammatory rheumatic diseases; results from the turkbio registry
Authors: S. Uslu, G. Can, S. Senel, E. Dalkilic, N. Inanc, S. Akar, S.B. Kocaer, M. Birlik, S. Capar, N. Akkoc, F. Onen
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Biosimilar infliximab (CT-P13) has been used to treat patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) in Turkey since 2013. <h3>Objectives</h3> The aim of this study was to examine its efficacy, drug survival and compare it to the original reference infliximab (inf) in patients with inflammatory rheumatic diseases based on the database from the TURKBIO registry. <h3>Methods</h3> All patients with RA, SpA, PsA, and other diseases receiving CT-P13 and inf registered in the TURKBIO database between the dates of <sup>June 2013</sup> and January 2017 were included in the study. Demographic information, laboratory parameters and disease indices were collected (at baseline, and months 6 and 12). We used Kaplan Meier survival curves to examine drug survival patterns. <h3>Results</h3> Data collected from a total number of 614 patients were analysed (table 1). The analysis of each treatment group was made according to gender, age, and diagnosis. In both groups most of the patients were diagnosed as having axial SpA, followed by RA, PsA and other diseases. CT-P13 group had female predominance. In patients with RA and PsA, baseline DAS28 scores were found to be higher in CT-P13 group. Baseline values of ASDAS-CRP in SpA patients and CRP in all patients were similar for both groups (table 2). Mean CRP levels at month 6 and ASDAS scores at month 12 were found to be higher in inf group. The ratio of males was higher in axial SpA patients receiving inf, but did not statistically affect the 12th month ASDAS results. The results of the database analysis showed that the drug survival rate of CT-P13(78,4%) is higher than inf(63,6%) at year 4 (figure 1). At 4 year follow-up, drug withdrawal was observed in both groups due to ineffectiveness (CT P13;n=13 54,16%, inf;n=89 41,58%) and side effects (CT-P13;n=8 33,33%, inf;n=43 20,09%). In CT-P13 group, six patients had switched from inf to biosimilar and other 20 had used ≥1 previous biologicals. Of the 503 patients who used inf, 164 had used ≥1 biologicals previously. <h3>Conclusions</h3> The results of this study demonstrated long term higher drug survival rate of biosimilar CT-P13. The study also suggested that efficacy of CT-P13 on disease activity was similar to original infliximab in patients with inflammatory rheumatic diseases. <h3>Disclosure of Interest</h3> None declared
Time-to-event analysis for sports injury research part 2: time-varying outcomes
Authors: Rasmus Oestergaard Nielsen, Michael Lejbach Bertelsen, Daniel Ramskov, Merete Møller, Adam Hulme, Daniel Theisen, Caroline F Finch, Lauren Victoria Fortington, Mohammad Ali Mansournia, Erik Thorlund Parner
Journal: British Journal of Sports Medicine (2018)

Time-to-event modelling is underutilised in sports injury research. Still, sports injury researchers have been encouraged to consider time-to-event analyses as a powerful alternative to other statistical methods. Therefore, it is important to shed light on statistical approaches suitable for analysing training load related key-questions within the sports injury domain.In the present article, we illuminate: (i) the possibilities of including time-varying outcomes in time-to-event analyses, (ii) how to deal with a situation where different types of sports injuries are included in the analyses (ie, competing risks), and (iii) how to deal with the situation where multiple subsequent injuries occur in the same athlete.Time-to-event analyses can handle time-varying outcomes, competing risk and multiple subsequent injuries. Although powerful, time-to-event has important requirements: researchers are encouraged to carefully consider prior to any data collection that five injuries per exposure state or transition is needed to avoid conducting statistical analyses on time-to-event data leading to biased results. This requirement becomes particularly difficult to accommodate when a stratified analysis is required as the number of variables increases exponentially for each additional strata included. In future sports injury research, we need stratified analyses if the target of our research is to respond to the question: 'how much change in training load is too much before injury is sustained, among athletes with different characteristics?' Responding to this question using multiple time-varying exposures (and outcomes) requires millions of injuries. This should not be a barrier for future research, but collaborations across borders to collecting the amount of data needed seems to be an important step forward.
HOUT-07. AN EVALUATION OF THE TREATMENT COURSE IN PATIENTS WITH GLIOBLASTOMA MULTIFORME
Authors: Alper Dincer, Matthew Carr, Lakshmi Ravindra, Fan Zhang, Camille Hochheimer, Andrew Rock, Charles Opalak, Aravind Somasundaram, Kathryn Workman, Adam Sima, William Broaddus
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM) is a malignant brain tumor with a mean overall survival of 15 months using current treatment modalities. Previous studies have shown delays in treatment result in worse outcomes. Demographic and socioeconomic factors may have a role in treatment course variations. Therefore, the objective of this study was to investigate factors that influence time to treatment and effect overall survival in patients with GBM. Records from patients who were diagnosed with GBM and underwent surgery, radiotherapy, or chemotherapy at VCU Health between 2005 and 2015 were retrospectively reviewed. Linear regression was used to determine whether demographics, socioeconomic status, or presenting symptoms were associated with the time from first clinic visit to time of surgery, chemotherapy, radiotherapy first treatment, and time until all treatments were initiated. Then, cox proportional hazards regression assessed whether these five outcomes were independently related to overall survival. 126 patients were included in the study. Median survival was 10.6 months. None of the demographic factors or presenting symptoms were associated with time to treatment outcomes. Time to radiotherapy, chemotherapy, and all treatment initiation were significantly associated with overall survival after controlling for age, tumor location, and extent of resection (p< 0.01). A thirty-day decrease in time to radiotherapy, chemotherapy, and all treatment initiation were associated with increased mortality hazards of 1.05, 1.08, and 1.04, respectively. DISCUSSION: Our results indicated that demographics, socioeconomic factors, and presenting symptoms do not contribute to delays in treatment. Our study also revealed that, contrary to current literature, patients with shorter time to initiation of treatment had poorer outcomes. This could represent a specific population that presents later in their disease course and thus receives more aggressive treatment. Further investigation is therefore needed to elucidate the cause of this relationship and factors causing decreased survival in this population.
RTHP-35. SURVIVAL IMPACT OF DELAYS PROLONGING THE OVERALL DURATION OF ADJUVANT RADIATION THERAPY FOR PATIENTS WITH GLIOBLASTOMA
Authors: Mehran Yusuf, Jeremy Gaskins, Mark Amsbaugh, Shiao Woo, Eric Burton
Journal: Neuro-Oncology (2018)

Though conventionally fractionated chemoradiation (CRT) is well tolerated by selected patients with newly diagnosed glioblastoma (GBM), both adverse health related and non-health related factors can lead to unplanned interruptions in treatment. The effects of prolonged time to completion (TTC) of radiation therapy (RT) on overall survival (OS) for these patients are unclear. The National Cancer Database (NCDB) was queried for all adult patients with newly diagnosed GBM undergoing surgical resection followed by adjuvant CRT with conventionally fractionated RT (6000 - 6600 cGy in 30 - 33 fractions) from 2005 to 2012. TTC was defined as the interval from first to last fraction of RT. Recursive partitioning analysis (RPA) was used to determine a threshold for TTC of adjuvant RT. Cox proportional hazards modeling was used to identify covariates associated with OS. A total of 13,489 patients were included in our cohort. Patients who completed adjuvant RT within the RPA-defined threshold of 46 days from initiation of RT (median OS: 14.0 months, 95% CI 13.7 - 14.3 months) had significantly improved OS compared to patients with TTC of 47 days or greater (median OS: 12.0 months, 95% CI 11.4 - 12.6 months, p<0001). CONCLUSIONS: Delays in completing adjuvant radiation therapy were associated with a worse survival outcome. Any unnecessary delays in completing adjuvant RT should be minimized while ensuring the safe delivery of therapy.
Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus
Journal: New England Journal of Medicine (2018)

Diabetes mellitus is associated with an increased risk of cardiovascular events. Aspirin use reduces the risk of occlusive vascular events but increases the risk of bleeding; the balance of benefits and hazards for the prevention of first cardiovascular events in patients with diabetes is unclear.We randomly assigned adults who had diabetes but no evident cardiovascular disease to receive aspirin at a dose of 100 mg daily or matching placebo. The primary efficacy outcome was the first serious vascular event (i.e., myocardial infarction, stroke or transient ischemic attack, or death from any vascular cause, excluding any confirmed intracranial hemorrhage). The primary safety outcome was the first major bleeding event (i.e., intracranial hemorrhage, sight-threatening bleeding event in the eye, gastrointestinal bleeding, or other serious bleeding). Secondary outcomes included gastrointestinal tract cancer.A total of 15,480 participants underwent randomization. During a mean follow-up of 7.4 years, serious vascular events occurred in a significantly lower percentage of participants in the aspirin group than in the placebo group (658 participants [8.5%] vs. 743 [9.6%]; rate ratio, 0.88; 95% confidence interval [CI], 0.79 to 0.97; P=0.01). In contrast, major bleeding events occurred in 314 participants (4.1%) in the aspirin group, as compared with 245 (3.2%) in the placebo group (rate ratio, 1.29; 95% CI, 1.09 to 1.52; P=0.003), with most of the excess being gastrointestinal bleeding and other extracranial bleeding. There was no significant difference between the aspirin group and the placebo group in the incidence of gastrointestinal tract cancer (157 participants [2.0%] and 158 [2.0%], respectively) or all cancers (897 [11.6%] and 887 [11.5%]); long-term follow-up for these outcomes is planned.Aspirin use prevented serious vascular events in persons who had diabetes and no evident cardiovascular disease at trial entry, but it also caused major bleeding events. The absolute benefits were largely counterbalanced by the bleeding hazard. (Funded by the British Heart Foundation and others; ASCEND Current Controlled Trials number, ISRCTN60635500 ; ClinicalTrials.gov number, NCT00135226 .).
SURG-13. THIRD HARMONIC GENERATION (THG) IMAGING: A NOVEL TOOL FOR INTRA-OPERATIVE HISTOLOGIC ANALYSIS OF FRESH HUMAN GLIOMA TISSUE
Authors: Pieter Wesseling, Andy Zhang, Jan de Munck, Niels Verburg, Philip de Witt Hamer, Marloes Groot
Journal: Neuro-Oncology (2018)

Label-free optical techniques such as optical coherence tomography and Raman techniques are reported to hold promise for improved surgical management of central nervous system (CNS) tumors because of their high resolution and intra-operative applicability in fresh tissue samples. We have recently reported on third harmonic generation (THG) imaging as an alternative, label-free tool for fast imaging of histologic characteristics in fresh, unprocessed human tissues. AIM: To determine the potential of THG microscopy for assessment of tumor load in unprocessed tissue samples of patients with a diffuse glioma. MATERIALS & Freshly obtained CNS tissue samples (n = 55) of 23 patients with diffuse glioma were analyzed using THG microscopy and subsequently processed for routine pathological analysis. Later on, the histology as seen in H&E-stained sections of these samples was correlated with the THG images. Furthermore, using automated image analysis, an algorithm was developed for classification of the THG images as tumor versus non-tumor in order to further facilitate exploitation of THG microscopy as a real-time, intra-operative diagnostic support tool. In all samples, THG microscopy revealed histology-grade characteristics with information on a spectrum of cellular and extracellular components. In most tumor-containing samples, THG imaging readily allowed for visualization of (a gradient of invasive) tumor cells in the CNS parenchyma. Interpretation of the THG images by automated, quantitative image analysis, with particular emphasis on cell density and composition of the neuropil, provided an observer-independent interpretation of the same images. While in depth comparative analysis is still ongoing, preliminary results of comparison of (qualitative and quantitative) information in THG and H&E images are very promising. CONCLUSIONS: THG microscopy enables intra-operative visualization of histopathological characteristics in unprocessed human brain tissue. Qualitative and quantitative analysis of THG images of ex-vivo (and ultimately in-situ) brain tissue has great potential for improving CNS tumor surgery.
CBMT-37. FDA-APPROVED HDAC INHIBITORS ANTAGONIZE THE WARBURG EFFECT AND CAUSE UNIQUE METABOLIC VULNERABILITIES
Authors: Yiru Zhang, Chiaki Ishida, Georg Karpel-Massler, Markus Siegelin
Journal: Neuro-Oncology (2018)

Histone deacetylase inhibition is a potential new strategy for the treatment of glioblastoma (GBM) and FDA-approved for multiple myeloma. However, resistance to therapy is a major issue. By conducting a global transcriptome with subsequent gene set enrichment analysis in stem-like GBM cells and PDX models coupled with a comprehensive polar and non-polar untargeted metabolite analysis, we have unraveled that HDAC – inhibition results in global reprogramming of metabolism, revealing unique metabolic vulnerabilities. Acute HDAC – inhibition suppresses c-myc protein levels and thereby blunts glycolysis and the pentose phosphate pathway. Acutely, this results in lower ATP levels coupled with activation of AMPK, as well as dysregulation of redox equivalents. Furthermore, GBM cells activate mitochondrial metabolism oxidative phosphorylation (OXPHOS) with an increase in mitochondrial fusion, mitochondrial biogenesis and higher mitochondrial oxygen consumption rate coupled with increased fatty acid oxidation (FAO), which is mediated by the master regulator transcription factors, PGC1a and PPARD. In turn, GBM cells become addicted to OXPHOS and susceptible to apoptosis induction by inhibitors of mitochondrial translation and OXPHOS. In like manner, the clinical validated CPT1 inhibitor, etomoxir, reduces oxygen consumption rate in HDAC – inhibitor treated cells and synergistically induces apoptosis in GBM cells, highlighting the dependence of HDAC – inhibitor treated cells on FAO. HDAC – inhibitor resistant cells display a highly mitochondrial oxidative phenotype with increased number and size of mitochondria and substantial higher oxygen consumption rate, a transcriptional signature of FAO and reliance on oxidative energy metabolism. To fuel FAO, HDAC – inhibitor treated cells activate lysosomal, autophagic signaling. Finally, we show that interference with mitochondrial energy metabolism along with HDAC – inhibition results in synergistic growth inhibition in six xenograft model systems, reemphasizing the translational relevance of our findings.
DRES-18. SUMO1 AND VALOSIN-CONTAINING PROTEIN REGULATE RETINOID RECEPTOR PROTEIN TURNOVER– A PROCESS DISRUPTED IN GLIOBLASTOMA
Authors: Virginia Rodriguez, Rolanda Bailey, Mioara Larion, Mark Gilbert
Journal: Neuro-Oncology (2018)

Resistance to therapeutic use of retinoids in glioblastoma (GBM) has been observed for over 20 years; however, the exact mechanism of resistance remains unknown. To better understand retinoic acid resistance in GBM, we studied the turnover mechanism of retinoid receptor proteins in normal neural stem cells and glioma stem-like cells (GSCs). Currently, it is believed that cellular stress induces global sumoylation of proteins in glioma, yet the precise role of sumoylation is not fully understood. Protein expression and posttranslational modification (PTM) of the endogenous retinoid receptors were analyzed using Western blots, immunoprecipitations, and siRNA. The discovery of the novel binding partner of retinoid receptors was achieved using immunoprecipitation and mass spectrometry. Promoter luciferase assays were used to measure transcriptional activities. RESULTS AND CONCLUSIONS: Our studies reveal that sumoylation of retinoid receptors occurs in both normal neural stem cells and GSCs; however, protein turnover of the receptor is disrupted in glioma. We show that sumoylation is a PTM required for proteasomal degradation of retinoid receptors. Degradation via the proteasomal pathway is necessary for receptor protein turnover and transcriptional activity. We also identify that the valosin-containing protein (VCP/p97/Cdc48) participates in the PTM of retinoid receptors and impacts the transcriptional activity. The defect in glioma occurs after the sumo modification step and results in the accumulation of high molecular weight forms of the receptors that fail to get degraded. Our findings expand our understanding of the turnover mechanism of nuclear receptors in normal cells. In addition, our findings provide a mechanism for the retinoic acid resistance in glioma cells that involves the disruption of protein turnover and decrease in transcriptional activity. Our studies suggest that the use of combinatory therapies that target retinoid receptors and induce proteasomal degradation of the receptors to ensure protein turnover may be a more effective approach.
Abstract 20114: Impact of Genetic Testing on Cascade Screening for Familial Hypercholesterolemia - A Randomized Controlled Trial
Authors: Ezim Ajufo, Emil M deGoma, Tracey Sikora, Masako Ueda, Kristen Dilzell, Anna Raper, Stephanie DerOhannessian, Marina Cuchel, Daniel J Rader
Journal: Circulation (2017)

Background: More than one million individuals in the US are estimated to have Familial Hypercholesterolemia (FH), however fewer than 1% have been diagnosed. Family-based cascade screening from iden...
Survivorship in adults with malignant brain and other central nervous system tumor from 2000–2014
Authors: Haley Gittleman, Alexander Boscia, Quinn T Ostrom, Gabrielle Truitt, Yi Fritz, Carol Kruchko, Jill S Barnholtz-Sloan
Journal: Neuro-Oncology (2018)

The goal of this study was to provide up-to-date and comprehensive statistics on incidence, survival, and prevalence rates for selected malignant brain and other CNS tumors in adults.
COMP-01. TRACKING THROUGH EDEMA: ENHANCED NEUROSURGICAL PLANNING USING ADVANCED DIFFUSION MODELING OF THE PERITUMORAL TISSUE MICROSTRUCTURE
Authors: Drew Parker, Lisa Desiderios, Steven Brem, Ragini Verma
Journal: Neuro-Oncology (2018)

Neurosurgical planning relies on diffusion tractography to model eloquent fibers. Peritumoral edema and neoplastic infiltration suppress the sensitivity to detect fiber tracts, particularly using deterministic tracking. Confounding effects of tumor infiltration and edema results in significant discordance between subcortical, intraoperative electrical stimulation (IES) and preoperative fiber track visualization. We hypothesized that tracking in peritumoral zone, which includes vasogenic edema and neoplastic infiltration, could be enhanced by using a bi-compartment diffusion modeling. Due to the known tendency of primary malignant tumors, glioblastoma, to infiltrate surrounding white matter (WM), the bi-compartment model will be validated to distinguish peritumoral tissue in gliomas versus secondary brain tumors (metastases). Patients with tumors (88 gliomas and 50 metastates) underwent 30 direction DTI and were fitted with standard tensor and Fernet, a free-water-invariant bi-compartment tensor model. Deterministic tractography was performed on each subject. Five WM tracts (corticospinal tract, inferior fronto-occipital, inferior longitudinal, arcuate and uncinate fasciculi) were extracted bilaterally in each patient using a shape-based clustering algorithm. For each subject, percentage change of edema volume was compared between standard and Fernet tensor models. Fernet-based tractography showed average increase in edema coverage of 87 +/- 25% (t=6.9, p CONCLUSIONS: Results show fiber tractography in peritumoral region is significantly improved with better diffusion modeling of peritumoral tissue microstructure. Additionally, difference in tracking between metastases and glioblastomas is representative of tracking being affected differentially due to infiltration in peritumoral regions. CLINICAL IMPLICATIONS: Our peritumoral tissue modeling incorporates edema and infiltration, leading to superior tracking, and hence robust surgical planning. In future, the peritumoral tissue maps could be used to elucidate differences in radiological diagnosis, surgical risk stratification, response to therapy, tumor invasion and tumor genetics, and neuroplasticity.