tbuckley/cabot-search huggingface dataset:
P092 Microarray pathway analysis comparing baricitinib and adalimumab in moderate to severe rheumatoid arthritis from a phase 3 study
Authors: P Emery, PC Taylor, ME Weinblatt, Y Tanaka, EC Keystone, ER Dow, R Higgs, WL Macias, G Rocha, TP Rooney, DE Schlichting, SH Zuckerman, IB McInnes, T Holzkaemper
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> In RA-BEAM (NCT01710358), baricitinib (BARI), an oral selective inhibitor of Janus kinase (JAK) 1 and JAK 2, showed significant improvements in patients (pts) with active RA who had an inadequate response to methotrexate compared to placebo (PBO) or adalimumab (ADA). <h3>Objectives</h3> To analyse pathways modulated by BARI compared with ADA (both relative to PBO) through 12 wks of treatment. <h3>Methods</h3> Pts (n=1307) were randomised 3:3:2 to PBO, BARI 4 mg QD, ADA 40 mg q 2 wks. Total RNA extracted from whole blood drawn at baseline (BL), wk4, and wk12 was analysed using the GeneChip Human Transcriptome Array 2.0 (Affymetrix). Data were analysed using a mixed effects model on a log2 transformed response. <h3>Results</h3> There was little overlap of the immune pathways modulated by both BARI and ADA at wk4 with no significant overlap by wk12. BARI downregulated JAK/Signal Transducer and Activator of Transcription (STAT) signalling pathways, like those induced by IFNs, IL-6, GM-CSF, IL-5, and IL-3. Expression of interferon responsive genes (IRGs) was downregulated by BARI and upregulated by ADA. BARI reduced IRGs by 75% at wk4 in pts that had high IFN gene expression at BL. ADA modulated complement pathways. Of interest, STAT transcripts were reduced at wk4 by BARI (STAT1, 2, 3, 5A, 5B, 6); by wk12 several STATs (STAT 1, 2, 5A) did not differ from PBO. Additional differences were noted in the number of genes modulated by each treatment. BARI modulated more genes than ADA at wks 4 and 12; BARI resulted in more gene modulation at wk12 than at wk4, whereas ADA gene modulation was similar at wks 4 and 12. Both the numbers and types of genes modulated by BARI diverged further from ADA at wk12 than at wk4. <h3>Conclusions</h3> Gene expression profiling showed significant differences between BARI and ADA treatments. BARI and ADA modulated JAK/STAT or complement pathways, respectively, and the drugs had opposite effects on interferons, indicating different and possibly complementary mechanisms of action of each targeted therapy. <h3>Acknowledgements</h3> Study support: Eli Lilly and Company and Incyte Corporation. Encore of ACR/ARHP-2017 Annual Scientific Meeting, Nov 4–8, 2016; San Diego, CA, USA. <h3>Disclosure of interest</h3> None declared
Incidence and risk factor analysis of the postoperative delirium after gastrointestinal surgery: An exploratory analysis of a prospective, randomized phase II trial.
Authors: Shinya Amano, Toru Aoyama, Mariko Kamiya, Junya Morita, Yukio Maesawa, Sho Sawazaki, Masakatsu Numata, Tsutomu Sato, Takashi Oshima, Yasushi Rino, Norio Yukawa, Munetaka Masuda
Journal: Journal of Clinical Oncology (2018)

30 Background: The postoperative complications, delirium are a particularly common morbidity after gastrointestinal surgery. Postoperative delirium makes patient management much more difficult, increases costs, and causes severe discomfort to the patient. The aim of this study was to evaluate the incidence of the postoperative delirium and a predictor for postoperative delirium using phase II clinical trial data. Methods: We analyzed the cases that were enrolled to randomized clinical trials of the efficacy and safety of TJ-54 (Yokukansan; a traditional Japanese medicine [Kampo]) for the prevention and/or treatment of postoperative delirium in a randomized phase II trial of patients receiving surgery for gastrointestinal and lung malignancies (UMIN000005423). The American Psychiatric Association’s the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) was used to assess. A uni- and multivariate logistic regression analyses was performed to identify risk factors for morbidity. Results: Between October 2009 and July 2011, a total of 186 patients were registered to the Yokukansan trial. Among them, 167 patients received surgery for gastrointestinal malignancy and were eligible for the present study. The incidence of postoperative delirium was 9.0% (15 patients) and postoperative delirium was the most common postoperative complication in the study. Risk factors for postoperative delirium were analyzed by uni- and multi-variate analyses using clinical factors determined before the enrollment of the study. Among these, high patients’ age ( &gt; 80 years) and low MMSE score ( &lt; 27) were identified as significant independent risk factor for postoperative delirium (Odds ratio: 3.90, 95% CI; 1.25-12.16, p = 0.013 and Odds ratio: 0.24, 95% CI; 0.08-0.73, p = 0.013). Conclusions: The major of the findings were that high patients’ age (≥ 80 years) and low MMSE score ( &lt; 27) were significant independent risk factors for predicting postoperative delirium. Careful attention for postoperative delirium is required in patients with high patients’ age and MMSE score when surgeons perform surgery for gastrointestinal malignancies. Clinical trial information: 000005423.
Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement
Authors: Johan Ljungberg, Mikael Janiec, Ingvar A. Bergdahl, Anders Holmgren, Johan Hultdin, Bengt Johansson, Ulf Näslund, Agneta Siegbahn, Tove Fall, Stefan Söderberg
Journal: Circulation (2018)

Background: Aortic valve stenosis (AS) is the most common indication for cardiac valve surgery; untreated AS is linked to high mortality. The etiological background of AS is unknown. Previous human studies were typically based on case-control studies. Biomarkers identified in prospective studies could lead to novel mechanistic insights. Methods: Within a large population survey with blood samples obtained at baseline, 334 patients were identified who later underwent surgery for AS (median age [interquartile range], 59.9 [10.4] years at survey and 68.3 [12.7] at surgery; 48% female). For each case, 2 matched referents were allocated. Plasma was analyzed with the multiplex proximity extension assay for screening of 92 cardiovascular candidate proteins. Conditional logistic regression models were used to assess associations between each protein and AS, with correction for multiple testing. A separate set of 106 additional cases with 212 matched referents was used in a validation study. Results: Six proteins (growth differentiation factor 15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9) were associated with case status in the discovery cohort; odds ratios ranged from 1.25 to 1.37 per SD increase in the protein signal. Adjusting the multivariable models for classical cardiovascular risk factors at baseline yielded similar results. Subanalyses of case-referent triplets (n=133) who showed no visible coronary artery disease at the time of surgery in the index person supported associations between AS and growth differentiation factor 15 (odds ratio, 1.40; 95% confidence interval, 1.10-1.78) and galectin-4 (odds ratio, 1.27; 95% confidence interval, 1.02-1.59), but these associations were attenuated after excluding individuals who donated blood samples within 5 years before surgery. In triplets (n=201), which included index individuals with concurrent coronary artery disease at the time of surgery, all 6 proteins were robustly associated with case status in all sensitivity analyses. In the validation study, the association of all but 1 (interleukin 17 receptor A) of these proteins were replicated in patients with AS with concurrent coronary artery disease but not in patients with AS without coronary artery disease. Conclusions: We provide evidence that 5 proteins were altered years before AS surgery and that the associations seem to be driven by concurrent atherosclerotic disease.
Government will cap legal costs of clinical negligence claims
Authors: Abi Rimmer
Journal: BMJ (2018)

A group of government, NHS, and legal experts will work to introduce a cap on the amount that lawyers can recover in clinical negligence cases, the Department of Health and Social Care has announced.

The proposed cap would apply to all cases up to £25 000 and could save the NHS £45m a year, it said.

There is currently no limit on legal costs that can be recouped from clinical negligence claims. The department said that claims, including legal bills, had …
OPTIMAL TR-BAND WEANING STRATEGY WHILE MINIMIZING VASCULAR ACCESS SITE COMPLICATIONS
Authors: Ryan Gindi, Sunay Shah, Akshay Khandelwal, Mohammad Alqarqaz, Mohammad Zaidan, Michele Voeltz, Gerald Koenig, Henry Kim, William W. O’Neill, Khaldoon Alaswad
Journal: Journal of the American College of Cardiology (2018)
Impact of percent positive biopsy cores on cancer-specific mortality for patients with high-risk prostate cancer.
Authors: David Dewei Yang, Vinayak Muralidhar, Brandon Arvin Virgil Mahal, Marie Vastola, Ninjiin Boldbaatar, Shelby A Labe, Michelle Daniel Nezolosky, Neil E. Martin, Martin T. King, Kent William Mouw, Peter F Orio, Toni K. Choueiri, Quoc-Dien Trinh, Paul L. Nguyen
Journal: Journal of Clinical Oncology (2018)

78 Background: A high percent positive biopsy cores (PBC), typically dichotomized at ≥50%, is prognostic of worse cancer-specific outcomes for patients with low- and intermediate-risk prostate cancer. The prognostic value of ≥50% PBC for patients with high-risk disease is poorly understood. We examined the association between ≥50% PBC and prostate cancer-specific mortality (PCSM) for patients with high-risk prostate cancer. Methods: We identified 7,569 men from the Surveillance, Epidemiology, and End Results program who were diagnosed with high-risk prostate cancer (Gleason 8-10, prostate-specific antigen &gt; 20 ng/mL, or cT3-T4 stage without evidence of nodal or metastatic disease) in 2010 or 2011 and had 6-24 cores sampled at biopsy. Multivariable Fine and Gray competing risks regression was utilized to examine the association between ≥50% PBC and PCSM, with adjustments for sociodemographic and clinicopathologic factors. Results: Median follow-up was 3.8 years (interquartile range 3.3-4.3 years). 56.2% of patients (4,253) had ≥50% PBC. The 4-year unadjusted cumulative incidences of PCSM were 2.0% (95% confidence interval [CI] 1.5-2.6%) and 5.6% (95% CI 4.9-6.4%) for patients with &lt; 50% and ≥50% PBC, respectively. On multivariable analysis, the presence of ≥50% PBC was associated with a significantly higher risk of PCSM (adjusted hazard ratio [AHR] 1.95, 95% CI 1.43-2.66, P&lt; 0.001). On subgroup analysis, ≥50% PBC was associated with a significantly higher risk of PCSM only for cT1-T2 disease (AHR 2.21, 95% CI 1.59-3.07, P&lt; 0.001) but not cT3-T4 disease (AHR 0.77, 95% CI 0.33-1.81, P= 0.547), with a significant interaction ( P interaction = 0.012). Conclusions: In this large, contemporary cohort of patients with high-risk prostate cancer, ≥50% PBC was independently associated with a two-fold increased risk of PCSM for patients with cT1-T2, but not cT3-T4, tumors. Percent PBC should be used to routinely risk stratify men with high-risk disease and identify patients who may benefit from intensification of therapy, such as adding docetaxel or abiraterone to radiotherapy with androgen deprivation therapy, to optimize cancer-specific outcomes.
Effect of SMARCB1 deficiency in renal medullary carcinoma (RMC) on genes associated with nucleosome assembly and telomere organization.
Authors: Pavlos Msaouel, Gabriel G. Malouf, Xiaoping Su, Hui Yao, Durga N Tripathi, Jianjun Gao, Priya Rao, Rong He, Jose A. Karam, Christopher G. Wood, Cheryl Lyn Walker, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2018)

614 Background: RMC is a highly aggressive tumor with close to universal fatality despite therapy. It is almost exclusively found in young African-Americans with sickle cell trait, and is characterized by complete loss of expression of SMARCB1, a major chromatin remodeler involved in regulation of gene expression. We investigated the effects of SMARCB1 loss on mutation frequency, gene expression, and cell growth in RMC. Methods: Whole exome sequencing (WES) and RNA sequencing (RNA-seq) were performed in RMC tissues from 15 and 11 patients respectively, each with matched adjacent normal kidney tissue controls. In vitro experiments were performed in a cell line (RMC2C) we established from a patient with RMC. SMARCB1 was conditionally re-expressed using a tetracycline-inducible lentivector. Gene ontology (GO) analysis was performed using DAVID. Results: WES showed that RMC harbors a low number (median of &lt; 25/tumor sample) of non-synonymous exomic single nucleotide variants (SNVs) or small indels. GO analysis revealed that the most significant pathways upregulated in RMC compared with normal tissue were those associated with nucleosome assembly and telomere organization (p values &lt; 0.0001). Re-expression of SMARCB1 at near-endogenous levels suppressed the growth rate of RMC2C cells. Subsequent silencing of SMARCB1 expression restored the growth rate of these cells. RNA-seq of RMC2C cells expressing SMARCB1 demonstrated that the most significant downregulated pathways compared with SMARCB1-negative RMC2C cells were those associated with nucleosome assembly and telomere organization (p values &lt; 0.0001). Conclusions: RMC harbors a remarkably simple genome, as evidenced by our WES analysis. Therefore, consistently detected alterations, such as SMARCB1 loss, are likely to serve as drivers for this disease. Indeed, in vitro restoration of SMARCB1 expression suppressed the growth of RMC cells and repressed genes associated with nucleosome assembly and telomere organization, identifying for the first time a causal link between loss of SMARCB1 and dysregulation of these genes. These results provide the basis for future therapeutic strategies targeting SMARCB1 loss in RMC.
O012 Joint-specific synovial TGF-Β1-induced AXL expression determines the outcome of inflammatory arthritis between ankle and knee joints
Authors: CEJ Waterborg, MGA Broeren, EN Blaney Davidson, MI Koenders, PLEM van Lent, WB van den Berg, PM van der Kraan, FAJ van de Loo
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Rheumatoid arthritis (RA) manifests in a symmetrical fashion in anatomically distinct synovial joints. The innate immune system, which plays a crucial role in the pathogenesis of RA, is regulated by anti-inflammatory feedback mechanisms such as the tyrosine kinase receptor family TYRO3, AXL and MER. Of importance, AXL is mainly expressed on sentinel cells. <h3>Objectives</h3> To investigate the synovial expression of AXL and its putative anti-inflammatory role in arthritis. <h3>Methods</h3> KRN serum transfer arthritis was induced in <i>Axl<sup>-/-</sup></i> and wild-type mice. Knee and ankle joints were scored macro- and microscopically. Synovial gene and protein expression of <i>Axl</i> was determined in naive and TGF-β1-overexpressing joints. <i>AXL</i> expression was determined in M1-like or M2-like macrophages and RA synovium. Human macrophages and synovial micromasses were stimulated with TGF-β1 or the AXL inhibitor R428. <h3>Results</h3> The ankle joints of <i>Axl<sup>-/-</sup></i> mice showed an increased macroscopic disease score during arthritis development (p&lt;0.001 at day 7). In agreement with this, ankle joints of <i>Axl<sup>-/-</sup></i> mice showed exacerbated arthritis pathology whereas no effect of <i>Axl</i> gene deletion was observed on gonarthritis pathology. To explain this spatial difference, we examined the synovium of naive mice. In contrast to the knee, the ankle synovial cells prominently expressed AXL. Moreover, the M2-like macrophage phenotype was the dominant cell type in the naive ankle joint. Human M2-like macrophages expressed higher levels of AXL and blocking AXL increased their inflammatory response. In the murine ankle synovium, gene expression of <i>Tgfb1</i> was increased and <i>Tgb1</i> correlated with <i>Axl</i> (Pearson r=0.8860, p=0.0012). Moreover, <i>TGFB1</i> and <i>AXL</i> expression also correlated in human RA synovium (Pearson r=0.7233, p=0.0035). In human macrophages and synovial micromasses, TGF-β1 enhanced AXL expression. Moreover, TGF-β1 overexpression in naive murine knee joints induced synovial AXL expression. <h3>Conclusions</h3> Differences in synovial AXL expression are in accordance with the observation that AXL dampens arthritis in ankle, but not in knee joints. We provide evidence that the local differences in AXL expression could be due to TGF-β1, and suggest similar pathways operate in RA synovium. <h3>Disclosure of interest</h3> None declared
Two thirds of physicians support seven day working
Authors: Anne Gulland
Journal: BMJ (2015)

Nearly seven in 10 physicians support a seven day a week service, a census of doctors carried out by the Royal College of Physicians has found.1

Its annual census showed that 68% of physicians would “in principle” support the government’s plans for a seven day a week NHS. Data from the census was first published in January2 but without data from Scotland, which have now been …
Contemporary trends in abiraterone and enzalutamide prescription by provider specialty.
Authors: Daniel Pucheril, Ye Wang, Dimitar V. Zlatev, Paul L. Nguyen, Adam S. Kibel, Steven Lee Chang
Journal: Journal of Clinical Oncology (2018)

366 Background: Androgen deprivation therapy (ADT) with LHRH-agonists and anti-androgens, is established in the management of prostate cancer and is administered by urologists, medical oncologists, and radiation oncologists. Newer agents for ADT, abiraterone acetate (ABI) and enzalutamide (ENZA) were approved by the FDA in 2011 and 2012, respectively, for the management of metastatic castrate resistant prostate cancer (mCRPC) after failing chemotherapy. We evaluated the contemporary economic burden of ABI and ENZA and their adoption by specialty. Methods: Because a majority of men with mCRPC are &gt; 65 years of age, we utilized Medicare Part D data from 2013-15. The specific outcome variables of interest included the aggregate reimbursement and total number of prescriptions for ABI and ENZA, by specialty. Descriptive statistics and trend analysis were performed. Results: From 2013-15, the total number of prescription rose from 52457 to 81058 for ABI and from 17141 to 69181 for ENZA. Though medical oncologists prescribed more than 75% of ABI/ENZA prescriptions each year, the proportion of prescriptions written by urologists increased annually. The greatest increase in the percentage of prescriptions originating from urology occurred from 2013-2014 for ABI (3.96% to 8.62%) and from 2014-15 for ENZA (5.42% to 15.64%); meanwhile, prescriptions by radiation oncology were negligible throughout the study. Southern states accounted for greater than one third of ABI and ENZA prescriptions. By 2015, the aggregate reimbursement of Part D claims for ENZA and ABI was $790 million each. Among all medication claims, ENZA and ABI represent the 29th and 30th most expensive by aggregate cost. Conclusions: While medical oncologists account for the vast majority of ENZA and ABI prescriptions, the prescriptions by urologists is increasing while prescriptions by radiation oncologists remain negligible. Though approved for mCRPC patients, ENZA and ABI are already among the costliest medications covered by Medicare. As Level 1 indications for the use of these medications increase and now include castrate-sensitive patients, further study should be directed at determining optimal timing and indication for prescription.
Effect of stereotactic radiation (SBRT) on survival in a preclinical model of spontaneous pancreatic cancer with induction gemcitabine/nab-paclitaxel.
Authors: Cullen M. Taniguchi, Jessica Molkentine, Tara N Fujimoto, Lauren Elizabeth Colbert, Amit Deorukhkar, Joseph M. Herman
Journal: Journal of Clinical Oncology (2018)

273 Background: There are no useful preclinical models that resemble relevant fractionated radiation, such as SBRT, with relevant chemotherapy. Most preclinical studies use a single fraction of radiation to large fields, causing significant toxicity and/or insufficient dose which leads to accelerated repopulation and worsened outcomes. Here, we employ mice with spontaneous pancreatic tumors, and treat them in a preclinical trial utilizing gemcitabine/nab-paclitaxel +/-SBRT. Methods: Mice with an activated KRas (G12D) allele and heterozygous for p53 expression only in the pancreas (KPC) were created and spontaneous tumors were diagnosed via weekly palpation and ultrasound. Mice with single tumors that were between 3-7mm at diagnosis were sequentially randomized to received either no treatment, gemcitabine/nab-paclitaxel x 2 weeks, or gemcitabine/nab-paclitaxel x 2 weeks followed by 8Gy x 5 daily fractions of SBRT to the pancreatic tumor. SBRT was delivered using X-RAD 225Cx (Precision X-Ray, Inc) small animal irradiator under image guidance by cone beam micro CT using AP/PA technique with a 10mm collimator. Every mouse was subjected to necropsy and a cause of death assigned. Tumor growth was monitored by small animal ultrasound. Kaplan-Meier survival analysis was performed to assess efficacy of treatments. Results: A total of 40 mice were enrolled with 12 receiving chemotherapy alone, 13 receiving chemotherapy +SBRT and 15 mice had no further treatment. The addition of induction chemotherapy improves lifespan compared to untreated mice. The addition of SBRT further improved survival. Causes of death in untreated animals of the gemcitabine/nab-paclitaxel group were largely from local progression, whereas the addition of SBRT provided local control causing most of the mice in this cohort to die from metastatic progression. Conclusions: SBRT improves survival when added to gem/nab-paclitaxel in a preclinical model, which may reflect favorable biology for this approach. Our novel system employs similar SBRT fields and doses, and may thus be useful for the evaluation of other chemotherapeutic regimens with SBRT.