tbuckley/cabot-search huggingface dataset:
Trends in Adult Cancer–Related Emergency Department Utilization
Authors: Donna R. Rivera, Lisa Gallicchio, Jeremy Brown, Benmei Liu, Demetrios N. Kyriacou, Nonniekaye Shelburne
Journal: JAMA Oncology (2017)

<h3>Importance</h3> The emergency department (ED) is used to manage cancer-related complications among the 15.5 million people living with cancer in the United States. However, ED utilization patterns by the population of US adults with cancer have not been previously evaluated or described in published literature. <h3>Objective</h3> To estimate the proportion of US ED visits made by adults with a cancer diagnosis, understand the clinical presentation of adult patients with cancer in the ED, and examine factors related to inpatient admission within this population. <h3>Design, Setting, and Participants</h3> Nationally representative data comprised of 7 survey cycles (January 2006-December 2012) from the Nationwide Emergency Department Sample were analyzed. Identification of adult (age ≥18 years) cancer-related visits was based on Clinical Classifications Software diagnoses documented during the ED visit. Weighted frequencies and proportions of ED visits among adult patients with cancer by demographic, geographic, and clinical characteristics were calculated. Weighted multivariable logistic regression was used to examine the associations between inpatient admission and key demographic and clinical variables for adult cancer–related ED visits. <h3>Main Outcomes and Measures</h3> Adult cancer–related ED utilization patterns; identification of primary reason for ED visit; patient-related factors associated with inpatient admission from the ED. <h3>Results</h3> Among an estimated 696 million weighted adult ED visits from January 2006 to December 2012, 29.5 million (4.2%) were made by a patient with a cancer diagnosis. The most common cancers associated with an ED visit were breast, prostate, and lung cancer, and most common primary reasons for visit were pneumonia (4.5%), nonspecific chest pain (3.7%), and urinary tract infection (3.2%). Adult cancer–related ED visits resulted in inpatient admissions more frequently (59.7%) than non–cancer-related visits (16.3%) (<i>P</i> &lt; .001). Septicemia (odds ratio [OR], 91.2; 95% CI, 81.2-102.3) and intestinal obstruction (OR, 10.94; 95% CI, 10.6-11.4) were associated with the highest odds of inpatient admission. <h3>Conclusions and Relevance</h3> Consistent with national prevalence statistics among adults, breast, prostate, and lung cancer were the most common cancer diagnoses presenting to the ED. Pneumonia was the most common reason for adult cancer–related ED visits with an associated high inpatient admission rate. This analysis highlights cancer-specific ED clinical presentations and the opportunity to inform patient and system-directed prevention and management strategies.
Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab
Authors: D. Arnold, C.S. Fuchs, J. Tabernero, A. Ohtsu, A.X. Zhu, E.B. Garon, J.R. Mackey, L. Paz-Ares, A.D. Baron, T. Okusaka, T. Yoshino, H.H. Yoon, M. Das, D. Ferry, Y. Zhang, Y. Lin, P. Binder, A. Sashegyi, I. Chau
Journal: Annals of Oncology (2017)

BackgroundRamucirumab, the human immunoglobulin G1 monoclonal antibody receptor antagonist of vascular endothelial growth factor receptor 2, has been approved for treating gastric/gastroesophageal junction, non-small-cell lung, and metastatic colorectal cancers. With the completion of six global, randomized, double-blind, placebo-controlled, phase III trials across multiple tumor types, an opportunity now exists to further establish the safety parameters of ramucirumab across a large patient population.Materials and methodsAn individual patient meta-analysis across the six completed phase III trials was conducted and the relative risk (RR) and associated 95% confidence intervals (CIs) were derived using fixed-effects or mixed-effects models for all-grade and high-grade adverse events (AEs) possibly related to vascular endothelial growth factor pathway inhibition. The number needed to harm was also calculable due to the placebo-controlled nature of all six registration standard trials.ResultsA total of 4996 treated patients (N = 2748 in the ramucirumab arm andN = 2248 in the control, placebo arm) were included in this meta-analysis. Arterial thromboembolic events [ATE; all-grade, RR: 0.8, 95% CI 0.5–1.3; high-grade (grade ≥3), RR: 0.9, 95% CI 0.5–1.7], venous thromboembolic events (VTE; all-grade, RR: 0.7, 95% CI 0.5–1.1; high-grade, RR: 0.7, 95% CI 0.4–1.2), high-grade bleeding (RR: 1.1, 95% CI 0.8–1.5), and high-grade gastrointestinal (GI) bleeding (RR: 1.1, 95% CI 0.7–1.7) did not demonstrate a definite increased risk with ramucirumab. A higher percentage of hypertension, proteinuria, low-grade (grade 1–2) bleeding, GI perforation, infusion-related reaction, and wound-healing complications were observed in the ramucirumab arm compared with the control arm.ConclusionsRamucirumab may be distinct among antiangiogenic agents in terms of ATE, VTE, high-grade bleeding, or high-grade GI bleeding by showing no clear evidence for an increased risk of these AEs in this meta-analysis of a large and diverse patient population. Ramucirumab is consistent with other angiogenic inhibitors in the risk of developing certain AEs.Clinical Trial Numbers: NCT00917384 (REGARD), NCT01170663 (RAINBOW), NCT01168973 (REVEL), NCT01183780 (RAISE), NCT01140347 (REACH), and NCT00703326 (ROSE).
NAD metabolism fuels human and mouse intestinal inflammation
Authors: Romana R Gerner, Victoria Klepsch, Sophie Macheiner, Kathrin Arnhard, Timon E Adolph, Christoph Grander, Verena Wieser, Alexandra Pfister, Patrizia Moser, Natascha Hermann-Kleiter, Gottfried Baier, Herbert Oberacher, Herbert Tilg, Alexander R Moschen
Journal: Gut (2017)

Objective Nicotinamide phosphoribosyltransferase (NAMPT, also referred to as pre-B cell colony-enhancing factor or visfatin) is critically required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD) supply catalysing the rate-limiting step of the NAD salvage pathway . NAMPT is strongly upregulated in inflammation including IBD and counteracts an increased cellular NAD turnover mediated by NAD-depleting enzymes. These constitute an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD metabolism. Design We investigated the impact of NAMPT inhibition by the small-molecule inhibitor FK866 in the dextran sulfate sodium (DSS) model of colitis and the azoxymethane/DSS model of colitis-associated cancer. The impact of NAD depletion on differentiation of mouse and human primary monocytes/macrophages was studied in vitro. Finally, we tested the efficacy of FK866 compared with dexamethasone and infliximab in lamina propria mononuclear cells (LPMNC) isolated from patients with IBD. Results FK866 ameliorated DSS-induced colitis and suppressed inflammation-associated tumorigenesis in mice. FK866 potently inhibited NAMPT activity as demonstrated by reduced mucosal NAD, resulting in reduced abundances and activities of NAD-dependent enzymes including PARP1, Sirt6 and CD38, reduced nuclear factor kappa B activation, and decreased cellular infiltration by inflammatory monocytes, macrophages and activated T cells. Remarkably, FK866 effectively supressed cytokine release from LPMNCs of patients with IBD. As FK866 was also effective in Rag1 −⁄− mice, we mechanistically linked FK866 treatment with altered monocyte/macrophage biology and skewed macrophage polarisation by reducing CD86, CD38, MHC-II and interleukin (IL)-6 and promoting CD206, Egr2 and IL-10. Conclusion Our data emphasise the importance of NAD immunometabolism for mucosal immunity and highlight FK866-mediated NAMPT blockade as a promising therapeutic approach in acute intestinal inflammation.
CQC’s plans to revamp GP inspections will not reduce bureaucracy, says royal college
Authors: Gareth Iacobucci
Journal: BMJ (2017)

The Care Quality Commission’s proposals to revamp the way it inspects general practices in England will not reduce the bureaucratic burden on practices and should be reconsidered, the Royal College of General Practitioners has said.

The CQC is consulting on plans that would reduce the frequency of inspections for practices that have received “good” or “outstanding” ratings. But the changes would also require practices to share information on quality of care with the regulator and to undergo regulatory reviews annually.

The CQC has not yet announced the outcome of the consultation, which closed on 8 August, but sent a letter to practices on 30 August updating …
Breast cancer risk according to serum 25-hydroxyvitamin D: meta-analysis of dose-response
Authors: Cedric Garland, Edward Gorham, Sharif Mohr, William Grant, Frank Garland
Journal: Cancer Research (2008)

3078  Background: An inverse association was observed between serum 25-hydroxyvitamin D [25(OH)D] levels and risk of female breast cancer in four recent observational studies. However, the exact 25(OH)D serum levels associated with a specific level of reduction in breast cancer incidence are still imprecise.  Methods: Data were combined from all studies that provided data on risk of breast cancer by quantile of serum 25(OH)D, using Review Manager (Copenhagen: Nordic Cochrane Centre, 2007). The analysis was performed according to published international standards for meta-analyses of data from observational studies. The number of individuals and person-years at risk in each quantile (generally quartiles or quintiles) of each study was determined, and a record was created for each individual from each study, with a study number identifying the study, a serial number for the individual, the median 25(OH)D concentration in the individual’s quantile in their study, and a code indicating whether the individual was a case or noncase. Records from the cohort studies were combined into an inclusive dataset in which individuals were divided into quintiles of 25(OH)D. There was an approximately equal number of individuals in each quintile. Measures of risk (incidence rates or odds ratios) were calculated for each quintile, providing an estimate of the pooled dose-response relationship. The procedure was performed separately for cohort and case-control studies. Results for each type of study, and all studies combined, were plotted and tested for goodness of fit to a classical dose-response curve.  Results: A sigmoid dose-response gradient was observed between serum 25(OH)D and risk of breast cancer, and was approximately consistent across all studies. A higher serum 25(OH)D level (100-120 nmol/L) was associated with a projected 50% lower risk of breast cancer, compared to the serum 25(OH)D level associated in previous observational studies with 50% lower risk of colon cancer (80 nmol/L).  Conclusions: Serum 25(OH)D is recognized as the optimal measure of vitamin D status. This study provides the most precise estimate available to date of the dose-response curve of the inverse association of 25(OH)D with risk of breast cancer, as estimated by observational studies. A substantially higher serum 25(OH)D level was needed for a projected reduction by half in incidence of breast cancer than for a similar reduction in risk of colon cancer, based on observational studies. The dose-response curve will help project the association of vitamin D deficiency states with risk of breast cancer, and will provide useful information for planning future clinical trials. Additional cohort and other epidemiological studies also would be worthwhile to further characterize this association.
Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth
Authors: Andrew A. Gibb, Paul N. Epstein, Shizuka Uchida, Yuting Zheng, Lindsey A. McNally, Detlef Obal, Kartik Katragadda, Patrick Trainor, Daniel J. Conklin, Kenneth R. Brittian, Michael T. Tseng, Jianxun Wang, Steven P. Jones, Aruni Bhatnagar, Bradford G. Hill
Journal: Circulation (2017)

Exercise promotes metabolic remodeling in the heart, which is associated with physiological cardiac growth; however, it is not known whether or how physical activity-induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiological cardiac growth.We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart.Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, in the recovered state following exercise adaptation, there was an increase in myocardial phosphofructokinase activity and glycolysis. In mice, cardiac-specific expression of a kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgene (GlycoLo mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of GlycoLo mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in the heart (GlycoHi mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiological cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose-fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling.Exercise-induced decreases in glycolytic activity stimulate physiological cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart.
Abstract 394: Multiple Cellular Mechanisms Underlie the Trafficking-deficient Phenotype for Kv11.1 (hERG) Mutations Linked to Long QT Syndrome
Authors: Jennifer L Smith, Allison R Reloj, Corey L Anderson, Craig T January, Brian T Delisle
Journal: Circulation Research (2016)

Type 2 Long QT syndrome (LQT2) is commonly caused by missense mutations that disrupt the trafficking of Kv11.1 channels. The goal of this study is to determine the cellular mechanisms that underlie the trafficking-deficient phenotype for LQT2-linked mutations located in different channel domains. We expressed the pore-domain mutation G601S and the cyclic nucleotide binding domain mutation F805C in human embryonic kidney 293 (HEK293) cells or human inducible pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). HEK293 cells or hiPSC-CMs expressing G601S showed a diffuse intracellular anti-Kv11.1 staining pattern that colocalized with the transitional endoplasmic reticulum (ER) marker BAP31, but not markers for the rough ER (calnexin), ER-associated degradation compartment (derlin1), ER exit sites (Sec31), or the ER-Golgi intermediate compartment (ERGIC53). Culturing cells in the drug E-4031 (10 μM, 24 hrs), which corrects the G601s trafficking-deficient phenotype, decreased its colocalization with BAP31. Unlike G601S, the trafficking-deficient phenotype for F805C is not corrected by culturing cells in E-4031. Expressing F805C in HEK293 cells or hiPSC-CMs showed a very different anti-Kv11.1 staining pattern that consisted of several discrete aggregates. In hiPSC-CMs, the F805C aggregates partially overlapped with derlin1 staining and co-transfected green fluorescent protein (gfp) in the cytosol. Incubating cells in the proteasome inhibitor bortezomib (10 μM, 4 hrs) dispersed the F805C aggregates to generate a diffuse intracellular staining pattern. We conclude that G601S and F805C localize to distinct ER subcompartments: G601S is sequestered in the transitional ER and F805C localizes to an ER associated degradation subcompartment that is sensitive to proteasome inhibition.
T-cell receptor sequencing reveals decreased diversity 18 years after early thymectomy
Authors: Judith Gudmundsdottir, Christina Lundqvist, Hanna Ijspeert, Eva van der Slik, Sólveig Óskarsdóttir, Susanne Lindgren, Vanja Lundberg, Martin Berglund, Jenny Lingman-Framme, Esbjörn Telemo, Mirjam van der Burg, Olov Ekwall
Journal: Journal of Allergy and Clinical Immunology (2017)
SP0157 Metabolic phenotype: the two faces of obesity in osteoarthritis
Authors: F Berenbaum
Journal: Annals of the Rheumatic Diseases (2017)

Osteoarthritis (OA) has long been considered as the consequence of tear and wear due to mechanical triggers. In that paradigm, the increased risk of OA in obese patients can be explained by overload on weight-bearing joints. The discovery of an increased risk of hand OA in obese patients has changed the paradigm by opening up an additional hypothesis (not ruling out the mechanical hypothesis) based on systemic factors secreted by the adipose tissue (even the central one or/and the intraarticular one), which could have a deleterious effect on joints. More recently, cohorts data have suggested that obese patients with a metabolic syndrome (MetS) (an association of cardiometabolic factors that increase the risk of cardiovascular events i.e. diabetes, hypertension, dyslipidemia) have an increased risk of OA compared to obese patients without MetS. The most recent researches in that field highlight the role of metabolic-triggered inflammation (called meta-inflammation) on the initiation/progression of OA and the role of each of the components of the MetS independently (hyperglycemia, insulinoresistance, oxLDL, endothelial dysfunction, etc.). A better understanding of this newly defined OA phenotype, namely the MetS-associated OA, should lead to the discovery of new drugs specifically targeting this phenotype or/and to assess the efficacy of drugs in OA already on the market for diabetes, hypertension or dyslipidemia. <h3>Disclosure of Interest</h3> F. Berenbaum Grant/research support from: Servier, TRB Chemedica, Consultant for: Pfizer, AbbVie, GSK, Flexion Therapeutics, Nordic Bioscience, MerckSerono, Jansen, Expanscience
Outcomes of anti-PD-1 therapy in mesothelioma and correlation with PD-L1 expression.
Authors: Gareth Rivalland, Steven Chuan-Hao Kao, Nick Pavlakis, Brett Gordon Maxwell Hughes, Bibhusal Thapa, Abhijit Pal, Marzena Walkiewicz, Allan Solomon Zimet, Shane White, Ken O'Byrne, Paul Mitchell, Thomas John
Journal: Journal of Clinical Oncology (2017)

8514 Background: Early phase trials of anti-programmed death 1 (PD-1) antibodies have demonstrated important responses in malignant mesothelioma (MM). Expression of the ligand, PD-L1, is a potential biomarker for PD-1 directed therapy use and is expressed in a significant proportion of MM. We present results for a cohort treated with PD-1 inhibitory antibodies and assessed for PD-L1 expression. Methods: Patients (pts) with unresectable pleural or peritoneal mm treated with anti-PD-1 antibodies were included. Data was collected retrospectively. Radiological response was assessed using RECIST 1.1. Overall survival (OS) and progression-free survival (PFS) were evaluated. PD-L1 expression was assessed with IHC clone E1L3N (Cell Signaling Technology). PD-L1 positivity was defined as membranous expression on tumour cells: &gt; 5% for PD-L1+ and &gt; 50% for PD-L1 hi . Results: Forty-six pts were treated between July 2015 and January 2017. Median age was 66.5 years, ECOG PS was 0/1 in 3/46 (7%) and 35/46 (76%) respectively. Most were male (83%), and 43/46 (93%) had ≥1 prior therapy, with a median of 2 (range 0 - 5). The predominant histology was epithelioid (n = 32/46; 70%). Pembrolizumab was used in 45/46 and BGB-A317 (a PD-L1 antibody) in 1 pt. Of the 46 pts, the overall response rate (ORR) was 15% (7 PR) with 15/46 (33%) achieving stable disease, giving a DCR of 44%. Progression was seen in 24/46 (52%). Median OS for the entire cohort was 8.0 months (95% CI: 2.3 – 11.9). Median duration of response was not yet reached (range 1.5 -19.8). PD-L1 testing was performed in 14 samples, with PD-L1+ in 5 (36%) and PD-L1 hi in 4 (29%). The ORR was 40% (2 PR, 3 SD) with PD-L1+, 50% (2 PR, 2 SD) with PD-L1 hi and 22% (2/9 patients) with negative expression. PFS and OS were greater with both PD-L1+ (PFS HR: 0.26, 95% CI 0.05 – 1.32, p = 0.10) and PD-L1 hi (PFS HR: 0.17, 95% CI 0.02 – 1.47, p = 0.11). PD-L1+ positivity remained a borderline predictor of improved survival on multivariate analysis (p = 0.06). Complete PD-L1 analysis will be presented at the meeting. Conclusions: PD-1 targeted therapy demonstrated a clinically significant response rate in this cohort of mm patients. Initial analysis suggests PD-L1 expression is correlated with improved response and survival.
Methanobrevibacter oralis detected along with Aggregatibacter actinomycetemcomitans in a series of community-acquired brain abscesses
Authors: V.D. Nkamga, R. Lotte, D. Chirio, M. Lonjon, P.-M. Roger, M. Drancourt, R. Ruimy
Journal: Clinical Microbiology and Infection (2017)
Attention-mediated neurocognitive profiles in survivors of pediatric brain tumors: comparison to children with neurodevelopmental ADHD
Authors: Kristina K Hardy, Victoria W Willard, Anthony Gioia, Christina Sharkey, Karin S Walsh
Journal: Neuro-Oncology (2017)

Attention and working memory symptoms are among the most common late effects in survivors of pediatric brain tumors, and are often associated with academic and psychosocial difficulties. Diagnostic and treatment approaches derived from the literature on attention-deficit hyperactivity disorder (ADHD) have frequently been applied to survivors, yet the extent of overlap in cognitive profiles between these groups is unclear. The objective of the present study is to compare neurocognition in survivors of brain tumors and children with neurodevelopmental ADHD.Neuropsychological data were abstracted from clinically referred brain tumor survivors (n = 105, Mage = 12.0 y, 52.4% male) and children with ADHD (n = 178, Mage = 11.1 y, 64.0% male). Data consist of a battery of parent-report questionnaires and performance-based neuropsychological measures.Twenty-five survivors (23.8%) of pediatric brain tumors met symptom criteria for ADHD. Participants with neurodevelopmental ADHD and survivors who met ADHD criteria had significantly greater parent- (P < 0.001) and teacher-reported (P < 0.001) working memory and behavior regulation difficulties than survivors of tumor who did not meet criteria. Children with ADHD symptoms also performed worse on measures of sustained attention than survivors without ADHD symptoms (P < 0.001). Additionally, survivors with ADHD symptoms had greater performance-based working memory difficulties than either survivors without attention problems or children with neurodevelopmental ADHD (P = 0.002).Nearly a quarter of survivors with attention symptoms have functional profiles that are similar to children with neurodevelopmental ADHD. They also experience more neurocognitive impairments than survivors without attentional difficulties, particularly in working memory. Screening for ADHD symptoms may help providers triage a subset of individuals in need of earlier or additional neuropsychological assessment.