tbuckley/cabot-search huggingface dataset:
FRI0339 Sledai-2k responder index-50 is effective in demonstrating partial response in a phase 2, randomised placebo-controlled study of ustekinumab in patients with active systemic lupus erythematosus
Authors: Z. Touma, M.B. Urowitz, D.D. Gladman, C. Wagner, B. Hsu, M. Chevrier, S. Rose, B. Zhou, R. Gordon
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Ustekinumab (UST), a monoclonal antibody that targets shared p40 subunit of cytokines IL-12 and IL-23, is being investigated in pts w/active systemic lupus erythematosus(SLE). While traditional SLE Disease Activity Index 2000(SLEDAI-2K)scoring assesses complete SLE response for individual disease manifestations, SLEDAI-2K Responder Index-50(S2K RI-50)can be used to evaluate SLE responses using partial improvement(≥50%)in each domain. <h3>Objectives</h3> To evaluate SLEDAI-2K vs S2K RI-50 response in a randomised, PBO-controlled trial of UST in pts w/active SLE. <h3>Methods</h3> We conducted a Ph2, PBO-controlled study in adults w/active disease(SLEDAI score ≥6 w/≥1 BILAG A and /or ≥2 BILAG B scores)despite standard-of-care therapy. Pts(n=102)were randomised(3:2) to UST IV~6 mg/kg or PBO at wk0, followed by SC inj of UST 90 mg q8w or PBO beginning at wk8, both added to standard-of-care. We calculated S2K RI-50 response at wk24 using various thresholds to define response including decrease of at least 1,2,3,4,5, or6 points from baseline(BL) in S2K RI-50 score. We also compared proportion of pts w/SLEDAI-2K response vs S2K RI-50 response in pts receiving UST(n=62)vs PBO(n=40)at wk24. <h3>Results</h3> Change from BL SLEDAI-2K and S2K RI-50 scores were strongly correlated(R=0.89,p&lt;0.0001)at wk24. A greater proportion of UST vs PBO pts achieved S2K RI–50 response at wk24, regardless of threshold used to define response (table 1). The greatest differences in S2K RI–50 response rates between UST vs PBO were observed for a 4-point decrease(23.1%,p=0.010),a 5-point decrease(26.8%,p=0.010), and 6-point decrease (25.5%;p=0.016) from BL. S2K RI-50 captured more responders than SLEDAI-2K at wk24, however, the difference in SLEDAI-2K 4-point response in UST vs PBO was ▵27%(p=0.005)while S2K RI-50 was ▵23%(p=0.010). <h3>Conclusions</h3> S2K RI-50 is an instrument that can capture partial clinically important improvement of ≥50% in SLE disease manifestations. The data suggests cutpoints for defining S2K RI-50 response in clinical trials of pts w/moderate-severe SLE disease activity. <h3>Disclosure of Interest</h3> Z. Touma Grant/research support from: Janssen Research and Development, LLC, M. Urowitz Grant/research support from: Janssen Research and Development, LLC, D. Gladman Grant/research support from: Janssen Research and Development, LLC, C. Wagner Employee of: Janssen Research and Development, LLC, B. Hsu Employee of: Janssen Research and Development, LLC, M. Chevrier Employee of: Janssen Research and Development, LLC, S. Rose Employee of: Janssen Research and Development, LLC, B. Zhou Employee of: Janssen Research and Development, LLC, R. Gordon Employee of: Janssen Research and Development, LLC
Effects of Alcohol Consumption and Metabolic Syndrome on Mortality in Patients With Nonalcoholic and Alcohol-Related Fatty Liver Disease
Authors: Zobair M. Younossi, Maria Stepanova, Janus Ong, Yusuf Yilmaz, Ajay Duseja, Yuichiro Eguchi, Mohamed El Kassas, Marlen Castellanos-Fernandez, Jacob George, Ira M. Jacobson, Elisabetta Bugianesi, Vincent Wai-Sun Wong, Marco Arrese, Victor de Ledinghen, Manuel Romero-Gomez, Nahum Mendez-Sanchez, Aijaz Ahmed, Robert Wong, Georgios Papatheodoridis, Lawrence Serfaty, Issah Younossi, Fatema Nader, Mariam Ziayee, Arian Afendy
Journal: Clinical Gastroenterology and Hepatology (2018)
Person centred care that includes antipsychotic review reduces agitation in dementia patients, finds study
Authors: Susan Mayor
Journal: BMJ (2018)

Using a person centred care programme that includes a review of the use of antipsychotics significantly reduced agitation in patients with dementia living in care homes, a UK study showed,1 which demonstrated that this approach also reduced hospital and GP visits.

The study randomised 69 care homes in three regions of the UK (south London, north London, and Buckinghamshire) to adopt the Wellbeing and Health for people with Dementia (WHELD) programme or continue with usual treatment and care for residents with dementia and agitation over a nine month period.

WHELD provides training for two carer “champions” in each care home …
Real world data on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) use in advanced/metastatic non-small cell lung cancer (NSCLC) with EGFR mutations in Singapore
Authors: B. Chua, E.H. Tan, D.W.-T. Lim, M.-K. Ang, D.S.W. Tan, Q.-S. Ng, R. Kanesvaran, A. Jain, W.-L. Tan, C.K. Toh, T. Rajasekaran
Journal: Annals of Oncology (2018)
Personalized prognostic model incorporating axillary lymph node ratio and molecular subtype for predicting long-term survival in node-positive patients with breast cancer: A large-scale, multicenter study
Authors: J. Lai, Z. Pan, H. Deng, J. Peng, P. Chen, G. Ye, F. Yu, M. Zeng, K. Chen, F. Su
Journal: Annals of Oncology (2018)
Rare TBK1 variants in patients with frontotemporal dementia and amyotrophic lateral sclerosis in a Chinese cohort
Authors: Bin Jiao, Qiying Sun, Zhenhua Yuan, Junling Wang, Lin Zhou, Xinxiang Yan, Beisha Tang, Lu Shen
Journal: Translational Neurodegeneration (2018)

The TANK-Binding Kinase 1 (TBK1) gene has recently been identified as the third or fourth most frequent cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The aim of this study was to assess the genetic contribution of TBK1 in a Chinese cohort. A total of 270 cases with ALS, FTD, or their combination were recruited into this study. All the coding exons of TBK1 and intron-exon boundaries were sequenced using Sanger sequencing. The frequency of TBK1 variants and the correlation with clinical phenotypes were analyzed. A novel mutation (c.1959_1960insGT, p.E653fs) was identified in a sporadic case with semantic dementia, secondarily developing ALS. Another novel variant (c.2063_2064delTT, p.L688Rfs*14) was found in an ALS-FTD family. Totally, the TBK1 variants could only account for 0.7% of cases. This study enlarges the genetic and phenotypic spectrum of TBK1 mutation in a Chinese cohort. Our data indicates that TBK1 mutation is not a common cause for ALS and FTD in Chinese patients.
Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge
Authors: C.M. Parseghian, J.M. Loree, V.K. Morris, X. Liu, K.K. Clifton, S. Napolitano, J.T. Henry, A.A. Pereira, E. Vilar, B. Johnson, B. Kee, K. Raghav, A. Dasari, J. Wu, N. Garg, V.M. Raymond, K.C. Banks, A.A. Talasaz, R.B. Lanman, J.H. Strickler, D.S. Hong, R.B. Corcoran, M.J. Overman, S. Kopetz
Journal: Annals of Oncology (2018)

BackgroundColorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy.Patients and methodsWe present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies.ResultsOur analysis showed that RAS and EGFR relative mutant allele frequency decays exponentially (r2=0.93 for RAS; r2=0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model.ConclusionThese results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation.
Effects of Adjuvant Tamoxifen and of Cytotoxic Therapy on Mortality in Early Breast Cancer
Journal: New England Journal of Medicine (1988)

We sought information worldwide on mortality according to assigned treatment in all randomized trials that began before 1985 of adjuvant tamoxifen or cytotoxic therapy for early breast cancer (with or without regional lymph-node involvement). Coverage was reasonably complete for most countries. In 28 trials of tamoxifen nearly 4000 of 16,513 women had died, and in 40 chemotherapy trials slightly more than 4000 of 13,442 women had died. The 8106 deaths were approximately evenly distributed over years 1, 2, 3, 4, and 5+ of follow-up, with little useful information beyond year 5. Systematic overviews of the results of these trials demonstrated reductions in mortality due to treatment that were significant when tamoxifen was compared with no tamoxifen (P less than 0.0001), any chemotherapy with no chemotherapy (P = 0.003), and polychemotherapy with single-agent chemotherapy (P = 0.001). In tamoxifen trials, there was a clear reduction in mortality only among women 50 or older, for whom assignment to tamoxifen reduced the annual odds of death during the first five years by about one fifth. In chemotherapy trials there was a clear reduction only among women under 50, for whom assignment to polychemotherapy reduced the annual odds of death during the first five years by about one quarter. Direct comparisons showed that combination chemotherapy was significantly more effective than single-agent therapy, but suggested that administration of chemotherapy for 8 to 24 months may offer no survival advantage over administration of the same chemotherapy for 4 to 6 months. Because it involved several thousand women, this overview was able to demonstrate particularly clearly that both tamoxifen and cytotoxic therapy can reduce five-year mortality.
Enasidenib Is Highly Active in Previously Untreated IDH2 Mutant AML: Early Results from the Beat AML Master Trial
Authors: Eytan M. Stein, Abigail Shoben, Uma Borate, Maria R. Baer, Wendy Stock, Prapti A. Patel, Tibor Kovacsovics, William Blum, Jo-Anne Vergilio, Nyla A. Heerema, Leonard Rosenberg, Sonja Marcus, Mona Stefanos, Jordan Chervin, Brian J. Druker, Amy Burd, John C. Byrd, Ross L. Levine, Alice S. Mims
Journal: Blood (2018)
Endoscopic Retrograde Cholangiopancreatography
Authors: Ioana Baiu, Brendan Visser
Journal: JAMA (2018)

Endoscopic Retrograde CholangiopancreatographyEndoscopic retrograde cholangiopancreatography (ERCP) is performed by gastroenterologists or surgeons to evaluate the bile duct, pancreatic duct, and ampulla.Bile and pancreatic enzymes are released into the small bowel to assist digestion.Bile flows from the liver, is stored in the gallbladder, then flows through the common bile duct.Similarly, pancreatic enzymes flow from the pancreas through the pancreatic duct.The ampulla is the confluence of the biliary and pancreatic ducts.Both of these ducts can become blocked or narrowed by stones, tumors, or inflammation.
Phase Ib/II study of biweekly TAS-102 with bevacizumab combination for patients with metastatic colorectal cancer refractory to standard therapies (BiTS study): Phase Ib results
Authors: Y. Kagawa, H. Satake, T. Kato, K. Oba, H. Yasui, M. Nakamura, T. Watanabe, K. Hirata, K. Muro, Y. Komatsu, T. Yoshino, K. Yamazaki, H. Mishima, M. Kotaka, A. Tsuji, Y. Kakeji, E. Oki, N. Nagata, S. Junichi
Journal: Annals of Oncology (2018)
Effect of Disease Activity at Three and Six Months After Diagnosis on Long‐Term Outcomes in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
Authors: Seerapani Gopaluni, Oliver Flossmann, Mark A. Little, Paul O'Hara, Pirow Bekker, David Jayne
Journal: Arthritis & Rheumatology (2018)

Objective The treatment of antineutrophil cytoplasmic antibody ( ANCA )–associated vasculitis ( AAV ) aims to suppress disease activity and prevent subsequent disease flare. This study sought to explore the association of early disease control with long‐term outcomes to validate early disease control as an end point for future clinical trials in AAV . Methods Data from 4 European Vasculitis Society inception clinical trials in AAV (1995–2002) and subsequent data on long‐term outcomes from the trial data registry were studied. Clinical parameters in patients with AAV at baseline and at 3 and 6 months after diagnosis were assessed to study the long‐term risk of death and end‐stage renal failure ( ESRF ). At 6 months, outcomes were defined based on a disease status of either sustained remission (remission by 3 months, sustained to 6 months), late remission (remission after 3 months and by 6 months), relapsing disease (remission by 3 months but relapse by 6 months), or refractory disease (no remission by 6 months). Results Of the 354 patients with AAV who were followed up for a median of 5.7 years, 46 (13%) developed ESRF , 66 (18.6%) died, and 89 (25.1%) had either died or developed ESRF . At 6 months, predictors of the composite end point of death or ESRF were as follows: age (hazard ratio [ HR ] 1.02, 95% confidence interval [95% CI ] 1–1.05; P = 0.012), estimated glomerular filtration rate ( HR 0.94, 95% CI 0.92–0.95; P &lt; 0.001), and disease status at 6 months (late remission, HR 2.94, 95% CI 1.1–7.85 [ P = 0.031]; relapsing disease, HR 8.21, 95% CI 2.73–24.65 [ P &lt; 0.001]; refractory disease, HR 4.89, 95% CI 1.96–12.18 [ P = 0.001]). Similar results were observed when these analyses were performed separately for death and for ESRF . Conclusion The results of this study suggest that disease status at 3 and 6 months following the diagnosis of AAV may be predictive of the long‐term risk of mortality and ESRF , and therefore these may be valid end points for induction trials in AAV . The current findings need to be validated in a larger data set.
FRI0088 Psychological impact in rheumatoid arthritis: role of specific treatment and associated measures
Authors: X. Grapton, P. Lemesle, L. Arabian, V. Strotz
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Psychological issues in rheumatoid arthritis (RA) are often spontanously mentioned by patients or identified by rheumatologists. Besides classic follow up parameters like DAS28, we have to consider those issues to improve our patients psychological well-being. <h3>Objectives</h3> Explore reasons of psychological impact in RA. Analyse in a quantitative way symptoms of discontent and their repercussions. Evaluate consequences of disease treatment on those symptoms and propose recommendations for rheumatologists. <h3>Methods</h3> RA cases were collected by a group of 20 private practice rheumatologists in the Paris area. Basic informations about the patient and his disease were provided by his rheumatologist. Questionnaire including 14 items about psychological and life quality involvement was filled in by the patient. <h3>Results</h3> 167 cases collected : 82% women, mean age 57 years, 56% moderate and 14% severe disease, 76% ACPA positive, 73% structural damage. Initial DAS28 4,7. Post treatment DAS28 2.7. Drugs: classic DMARDs 95%, corticosteroids 73%, biological DMARDs 22%, combination therapy 76%. In 82% of the cases, the rheumatologist recommends more than only specific RA drug treatment: rest (47%), physiotherapy, ergotherapy, balneotherapy (42%), adapting professionnel activity and environment, help for housework (33%), psychological support or psychoactive drugs (19%), yoga or other relaxation exercices (11%), balneology… Psychological repercussions are spontaneously mentioned by 71% of the patients. Psychological state is altered by : disease announcement, pain (85%), physical fatigue (71%), handicap (58%), other people’s attitude. Are limited : housework (51%), getting about (44%), do-it-yourself (55%), sports (61%), artistic activities (41%), professional activity (29%). Social life is affected by : lack of being listened to (72%), lack of being understood (68%), lack of empathy (49%). RA treatment reduces all those factors by at least one third, except impact on family relations. Before treatment, RA patients report: sleeping trouble (70%), anxiety (57%), lack of motivation (55%), dependency (49%), frustration (42%), lack of self-esteem (37%), concentration problems (35%), disillusion (31%), depression (30%), family tension (29%), isolation (27%) and libido decrease (23%). After treatment, all those factors are 41%–55% less frequent, except libido decrease (−28%). 55% sleep better, 49% aren’t depressed anymore, concentration problems diminish by 48% and social life is improved by 50%. <h3>Conclusions</h3> There is a major psychological impact in RA patients, with repercussions on their well-being and life quality. This can be improved by specific anti RA treatment, but we must also consider other measures and, if necessary, psychological support and/or psychoactive drugs. All chosen items are improved, except impact on family relations. <h3>Disclosure of Interest</h3> None declared
An unusual cause of right iliac fossa pain
Authors: Omed Amin, David C Howlett
Journal: BMJ (2018)

A 34 year old woman presented to the emergency department with a history of worsening right iliac fossa pain over several days. She described the pain as alternating dull and sharp, and had found simple analgesia (paracetamol, non-steroidal anti-inflammatory drugs) to be ineffective. She had no other associated signs or symptoms and no history other than insertion of an intrauterine contraceptive device (IUCD) several years ago.

A transvaginal ultrasound was unremarkable except that it showed a trace of free fluid in the pelvis, close to the uterus, and the IUCD was not visualised. The patient …
John A. Galloway, MD, FACP: A Pharmaceutical Physician and Leader in Diabetes Therapy
Authors: James H. Anderson
Journal: Diabetes Care (2018)

John A. Galloway, MD, FACP.



There have been extraordinary individuals active in patient care, clinical research, professional and patient organizations, and pharmaceutical science who devoted their careers to constantly focusing on and campaigning for “what is best for the patient.” Dr. John A. Galloway has been that leader, whose clinical curiosity, insights, dedication, and commitment to others brought insulin therapy from the impurified, low-potency animal insulins to the modern insulins of today.

Born in Omaha, Nebraska, in 1928, Galloway moved to Washington, DC, and graduated from St. Albans School in 1946 and then from the University of Pennsylvania in Philadelphia in 1950 with a B.A. in English and Pre-Med. After 2 years in the U.S. Army and serving in combat in Korea, 1st Lt. Galloway was released to start medical school at the University of Nebraska College of Medicine in Omaha, where he gained his MD in 1956. Upon completion of his internship, he began his residency in internal medicine at Temple University Hospital in Philadelphia, serving as Chief Medical Resident from 1959–1960. This was followed by a Fellowship in Diabetes, Endocrinology and Nuclear Medicine with Charles R. Shuman, MD, at Temple, where Galloway and Shuman published the first report in the medical literature on the use of computers to analyze large volumes of clinical data in a study of surgery in patients with diabetes (1).

After a report in the Journal of Clinical Investigation by Solomon A. Berson, MD, and Rosalyn S. Yalow, PhD, a physicist, on a method they had developed for measuring insulin in the blood using immunologic techniques (the radioimmunoassay or RIA) (2), Shuman arranged for Galloway to attend the first workshop that Berson and Yalow gave on how to perform their assay. Also selected to attend were Lisa G. Heding from Novo Laboratory (now …
Abstract 15161: Adiponectin Exerts a Protective Role Against Vascular Remodeling During Hypertension
Authors: Crystal M Ghantous, Sarah Hanache, Firas Kobaissy, Asad Zeidan
Journal: Circulation (2015)

Introduction: Hypertension is associated with leptin production and ROS formation in vascular smooth muscle cells (VSMC) and contributes to vascular remodeling. Adiponectin (ADQ) has a cardioprotective role on the heart, but the protective role of ADQ on VSMC during hypertension has not been fully elucidated yet. Hypothesis: Mechanical stretch/hypertension is associated with a low ADQ/leptin ratio in VSMC, leading to VSMC remodeling. Methods: To mimic hypertension, the rat portal vein was cultured either mechanically stretched with 1.2 gram weights (due to the force-length relationship normalized to the human force of stretch during hypertension and the longitudinal orientation of its VSMC) or left unstretched. ADQ, leptin, eNOS, p-ERK1/2 and p-AKT expression in VSMC was evaluated by Western blot. The protective effect of adiponectin (5-10 μg/ml; 15 min-24 hr) was investigated on ROS formation by DHE staining and on hypertrophy by protein synthesis via [ 3 H]leucine incorporation. Results: Mechanical stretch for 24 hr reduced the expression of ADQ in VSMC (0.49 ± 0.08 fold, n=6, p&lt;0.05) and increased leptin (2.51 ± 0.39 fold, n=6, p&lt;0.05) compared to controls. Stretch (24 hr) decreased ADQ mRNA expression by 0.31 ± 0.11 fold (n=7, p&lt;0.05) and ADQ receptor R2 by 0.51 ± 0.21 fold (n=7, p&lt;0.05) but had no effect on ADQ receptor R1 (n=8). This effect of stretch was associated with increased protein synthesis by 1.39 ± 0.06 fold (n=6, p&lt;0.05), while exogenous ADQ significantly inhibited stretch-induced hypertrophy (n=6, p&lt;0.05). Stretch (15 min) increased p-ERK1/2 and p-AKT by 2.10 ± 0.25 and 4.03 ± 0.61 fold respectively (n=5, p&lt;0.05), but ADQ reduced p-ERK1/2 and p-AKT by 0.82 ± 0.26 and 0.55 ± 0.25 fold respectively (n=3, p&lt;0.05) in stretched vessels. eNOS expression decreased by 0.70 ± 0.06 fold (n=5, p&lt;0.05) after stretch for 24 hr, while ADQ increased eNOS in stretched veins by 2.02 ± 0.41 fold (n=3, p&lt;0.05). Stretch for 1 hr increased ROS by 5.69 ± 0.13 fold (n=3, p&lt;0.05), whereas ADQ significantly inhibited ROS in stretched vessels (1.71 ± 0.22 fold, n=3). Conclusion: Mechanical stretch reduces the ADQ/leptin ratio in VSMC. ADQ plays a protective role against vascular remodeling during hypertension by affecting eNOS, ERK, AKT, ROS and hypertrophy.
Video Assessment of the Frequency and Evaluations of Head Collision Events During the 2018 World Cup Tournament
Authors: Ajay Premkumar, Kevin X. Farley, Albert T. Anastasio, Su-Wei Lee, Faris Mirza, Michael B. Gottschalk, John Xerogeanes
Journal: JAMA Neurology (2018)

This study provides an analysis of head collisions between players in all 64 games in the 2018 World Cup tournament, as well as the frequency of evaluations by referees and clinicians after such collisions.