tbuckley/cabot-search huggingface dataset:
Impact of cardiac comorbidity on use and outcomes of adjuvant chemotherapy (ADJ) for colorectal cancer (CRC): A real-world population-based study.
Authors: Shiru Lucy Liu, Sharlene Gill, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2019)

491 Background: Cardiac comorbidities such as myocardial infarction (MI) and congestive heart failure (CHF) may pose challenges in the treatment of CRC. As the population ages, cancer patients (pts) will be increasingly affected by cardiac comorbidities. We performed a population-based analysis of CRC to evaluate the prevalence of MI and CHF, use of ADJ, and survival outcomes. Methods: We evaluated 8601 pts diagnosed with resected stage 2 or 3 CRC from 2004 to 2015 in Alberta, Canada. Baseline patient, tumor, and treatment characteristics were compared between those with and without MI or CHF. Survival analysis was conducted using Kaplan-Meier methods and Cox regression models. Results: In total, 506 (5.9%) patients (pts) had MI and 440 (5.1%) had CHF. CRC patients with prior MI or CHF were older (median 76 and 79 years, respectively) and had worse Charlson Comorbidity Index (median CCI 2 for both) than those without cardiac comorbidities (median age 67 and CCI 0) (p &lt; 0.001). Only 24% and 15% of pts with a MI or CHF history, respectively, received ADJ when compared to their counterparts (52% and 53%, respectively, p &lt; 0.001). Among those who received ADJ (N = 3409), an oxaliplatin-based regimen was used in 26% of MI pts versus 42% of those without MI (p = 0.002), and in 31% of CHF pts versus 42% of those without CHF. Kaplan-Meier analysis revealed significantly worse overall survival (OS) in pts with prior MI (9.1 vs 4.3 years, p &lt; 0.001) or CHF (9.2 vs. 2.7 years, p &lt; 0.001) when compared to those without. However, cancer-specific survival (CSS) was not statistically different with or without MI (p = 0.348) and with or without CHF (p = 0.611). In Cox regression that adjusted for use of ADJ, MI was no longer a significant predictor of OS (HR = 1.01, 95% confidence interval (CI) 0.88-1.15), but CHF remained significant (HR 0.65, 95% CI 0.57-0.74). Neither MI nor CHF were predictors of CSS (HR 1.09, 95% CI 0.98-1.33, and HR 0.94, 95% CI 0.77-1.15). Conclusions: CRC pts with MI or CHF experienced lower use of ADJ and worse OS, but no difference in CSS was observed. ADJ-treated pts with prior MI appeared to benefit while worse outcomes in pts with prior CHF appear to be driven by non-cancer related causes.
Omalizumab Treatment Patterns in Chronic Idiopathic Urticaria (CIU): Evidence from a Large Allergy Practice in the United States (US)
Authors: Brian D. Stone, Abhishek Kavati, Maryia Zhdanava, Benjamin Ortiz, Jason Lecocq, Bradd Schiffman, Hoi Ching Cheung, Patrick Lefebvre
Journal: Journal of Allergy and Clinical Immunology (2019)
Fines for claiming free prescriptions rose by 30% last year
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The number of penalty prescription charges issued to patients in England rose by a third last year and has increased by 60% in the past three years, The BMJ has learnt.

Figures released under freedom of information legislation show that 1 379 957 penalty notices were issued in 2018. Previous numbers were 1 052 430 in 2017 and 864 366 in 2016.

The figures were disclosed by the NHS Business Services Authority, which issues the penalty charges if it believes that a patient has incorrectly claimed free NHS prescriptions or free or reduced cost dental treatment.

The disclosure comes amid a major government crackdown on prescription fraud.1 The NHS estimates that this type of fraud costs £256m (€290m; $330m) a year and has set a target to halve the losses by 2020. It launched a national campaign in September 2018, alerting patients that they needed …
Genetic reduction of eEF2 kinase alleviates pathophysiology in Alzheimer’s disease model mice
Authors: Brenna C. Beckelman, Wenzhong Yang, Nicole P. Kasica, Helena R. Zimmermann, Xueyan Zhou, C. Dirk Keene, Alexey G. Ryazanov, Tao Ma
Journal: Journal of Clinical Investigation (2019)

Molecular signaling mechanisms underlying Alzheimer's disease (AD) remain unclear. Maintenance of memory and synaptic plasticity depend on de novo protein synthesis, dysregulation of which is implicated in AD. Recent studies showed AD-associated hyperphosphorylation of mRNA translation factor eukaryotic elongation factor 2 (eEF2), which results in inhibition of protein synthesis. We tested to determine whether suppression of eEF2 phosphorylation could improve protein synthesis capacity and AD-associated cognitive and synaptic impairments. Genetic reduction of the eEF2 kinase (eEF2K) in 2 AD mouse models suppressed AD-associated eEF2 hyperphosphorylation and improved memory deficits and hippocampal long-term potentiation (LTP) impairments without altering brain amyloid β (Aβ) pathology. Furthermore, eEF2K reduction alleviated AD-associated defects in dendritic spine morphology, postsynaptic density formation, de novo protein synthesis, and dendritic polyribosome assembly. Our results link eEF2K/eEF2 signaling dysregulation to AD pathophysiology and therefore offer a feasible therapeutic target.
Whole Genome–Derived Tiled Peptide Arrays Detect Prediagnostic Autoantibody Signatures in Non–Small-Cell Lung Cancer
Authors: Yuanqing Yan, Nan Sun, Hong Wang, Makoto Kobayashi, Jon J. Ladd, James P. Long, Ken C. Lo, Jigar Patel, Eric Sullivan, Thomas Albert, Gary E. Goodman, Kim-Anh Do, Samir M. Hanash
Journal: Cancer Research (2019)

The majority of non-small-cell lung cancer (NSCLC) cases are diagnosed at advanced stages, primarily because earlier stages of the disease are either asymptomatic or may be attributed to other causes such as infection or long-term effects from smoking. Therefore, early detection of NSCLC would likely increase response and survival rates due to timely intervention. Here, we utilize a novel approach based on whole genome-derived tiled peptide arrays to identify epitopes associated with autoantibody reactivity in NSCLC as a potential means for early detection. Arrays consisted of 2,781,902 tiled peptides representing 20,193 proteins encoded in the human genome. Analysis of 86 prediagnostic samples and 86 matched normal controls from a high-risk cohort revealed 48 proteins with three or more reactive epitopes in NSCLC samples relative to controls. Independent mass spectrometry analysis identified 40 of the 48 proteins in prediagnostic sera from NSCLC samples, of which, 21 occurred in the immunoglobulin-bound fraction. In addition, 63 and 34 proteins encompassed three or more epitopes that were distinct for squamous cell lung cancer and lung adenocarcinoma, respectively. Collectively, these data show that tiled peptide arrays provide a means to delineate epitopes encoded across the genome that trigger an autoantibody response associated with tumor development. SIGNIFICANCE: This study provides a modality for early diagnosis of NSCLC for precision oncology that can be applied to other cancer types.
Phase Ib study of andecaliximab (GS-5745, ADX) in combination with S-1+platinum chemotherapy in Japanese subjects with advanced gastric or GEJ adenocarcinoma.
Authors: Kei Muro, Taroh Satoh, Kensei Yamaguchi, Atsuo Takashima, Shigenori Kadowaki, Daisuke Sakai, Takashi Ichimura, Seiichiro Mitani, Toshihiro Kudo, Keisho Chin, Shigehisa Kitano, Pankaj Bhargava, Marianna Zavodovskaya, JieJane Liu, Masato Fukui, Narikazu Boku
Journal: Journal of Clinical Oncology (2019)

53 Background: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. In preclinical models, anti-MMP9 inhibited tumor growth, reduced metastases, and increased survival. In this study, safety, tolerability, PK, exploratory biomarkers, and preliminary efficacy of ADX in combination with anti-cancer agents were assessed. Methods: The safety and efficacy of ADX in combination with S-1+cisplatin (SP) or S-1+oxaliplatin (SOX) were evaluated in subjects with systemic chemotherapy naïve advanced gastric or GEJ adenocarcinoma. For SP cohort, six Japanese subjects received ADX 800 mg via IV infusion Q2W. For SOX cohort, 10 subjects received ADX 1200 mg IV Q3W. All subjects continued until PD or unacceptable toxicity. Results: As of August 2018, a total of 16 subjects received S-1+platinum with six subjects enrolled into the SP combination cohort and 10 subjects enrolled into the SOX combination cohort. ≥ Grade 3 AEs were mainly neutropenia (31%), amylase increased, CPK increased, hepatic function abnormal, anorexia, hyperglycaemia, hyponatraemia, anaemia, stomatitis, and peripheral sensory neuropathy (each 6%). The ORR in subjects with measurable target lesions was 73% (8/11) based on investigator evaluation. Median PFS and OS have not been reached. Exploratory biomarker analyses are ongoing. Conclusions: Preliminary safety data demonstrate a manageable safety profile for ADX in combination with S-1+platinum, and the combination appears to show promising response rates. Clinical trial information: NCT02862535.
The Pan-PIM Kinase Inhibitor LGB321 Strongly Increases Ibrutinib Effects in CLL, By Blocking Anti-Apoptotic Pathways and Microenvironmental Interactions
Authors: Sarah Decker, Shifa Saleem, Sandra Kissel, Anabel Zwick, Konrad Aumann, Katja Zirlik, Justus Duyster, Christine Dierks
Journal: Blood (2018)
Empagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Left Ventricular Hypertrophy: A Subanalysis of the EMPA-REG OUTCOME Trial
Authors: Subodh Verma, C. David Mazer, Deepak L. Bhatt, Satish R. Raj, Andrew T. Yan, Atul Verma, Ele Ferrannini, Gudrun Simons, Jisoo Lee, Bernard Zinman, Jyothis T. George, David Fitchett
Journal: Diabetes Care (2019)

Molecular and cellular changes in the diabetic heart lead to aberrant myocardial remodeling, characterized by left ventricular hypertrophy (LVH) and eventual diastolic and/or systolic dysfunction (1,2). Although the differential effects of antihypertensive therapy on cardiovascular outcomes in patients with type 2 diabetes and LVH have been studied, those of antihyperglycemic therapy have not (3). In this post hoc analysis of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial, we report the effects of empagliflozin on cardiovascular outcomes in subjects with type 2 diabetes, established cardiovascular disease, and electrocardiogram (ECG) evidence of LVH.

EMPA-REG OUTCOME (NCT01131676, ClinicalTrials.gov) enrolled patients with type 2 diabetes, inadequate glycemic control, and established cardiovascular disease who had an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 at baseline. In total, 7,020 subjects were treated with empagliflozin 10 mg/day, empagliflozin 25 mg/day, or placebo in addition to standard of care (4). In subgroups with/without LVH at baseline (defined on ECG as RV5/V6 + SV1/V2 >3.5 mV or RaVL ≥1.3 mV plus ≥1 of the following: left atrial abnormality, left axis deviation, and ST- and/or T-wave changes consistent with LVH), we assessed the risks of cardiovascular death, all-cause mortality, and 3-point major adverse cardiovascular events (MACE) with pooled empagliflozin doses versus placebo. We excluded 134 participants without a baseline ECG, 7 who had a baseline ECG that was uninterpretable or did not have QT interval data, and 906 who took the study drug prior to ECG. Therefore, 5,973 participants had a usable baseline ECG (manually analyzed; 2,008 in the placebo group and 3,965 in the empagliflozin groups), of whom 140 had LVH (45 in the placebo group and 95 in the empagliflozin groups). We used a Cox proportional hazards model with factors for age, sex, region, treatment, …
Endogenous Production of IL1B by Breast Cancer Cells Drives Metastasis and Colonization of the Bone Microenvironment
Authors: Claudia Tulotta, Diane V. Lefley, Katy Freeman, Walter M. Gregory, Andrew M. Hanby, Paul R. Heath, Faith Nutter, J. Mark Wilkinson, Amy R. Spicer-Hadlington, Xinming Liu, Steven M.J. Bradbury, Lisa Hambley, Victoria Cookson, Gloria Allocca, Marianna Kruithof de Julio, Robert E. Coleman, Janet E. Brown, Ingunn Holen, Penelope D. Ottewell
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Breast cancer bone metastases are incurable, highlighting the need for new therapeutic targets. After colonizing bone, breast cancer cells remain dormant, until signals from the microenvironment stimulate outgrowth into overt metastases. Here we show that endogenous production of IL1B by tumor cells drives metastasis and growth in bone. Experimental Design: Tumor/stromal IL1B and IL1 receptor 1 (IL1R1) expression was assessed in patient samples and effects of the IL1R antagonist, Anakinra, or the IL1B antibody canakinumab on tumor growth and spontaneous metastasis were measured in a humanized mouse model of breast cancer bone metastasis. Effects of tumor cell–derived IL1B on bone colonization and parameters associated with metastasis were measured in MDA-MB-231, MCF7, and T47D cells transfected with IL1B/control. Results: In tissue samples from &amp;gt;1,300 patients with stage II/III breast cancer, IL1B in tumor cells correlated with relapse in bone (HR = 1.85; 95% CI, 1.05–3.26; P = 0.02) and other sites (HR = 2.09; 95% CI, 1.26–3.48; P = 0.0016). In a humanized model of spontaneous breast cancer metastasis to bone, Anakinra or canakinumab reduced metastasis and reduced the number of tumor cells shed into the circulation. Production of IL1B by tumor cells promoted epithelial-to-mesenchymal transition (altered E-Cadherin, N-Cadherin, and G-Catenin), invasion, migration, and bone colonization. Contact between tumor and osteoblasts or bone marrow cells increased IL1B secretion from all three cell types. IL1B alone did not stimulate tumor cell proliferation. Instead, IL1B caused expansion of the bone metastatic niche leading to tumor proliferation. Conclusions: Pharmacologic inhibition of IL1B has potential as a novel treatment for breast cancer metastasis.
Validity of hepatic cone-unit resection for hepatocellular carcinoma.
Authors: Satoru Imura, Shinichiro Yamada, Yu Saito, Shuichi Iwahashi, Tetsuya Ikemoto, Yuji Morine, Mitsuo Shimada
Journal: Journal of Clinical Oncology (2019)

228 Background: Anatomical liver resection (ALR) has been performed widely for hepatocellular carcinoma (HCC). However, there are difficult cases with typical ALR, due to tumor location or anatomical variation. The aim of this study is to review the cases of atypical ALR and to investigate the validity of small ALR for HCC. Methods: From 2007 to 2017, hepatic resection less than 2 segments was performed to 252 patients with HCC. (1) We reviewed cases with atypical ALR (eg. posterior segment + anterior dorsal area, S4 + S8 ventral area, etc.), and (2) Regarding the validity of cone-unite resection for single HCC, we compared the clinicopathological outcome with subsegmentectomy as a control. Results: (1) Atypical ALR was performed in 10% (17/169) of ALR less than 2 segments. There were 7 cases of extended anterior segmentectomy or extended S8 resection for patients having anterior or S8 portal branch that perfused to the right side of the right hepatic vein. Most of such atypical ALR tended to be indicated in right-side hepatectomy. (2) Liver function was well preserved in both groups, and it was better in subsegment group (ICGR15: 10.5 vs. 12.3%, ALB: 4.1 vs. 3.9g/dL). Regarding the tumor factor, the diameter was larger in the subsegment group than in the cone-unite group (2.8 vs. 2.1cm), and the proportion in which subsegmentectomy was performed in the case more than 3 cm was high (32 vs. 11%). There was no difference in OS and DFS between the two groups. Even when the tumor diameter was 3 cm or less, there was no difference in DFS between subsegment (n = 28) and cone-unite resection (n = 40). Conclusions: There are a number of cases that typical ALR is difficult, especially in the right-side hepatectomy. There was no difference in the prognosis depending on the range of resection, if HCC could be resected of subsegment or less. Therefore, depending on age and comorbidity, it is necessary to determine the type of hepatectomy without sticking to the subsegmentectomy.
A reliability study using Network-Oriented Research Assistant to evaluate the use of digital photographs in the assessment of atopic dermatitis
Authors: Meagan E Hughes, Hilary Aralis, Kevin W Bruhn, Jonathan Cotliar, Noah Craft, Ilana J DeLuca, Reyhaneh Hamidi, Kathy Nguyen, Mayha Patel, Vishal A Patel, Howard Sofen, Belinda H Tan, Consuelo V David
Journal: Journal of the American Academy of Dermatology (2019)
Safety and Efficacy of Belimumab Plus Standard Therapy for Up to Thirteen Years in Patients With Systemic Lupus Erythematosus
Authors: Daniel J. Wallace, Ellen M. Ginzler, Joan T. Merrill, Richard A. Furie, William Stohl, W. Winn Chatham, Arthur Weinstein, James D. McKay, W. Joseph McCune, Michelle Petri, James Fettiplace, David A. Roth, Beulah Ji, Amy Heath
Journal: Arthritis & Rheumatology (2019)

To investigate the long-term safety and efficacy of intravenous (IV) belimumab plus standard of care (SOC) therapy for systemic lupus erythematosus (SLE) in patients with active, autoantibody-positive SLE.The study was designed as a multicenter, open-label, continuation study of IV belimumab given every 4 weeks in conjunction with SOC therapy in patients with SLE who completed a phase II, double-blind study. Adverse events (AEs) and laboratory data were monitored from the first belimumab dose (in either study) until 24 weeks after the final dose. Efficacy assessments included SLE Responder Index (SRI) and flare index scores (each assessed at 16-week intervals) and glucocorticoid use (assessed at 4-week intervals).Of the 476 patients in the parent study, 298 (62.6%) entered the continuation study, of whom 96 (32.2%) remained in the study. Patients received belimumab for up to 13 years (median duration of exposure 3,334.0 days [range 260-4,332 days], total belimumab exposure 2,294 patient-years, median number of infusions 115.5 [range 7-155]). The percentage of patients with AEs each year remained stable or decreased. Normal serum IgG levels were maintained in the majority of patients over the study, and the rate of infections remained stable. The percentage of patients who achieved an SRI response increased from 32.8% (year 1) to 75.6% of those remaining on treatment at year 12. The glucocorticoid dose was decreased in patients who had been receiving >7.5 mg/day at baseline.This study is the longest to date to assess belimumab treatment in patients with SLE in clinical trials. Belimumab was well tolerated with no new safety concerns, and efficacy was maintained in patients who continued the study. For patients who initially exhibited a satisfactory response to belimumab, the treatment continues to be well tolerated and provides long-term disease control.
Middle Cerebral Artery Velocities Are Inversely Related to Hemoglobin Levels and Acutely Drop in Response to RBC Transfusion: Implications for Stroke Screening in SCD
Authors: Ajay Perumbeti, Obdulio Carreras, Jon A Detterich, Payal Shah, John Sunwoo, Michael Khoo, John C Wood, Thomas D. Coates
Journal: Blood (2018)
Abstract 17108: How to Prevent Hypernatremia After Tolvaptan Treatment?-Lessons Learned From 6-year Post Marketing Surveillance Study
Authors: Koichiro Kinugawa, Naoki Sato, Takayuki Inomata, Moriyoshi Yasuda, Yoshiyuki Shibasaki, Toshiyuki Shimakawa
Journal: Circulation (2017)

Introduction: Tolvaptan, a vasopressin type 2 receptor antagonist, is indicated for the treatment of severe hyponatremia in US, but the broader indication is applied in Japan, i.e. diuretic-resista...
Clinical Events After Deferral of LAD Revascularization Following Physiological Coronary Assessment
Authors: Sayan Sen, Yousif Ahmad, Hakim-Moulay Dehbi, James P. Howard, Juan F. Iglesias, Rasha Al-Lamee, Ricardo Petraco, Sukhjinder Nijjer, Ravinay Bhindi, Sam Lehman, Darren Walters, James Sapontis, Luc Janssens, Christiaan J. Vrints, Ahmed Khashaba, Mika Laine, Eric Van Belle, Florian Krackhardt, Waldemar Bojara, Olaf Going, Tobias Härle, Ciro Indolfi, Giampaolo Niccoli, Flavio Ribichini, Nobuhiro Tanaka, Hiroyoshi Yokoi, Hiroaki Takashima, Yuetsu Kikuta, Andrejs Erglis, Hugo Vinhas, Pedro Canas Silva, Sérgio B. Baptista, Ali Alghamdi, Farrel Hellig, Bon-Kwon Koo, Chang-Wook Nam, Eun-Seok Shin, Joon-Hyung Doh, Salvatore Brugaletta, Eduardo Alegria-Barrero, Martijin Meuwissen, Jan J. Piek, Niels van Royen, Murat Sezer, Carlo Di Mario, Robert T. Gerber, Iqbal S. Malik, Andrew S.P. Sharp, Suneel Talwar, Kare Tang, Habib Samady, John Altman, Arnold H. Seto, Jasvindar Singh, Allen Jeremias, Hitoshi Matsuo, Rajesh K. Kharbanda, Manesh R. Patel, Patrick Serruys, Javier Escaned, Justin E. Davies
Journal: Journal of the American College of Cardiology (2019)

Physicians are not always comfortable deferring treatment of a stenosis in the left anterior descending (LAD) artery because of the perception that there is a high risk of major adverse cardiac events (MACE). The authors describe, using the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) trial, MACE rates when LAD lesions are deferred, guided by physiological assessment using fractional flow reserve (FFR) or the instantaneous wave-free ratio (iFR).
Primary Immune Deficiency Treatment Consortium (PIDTC) update
Authors: Linda M. Griffith, Morton J. Cowan, Luigi D. Notarangelo, Donald B. Kohn, Jennifer M. Puck, William T. Shearer, Lauri M. Burroughs, Troy R. Torgerson, Hélène Decaluwe, Elie Haddad
Journal: Journal of Allergy and Clinical Immunology (2016)
Sensitivity and specificity of the NETest: A validation study.
Authors: Taymeyah E. Al-Toubah, Mauro Cives, Tiffany Valone, Kirsten Blue, Jonathan R. Strosberg
Journal: Journal of Clinical Oncology (2019)

222 Background: Secretory tumor markers traditionally measured in patients with NET, such as chromogranin A, are lacking in sensitivity and specificity, and consequently are of limited clinical utility. The NETest, a novel blood multigene RNA transcript assay, has been found to be highly sensitive and specific. We sought to validate the sensitivity of the NETest in a population consisting of metastatic well-differentiated NETs, and evaluate the specificity of the test in a mixed population of metastatic non-NET GI malignancies and healthy individuals. Methods: 100 individuals consented to be tested, comprising of 49 patients with metastatic well-differentiated NETs of gastroenteropancreatic and lung origin, 25 patients with other gastrointestinal cancers, and 26 healthy individuals. Samples were sent in a blinded fashion to a central laboratory (Wren Laboratories). A NETest value of 0-13% was considered within normal range. Results: Using the ULN of 13%, the sensitivity of the NETest was 98% (CI 89%-100%) with 48 true positive results and one false negative. The overall specificity (in a mixed population of healthy individuals and non-NET cancer patients) was 63% (CI 49%-75%), with 32 true negative and 19 false positive results. Among the 26 healthy individuals the specificity was 81% (CI 62%-92%); among patients with other GI cancers, specificity was 44% (CI 27%-63%). Using an alternate and updated normal range of 0-20%, sensitivity was unchanged (98%), but specificity improved to 100% among healthy patients, and 64% among patients with other cancers. Conclusions: The sensitivity of the NETest is exceptionally high in a population of metastatic well-differentiated NETs. Specificity within a healthy population of patients is exceptionally high when using a normal range of 0-20%, and moderately high when using a normal range of 0-13%. Specificity is lower when evaluating patients with other GI malignancies. Clinical trial information: NCT02948946.