tbuckley/cabot-search huggingface dataset:
Cocaine-Induced Coronary-Artery Vasoconstriction
Authors: R A Lange, R G Cigarroa, C W Yancy, J E Willard, J J Popma, M N Sills, W McBride, A S Kim, L D Hillis
Journal: New England Journal of Medicine (1989)

Intranasal cocaine is used frequently as a local anesthetic during many rhinolaryngologic procedures. Although its "recreational" use in high doses has been associated with chest pain and myocardial infarction, this association has not been established when cocaine is used in low doses as a topical anesthetic, and its effect on the coronary vasculature of humans is unknown. We studied the effects of intranasal cocaine (10 percent cocaine hydrochloride; 2 mg per kilogram of body weight) on the blood flow in and dimensions of the coronary arteries and on myocardial oxygen demand in 45 patients (34 men and 11 women, 36 to 67 years of age) who were undergoing cardiac catheterization for the evaluation of chest pain. Heart rate, arterial pressure, blood flow in the coronary sinus (measured by thermodilution), and the dimensions of the epicardial left coronary artery (measured by quantitative arteriography) were measured before and 15 minutes after the intranasal administration of saline (in 16 patients) or cocaine (in 29). No variables changed after the administration of saline. After cocaine was administered, the heart rate and arterial pressure rose, the coronary-sinus blood flow fell (from a mean [+/- SD] of 149 +/- 59 ml per minute to 124 +/- 53 ml per minute), and the diameter of the left coronary artery decreased by 8 to 12 percent (P less than 0.01 for all comparisons). No patient had chest pain or electrocardiographic evidence of myocardial ischemia after the administration of cocaine. Subsequently, the administration of the alpha-adrenergic blocking agent phentolamine caused all these values to return to base-line levels. There was no difference in response between the patients found to have disease of the left coronary artery (n = 28) and those without such disease (n = 17). We conclude that the intranasal administration of cocaine near the dose used for topical anesthesia causes vasoconstriction of the coronary arteries, with a decrease in the coronary blood flow, despite an increase in myocardial oxygen demand, and that these effects are mediated by alpha-adrenergic stimulation. It is reasonable to assume that these effects would be more pronounced at the much higher doses associated with the recreational use of cocaine.
Corticosteroid use in mCRPC patients treated with abiraterone or enzalutamide using real world data from three databases.
Authors: Lorie Ellis, R. Scott McKenzie, Dominic Pilon, Laurence Gozalo, Marie-Helene Lafeuille, Patrick Lefebvre
Journal: Journal of Clinical Oncology (2015)

e16071 Background: Abiraterone acetate (AA) combined with prednisone and enzalutamide (ENZ) are novel oral therapies offering survival benefit to mCRPC patients. This study evaluates concomitant corticosteroid use in AA and ENZ patients. Methods: Retrospective claims from Symphony Health Solutions (SHS), Information Management System LifeLink (IMS) and Truven Health Market Scan Research (THM) databases were pooled to conduct this study. AA or ENZ-treated patients with ≥ 1 prostate cancer diagnosis; > 1 year of pre-index observation and no AA or ENZ exposure were identified. The index date was the first AA or ENZ claim on/after 9/1/2012 with patients followed until 10/2013 (SHS and IMS), 07/2014 (THM) or loss to follow-up. Descriptive statistics were used to summarize the proportion of patients receiving corticosteroids and the length of concomitant use during the follow-up period. Results: A total of 5,973 patients were identified (AA: 4,596, ENZ: 1,387). Mean age was 72.5 years among AA patients and 72.0 years among ENZ patients. Mean exposure to treatment was 151 days for the AA cohort and 128 days for the ENZ cohort. Respectively 57.9% (n = 2,659) and 46.3% (n = 642) of patients in the AA and ENZ cohorts previously received corticosteroids during the 3-month period pre-index date. During the follow up period, corticosteroids were used in 86.5% (n = 3,976) of AA-treated patients and in 42.6% (n = 591) of ENZ-treated patients. Concomitant use of AA and corticosteroid was observed in 83.2% (n = 3,824) of the AA cohort and concomitant use of ENZ and corticosteroid in 32.9% (n = 456) of the ENZ cohort. Among patients with concomitant use, the average length of concomitant use was 113 days in AA patients and 46 days in ENZ patients. Similar patterns of prednisone use were observed. Conclusions: In this large real-world study a large proportion of patients treated with either AA or ENZ received concomitant corticosteroid treatment. Despite higher corticosteroid utilization in AA-treated patients, an important proportion of ENZ patients also used corticosteroids before and after treatment initiation.
Immune checkpoints on innate lymphoid cells
Authors: Laura Chiossone, Eric Vivier
Journal: The Journal of Experimental Medicine (2017)

In this issue of JEM, Taylor et al. (https://doi.org/10.1084/jem.20161653) describe PD-1 as a critical negative regulator of group 2 innate lymphoid cells (ILC-2s). PD-1 intrinsically controls proliferation and cytokine production of both mouse and human ILC-2s. PD-1 signaling inhibits STAT5 phosphorylation and the removal of this brake by knocking down PD-1 expression or by using anti–PD-1 blocking antibodies, translated in vivo into better clearance of helminth worm infection in mice.
Frequency of anaplastic lymphoma kinase (ALK) positive tumors among African American non-small cell lung cancer (NSCLC) patients.
Authors: Shirish M. Gadgeel, Michele L Cote, Gerold Bepler, Valerie Murphy, Agnes Malysa, Antoinette J. Wozniak, Ammar Sukari, Ann G. Schwartz
Journal: Journal of Clinical Oncology (2012)

7593 Background: ALK gene rearrangement is a recently identified molecular alteration in the tumors of a small proportion of NSCLC patients. Previous reports have shown that the rate of EGFR gene mutations may vary in NSCLC patients of different ethnic background. It is unclear if similar differences exist with regards to ALK positivity. We analyzed ALK expression in tumors of AA NSCLC patients and also assessed the epidemiologic features and outcomes of these patients, as well as the occurrence of known oncogene mutations. Methods: We identified 260 tumor tissues of AA NSCLC patients, enrolled on several epidemiologic studies conducted at our institution. Immunohistochemistry, using the anti-Alk D5F3 antibody (Cell Signaling Technology) was used to visualize ALK expression. Fifty-three of these tumors also underwent mutation analysis using the OncoCarta Panel V1 (Sequenom) to evaluate 238 mutations in 19 oncogenes. Results: Of the 260 tumors analyzed, 6 (2.3%, 95% CI- 0.5-4.1%) were ALK positive. All ALK positive patients had adenocarcinoma histology (6/157) while no patients with other NSCLC histologies were ALK positive, p=0.04. There was no difference in the rate of positivity based on sex, 1% (1/99) in males versus 3.1% (5/161) in females, p=0.27. Consistent with prior studies, patients with ALK positive tumors were slightly younger (median age 56 years vs 61 years, p = 0.27) and the positive rate was higher in never smokers 11% (2/18) than in ever smokers 1.6%, p=0.06. There was no correlation of ALK positivity with the stage of the disease at diagnosis. The survival of ALK positive and negative patients, adjusted for age, sex and stage, was similar (HR=0.77; 95% CI 0.19-3.13). Fifty-three tumors have been assessed for oncogene mutations in addition to ALK expression. Of these, 2 (3.8%) were ALK positive and neither of these tumors carried other tested mutations such as EGFR, Kras, PIK3 or AKT. Conclusions: The rate of ALK positive tumors among African-American NSCLC patients is similar to the general population and the demographic features of ALK positive AA patients is also similar to the general ALK positive NSCLC patient population.
Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis
Authors: Ashley R. Maiuri, Michael Peng, Ram Podicheti, Shruthi Sriramkumar, Caitlin M. Kamplain, Douglas B. Rusch, Christina E. DeStefano Shields, Cynthia L. Sears, Heather M. O'Hagan
Journal: Cancer Research (2017)

Abstract Aberrant silencing of genes by DNA methylation contributes to cancer, yet how this process is initiated remains unclear. Using a murine model of inflammation-induced tumorigenesis, we tested the hypothesis that inflammation promotes recruitment of epigenetic proteins to chromatin, initiating methylation and gene silencing in tumors. Compared with normal epithelium and noninflammation-induced tumors, inflammation-induced tumors gained DNA methylation at CpG islands, some of which are associated with putative tumor suppressor genes. Hypermethylated genes exhibited enrichment of repressive chromatin marks and reduced expression prior to tumorigenesis, at a time point coinciding with peak levels of inflammation-associated DNA damage. Loss of MutS homolog 2 (MSH2), a mismatch repair (MMR) protein, abrogated early inflammation-induced epigenetic alterations and DNA hypermethylation alterations observed in inflammation-induced tumors. These results indicate that early epigenetic alterations initiated by inflammation and MMR proteins lead to gene silencing during tumorigenesis, revealing a novel mechanism of epigenetic alterations in inflammation-driven cancer. Understanding such mechanisms will inform development of pharmacotherapies to reduce carcinogenesis. Cancer Res; 77(13); 3467–78. ©2017 AACR.
Use of Irbesartan to Maintain Sinus Rhythm in Patients With Long-Lasting Persistent Atrial Fibrillation
Authors: Antonio H. Madrid, Manuel G. Bueno, Jose M.G. Rebollo, Irene Marín, Gonzalo Peña, Enrique Bernal, Aníbal Rodriguez, Lucas Cano, José M. Cano, Pedro Cabeza, Concepción Moro
Journal: Circulation (2002)

Background — Data from studies of angiotensin-converting enzyme inhibitors provide evidence that the renin-angiotensin-aldosterone system plays a role as a mediator of atrial remodeling in atrial fibrillation. The present study has evaluated the effect of treatment with the angiotensin I type 1 receptor blocker irbesartan on maintaining sinus rhythm after conversion from persistent atrial fibrillation. Methods and Results — To be included in the present study, patients must have had an episode of persistent atrial fibrillation for &gt;7 days. The patients were then randomized and scheduled for electrical cardioversion. Two groups of patients were compared: Group I was treated with amiodarone, and group II was treated with amiodarone plus irbesartan. The primary end point was the length of time to a first recurrence of atrial fibrillation. From a total of 186 patients assessed in the study, 154 were analyzed with the use of intention-to-treat analysis. Seventy-five patients were randomly allocated to group I and 79 to group II. After 2 months of follow-up in the intention-to-treat analysis, the group treated with irbesartan had fewer patients with recurrent atrial fibrillation (Kaplan-Meier analysis, 84.79% versus 63.16%, P =0.008). The Kaplan-Meier analysis of time to first recurrence during the follow-up period (median time, 254 days [range, 60 to 710]) also showed that patients treated with irbesartan had a greater probability of remaining free of atrial fibrillation (79.52% versus 55.91%, P =0.007). Conclusions — Patients treated with amiodarone plus irbesartan had a lower rate of recurrence of atrial fibrillation than did patients treated with amiodarone alone.
Impact of metformin on survival in patients with type II diabetes and metastatic colorectal cancer.
Authors: Wen-zhuo He, Liang-ping Xia
Journal: Journal of Clinical Oncology (2015)

e14521 Background: Metformin has been associated with a potential anti-tumor effect. This study examined the impact of metformin on overall survival (OS) and progression free survival (PFS) of first line chemotherapy of patients with type II diabetes and metastatic colorectal cancer (mCRC). Methods: We retrospectively studied the medical records of 2542 patients who were diagnosed as mCRC at Sun Yat-sen university cancer center between 2005 and 2012. 136 patients were identified as having type II diabetes and mCRC. Further data were acquired determining the patients’ age, gender, body mass index (BMI), site of primary cancer, number of metastatic sites, chemotherapy regimens, OS and PFS of first-line chemotherapy. Results: Patients were divided into two groups; 45 patients taking metformin and 91 patients not taking. After a median follow-up of 26 months, there were 26 total deaths among 45 patients who used metformin, while 75 deaths among 91 patients who did not. Patients who used metformin had a median survival of 34.97 months compared with 21.13 months in those who did not use metformin (p = 0.001). What’s more, significantly longer PFS of first-line chemotherapy were also observed (7.33 months for patients with metformin and 6.25 months for those without, p = 0.041). Routinely clinical factors, including age, gender, BMI, site of cancer and number of metastatic sites were comparable between the two groups. Conclusions: Metformin use was associated with superior OS and PFS in mCRC patients who with type II diabetes.
PTU-063 Assessment of Sleep Impairment in Patients With Crohn’S Disease: Results from the Ustekinumab Certifi Study: Abstract PTU-063 Table
Authors: C Gasink, D Chan, L-L Gao, B Schenkel, C Han
Journal: Gut (2013)

<h3>Introduction</h3> To describe the extent of sleep impairment reported in CERTIFI (Ph2 evaluating UST in inducing &amp; maintaining clinical response &amp; remisison)using Jenkins Sleep Evaluation Questionnaire (JSEQ) &amp; establish a clinically meaningful improvement threshold for JSEQ. <h3>Methods</h3> Pts with moderate-to-severe CD(CDAI ≥220 &amp; ≤450) who had previously failed or were intolerant to ≥1 anti-TNF were randomised to PBO/UST induction at wk0. Primary endpt was clinical response (≥100-pt reduction in CDAI from BL) at wk6. Sleep impairment assessed using JSEQ (total score 0–20; higher scores indicate greater sleep impairment) at BL&amp;wk6. Relationships between BL sleep impairment, clinical disease activity (CDAI), &amp; HRQoL impact(IBDQ) evaluated using Pearson correlation. Clinically meaningful improvement threshold of JSEQ was established with the anchor-based [clinical response by reduction in CDAI of ≥70-pt or clinically meaningful improvement (≥16-pt) in IBDQ] &amp; distribution-based (change by one-half of the standard deviation [SD] of BL JSEQ score) methods. Prop of pts who achieved clinically meaningful improvements in JSEQ at wk6 was determined &amp; compared. <h3>Results</h3> At BL,both grps(n = 526) experienced similar degree of moderate sleep impairment, with JSEQ scores (mean±SD) of 11.0 ± 4.30(PBO)&amp;11.0 ± 4.59(UST),resp. About 60% were “waking up feeling tired and worn out”; about 30–35% of pts had trouble falling asleep, staying asleep,&amp; woke up several times during the night for 15–30 days in the previous month. At BL, JSEQ was correlated with CDAI (r = 0.19, p &lt; 0.0001)&amp;IBDQ(r = –0.39, p &lt; 0.0001). Using the anchor-based method, pts who achieved vs didn’t achieve clinically meaningful improvements in CDAI or IBDQ at wk6 vs BL, reported improvements(mean±SD)from BL in JSEQ of –2.52 ± 4.43vs-0.58 ± 3.51 &amp; –2.68 ± 4.16vs-0.16 ± 3.45, resp. Using distribution-based method, the JSEQ clinically meaningful improvement threshold was 2.25(SDof BL JSEQ = 4.50). 2 potential thresholds for clinically meaningful improvement in JSEQ (eg.reduction of &gt; 2 or &gt; 3 points from BL JSEQ score at wk6) were derived. More pts who received UST induction achieved both thresholds at wk6(Table). <h3>Conclusion</h3> Pts experience significant sleep problems as measured by JSEQ; magnitude of impairment correlates with disease activity. Both anchor- &amp;distribution-based methods derive similar thresholds representative of clinically meaningful improvements in JSEQ. UST induction resulted in a greater proportion of pts achieving clinically meaningful improvements in sleep impairments. <h3>Disclosure of Interest</h3> C. Gasink Employee of: Janssen R&amp;D, LLC, D. Chan Employee of: Janssen R&amp;D, LLC, L.-L. Gao Employee of: Janssen R&amp;D, LLC, B. Schenkel Employee of: Janssen Scientific Affairs, LLC, C. Han Employee of: 3. Janssen Pharmaceutical Services
Carbon Monoxide Poisoning
Authors: Lindell K Weaver
Journal: New England Journal of Medicine (2009)

A 39-year-old female executive has a several-month history of fatigue, headache, and memory lapse. During a period of feeling worse than usual, she called a friend, who arrived at the residence to find the woman semicomatose and called 911. The patient was given supplemental oxygen and transported to the emergency department, where she is alert and has nonfocal findings on examination. Her carboxyhemoglobin level is 18%. How should she be treated? What is her expected outcome?
Clinical Utility of Risk Models to Refer Patients with Adnexal Masses to Specialized Oncology Care: Multicenter External Validation Using Decision Curve Analysis
Authors: Laure Wynants, Dirk Timmerman, Jan Y. Verbakel, Antonia Testa, Luca Savelli, Daniela Fischerova, Dorella Franchi, Caroline Van Holsbeke, Elisabeth Epstein, Wouter Froyman, Stefano Guerriero, Alberto Rossi, Robert Fruscio, Francesco PG Leone, Tom Bourne, Lil Valentin, Ben Van Calster
Journal: Clinical Cancer Research (2017)

Abstract Purpose: To evaluate the utility of preoperative diagnostic models for ovarian cancer based on ultrasound and/or biomarkers for referring patients to specialized oncology care. The investigated models were RMI, ROMA, and 3 models from the International Ovarian Tumor Analysis (IOTA) group [LR2, ADNEX, and the Simple Rules risk score (SRRisk)]. Experimental Design: A secondary analysis of prospectively collected data from 2 cross-sectional cohort studies was performed to externally validate diagnostic models. A total of 2,763 patients (2,403 in dataset 1 and 360 in dataset 2) from 18 centers (11 oncology centers and 7 nononcology hospitals) in 6 countries participated. Excised tissue was histologically classified as benign or malignant. The clinical utility of the preoperative diagnostic models was assessed with net benefit (NB) at a range of risk thresholds (5%–50% risk of malignancy) to refer patients to specialized oncology care. We visualized results with decision curves and generated bootstrap confidence intervals. Results: The prevalence of malignancy was 41% in dataset 1 and 40% in dataset 2. For thresholds up to 10% to 15%, RMI and ROMA had a lower NB than referring all patients. SRRisks and ADNEX demonstrated the highest NB. At a threshold of 20%, the NBs of ADNEX, SRrisks, and RMI were 0.348, 0.350, and 0.270, respectively. Results by menopausal status and type of center (oncology vs. nononcology) were similar. Conclusions: All tested IOTA methods, especially ADNEX and SRRisks, are clinically more useful than RMI and ROMA to select patients with adnexal masses for specialized oncology care. Clin Cancer Res; 23(17); 5082–90. ©2017 AACR.
Liberal Democrat pledge to extend GP opening hours needs proper funding plan, say experts
Authors: Matthew Limb
Journal: BMJ (2017)

The Liberal Democrats’ general election manifesto has promised to increase income tax by a penny a pound to raise an extra £6bn (€7bn; $7.8bn) a year to be ringfenced for NHS and adult social care.

The money would fund “priority areas,” says the manifesto (www.libdems.org.uk/manifesto), such as improving mental healthcare, expanding access to community services, supporting struggling GPs, and extending general practice opening hours.

Around a third of the £6bn would go to social care, with about £3.5bn for health spending in England, Wales, and Northern Ireland next year, said analysts. The Health Foundation said that rising demand and cost pressures meant that there would still be a £9bn funding gap for the NHS in England by 2020-21 under the Liberal Democrats’ plan.

The party would set up a cross party convention, involving the devolved UK administrations, to work out a sustainable long term funding settlement if it came into power.

The manifesto said, “Our longer-term objective will …
Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial
Authors: Ian E Krop, Sung-Bae Kim, Antonio Gonzalez Martin, Patricia M LoRusso, Jean-Marc Ferrero, Tanja Badovinac-Crnjevic, Silke Hoersch, Melanie Smitt, Hans Wildiers
Journal: The Lancet Oncology (2017)
Genetic variants in EGFR and its ligands to predict response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.
Authors: Ana Sebio, David Páez, Juliana Salazar, Maria Tobena, Marta Martin-Richard, Agust Barnadas, Montserrat Baiget
Journal: Journal of Clinical Oncology (2013)

e14541 Background: Epidermal growth factor receptor (EGFR) activation via ligand binding results in signaling through several pathways that fundamentally contribute to cell proliferation. Increased cell proliferation has been proposed as a radioresistance mechanism that would occur upon EGFR activation by radiation therapy. In this study we have analyzed the potential role of single nucleotide polymorphisms (SNPs) in the EGFR gene and its ligands as pharmacogentic markers of response to chemoradiation in locally advanced rectal cancer. Methods: Seventy stage II and III rectal cancer patients treated with capecitabine plus radiotherapy were analyzed. Nineteen TagSNPs in three EGFR ligands (amphiregulin, epiregulin and epidermal growth factor) were selected using HapMap database and Haploview software. One functional SNP (R521K) in the EGFR gene was also analyzed. DNA was extracted from peripheral blood and genotype was performed using the BioMarkTM System (Fluidigm). The main end point of the study was to analyze the possible association of these polymorphisms with the pathologic complete response after neoadjuvant chemoradiotherapy. Results: In the amphiregulin gene region, the rs11942466 C&gt;A SNP was associated pathological complete response (37% in C/C vs. 21% in C/A and 0% in A/A; p=0.023). In the EGFR gene the R521K G&gt;A SNP was associated with response in the dominant model (35 % of patients harbouring an A allele achieved complete response compared to 13 % of patients with a G/G genotype; p=0.025). In the multivariate analysis the R521K G&gt;A polymorphism remained statistically significant with an odds ratio of 0.14 (95%CI: 0.026-0.76; p=0.023). Conclusions: EGFR and amphiregulin genetic variants might help identify patients who would benefit the most from neoadjuvant chemoradiotherapy based on capecitabine.
FAMILIAL ANNULAR ERYTHEMA..
Authors: J. MARTIN BEARE, P. FROGGATT, J. H. JONES, D. W. NEILL
Journal: British Journal of Dermatology (1966)

Journal Article FAMILIAL ANNULAR ERYTHEMA.: An Apparently New Dominant Mutation. Get access J. MARTIN BEARE, J. MARTIN BEARE Consultant Dermatologist, Royal Victoria Hospital and Royal Belfast Hospital for Sick Children Search for other works by this author on: Oxford Academic Google Scholar P. FROGGATT, P. FROGGATT Department of Social and Preventive Medicine, The Queen's University Search for other works by this author on: Oxford Academic Google Scholar J. H. JONES, J. H. JONES Department of Pathology, The Queen's University Search for other works by this author on: Oxford Academic Google Scholar D. W. NEILL D. W. NEILL Department of Biochemistry, Royal Victoria Hospital, Belfast Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 78, Issue 2, 1 February 1966, Pages 59–68, https://doi.org/10.1111/j.1365-2133.1966.tb12176.x Published: 01 February 1966