tbuckley/cabot-search huggingface dataset:
Effect of design modifications on trial outcomes in idiopathic pulmonary fibrosis (IPF): Analysis of data from ASCEND and CAPACITY (CAP)
Authors: Talmadge King, Williamson Bradford, Socorro Castro-Bernardini, Elizabeth Fagan, Ian Glaspole, Marilyn Glassberg, Eduard Gorina, Peter Hopkins, David Kardatzke, Lisa Lancaster, David Lederer, Steven Nathan, Carlos Pereira, Steven Sahn, Robert Sussman, Jeffrey Swigris, Paul Noble
Journal: European Respiratory Journal (2014)

Introduction:  ASCEND is a Phase 3 trial evaluating pirfenidone in IPF. Design modifications (vs. CAP) included a 1 year treatment period; centralised procedures for diagnosis, spirometry, and mortality adjudication; and modification of eligibility criteria to enrol patients with greater risk for disease progression.   Objective:  Assess the effect of design modifications on IPF trial outcomes.   Methods:  Modified criteria for ASCEND included: IPF diagnosis ≥6 months prior to randomization (vs. no time limit in CAP); % predicted forced vital capacity (%FVC) ≥50% and ≤90% and % predicted carbon monoxide diffusing capacity (%DLco) ≥30% and ≤90% (vs. %FVC or %DLco ≤90% in CAP); and forced expiratory volume in 1 second (FEV 1 )/FVC ratio ≥0.80 (vs. ≥0.70 in CAP). Central review of HRCT scans and lung biopsies was implemented to minimiseheterogeneity.   Results : Baseline characteristics in the ASCEND and CAP studies are summarized in  Table 1 . Lower median values for %FVC and %DL CO  and a longer median time since diagnosis were observed in ASCEND.   Conclusions:  Baseline characteristics in ASCEND were generally similar to those in CAP. Notable differences included lower %FVC and %DL CO  and a longer time since diagnosis in ASCEND, each of which has been shown to be independently associated with a higher risk of FVC decline.
Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT)
Authors: Scott M. Lippman, Phyllis J. Goodman, Eric A. Klein, Howard L. Parnes, Ian M. Thompson, Alan R. Kristal, Regina M. Santella, Jeffrey L. Probstfield, Carol M. Moinpour, Demetrius Albanes, Philip R. Taylor, Lori M. Minasian, Ashraful Hoque, Sarah Moody Thomas, John J. Crowley, J. Michael Gaziano, Janet L. Stanford, Elise D. Cook, Neil E. Fleshner, Michael M. Lieber, Philip J. Walther, Fadlo R. Khuri, Daniel D. Karp, Gary G. Schwartz, Leslie G. Ford, Charles A. Coltman
Journal: JNCI Journal of the National Cancer Institute (2005)

Prostate cancer continues to be a major health threat, especially among African American men. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), which opened on July 25, 2001, was planned to study possible agents for the prevention of prostate cancer in a population of 32,400 men in the United States, including Puerto Rico, and Canada. SELECT is a phase III randomized, placebo-controlled trial of selenium (200 microg/day from L-selenomethionine) and/or vitamin E (400 IU/day of all rac alpha-tocopheryl acetate) supplementation for a minimum of 7 years (maximum of 12 years) in non-African American men at least 55 years of age and African American men at least 50 years of age. SELECT is a large, simple trial that conforms as closely as possible with community standards of care. This commentary discusses the design problems the SELECT investigators had to resolve in developing the trial, including the role of prostate cancer screening, the best forms and doses of the study agents, and estimation of the event (prostate cancer) rate of men on the placebo arm.
Neuroprotection mediated by changes in the endothelial actin cytoskeleton
Authors: Ulrich Laufs, Matthias Endres, Nancy Stagliano, Sepideh Amin-Hanjani, Dao-Shan Chui, Shui-Xiang Yang, Tommaso Simoncini, Masaru Yamada, Elena Rabkin, Philip G. Allen, Paul L. Huang, Michael Böhm, Frederick J. Schoen, Michael A. Moskowitz, James K. Liao
Journal: Journal of Clinical Investigation (2000)

Cerebral blood flow is regulated by endothelium-derived nitric oxide (NO), and endothelial NO synthase–deficient (eNOS-deficient; eNOS–/–) mice develop larger cerebral infarctions following middle cerebral artery (MCA) occlusion. We report that disruption of Rho-mediated endothelial actin cytoskeleton leads to the upregulation of eNOS expression and reduces the severity of cerebral ischemia following MCA occlusion. Mice treated with the Rho inhibitor Clostridium botulinum C3 transferase (10 μg/d) or the actin cytoskeleton disrupter cytochalasin D (1 mg/kg) showed a two- to fourfold increase in vascular eNOS expression and activity. This increase in eNOS expression was not due to increases in eNOS gene transcription, but to prolongation of eNOS mRNA half-life from 10 ± 3 hours to 24 ± 4 hours. Indeed, endothelial cells overexpressing a dominant-negative Rho mutant (N19RhoA) exhibited decreased actin stress fiber formation and increased eNOS expression. Inhibition of vascular Rho guanosine-5′-triphosphate binding activity by the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin increased cerebral blood flow to ischemic regions of the brain, and mice treated with simvastatin, C3 transferase, or cytochalasin D showed smaller cerebral infarctions following MCA occlusion. No neuroprotection was observed with these agents in eNOS–/– mice. These findings suggest that therapies which target the endothelial actin cytoskeleton may have beneficial effects in ischemic stroke.
Caveolin-1, caveolae, and glioblastoma
Authors: M.-O. Parat, G. J. Riggins
Journal: Neuro-Oncology (2012)

Glioblastoma multiforme (GBM) is the most common malignant brain tumor and is characterized by high invasiveness, poor prognosis, and limited therapeutic options. Biochemical and morphological experiments have shown the presence of caveolae in glioblastoma cells. Caveolae are flask-shaped plasma membrane subdomains that play trafficking, mechanosensing, and signaling roles. Caveolin-1 is a membrane protein that participates in the formation of caveolae and binds a multitude of signaling proteins, compartmentalizing them in caveolae and often directly regulating their activity via binding to its scaffolding domain. Caveolin-1 has been proposed to behave either as a tumor suppressor or as an ongogene depending on the tumor type and progress. This review discusses the existing information on the expression and function of caveolin-1 and caveolae in GBM and the role of this organelle and its defining protein on cellular signaling, growth, and invasiveness of GBM. We further analyze the available data suggesting caveolin-1 could be a target in GBM therapy.
Frequency of Non–Cancer-Related Pain in Patients With Cancer
Authors: Lisa Barbera, Sean Molloy, Craig C. Earle
Journal: Journal of Clinical Oncology (2013)

TO THEEDITOR: In 2012, theJournal published an article of ours evaluating opioid prescriptions for elderly patients with cancer who reported pain. 1 Pain scores were captured as part of a provincial initiative to screen patients with cancer for symptoms at every visit to the cancer center. 2,3 The study found that 45% of patients with a pain severity score of 4 to 10 out of a possible 10 did not receive opioid analgesics. Possible explanations that have been raised for this observation include non– cancer-related pain and patient refusal to accept opioids. In that same year, the provincial cancer agency undertook a province-wide chart audit to evaluate the documentation at the time of the high pain score, including questions about pain etiology and interventions. Eleven cancer centers audited approximately 25 charts from each patient who reported a pain score of at least 4, for a total audit of 299 charts. Of these, 8% clearly documented that the pain was not related to cancer. An additional 5% of patients indicated that the pain was chronic, and 2% indicated that the pain was being managed in the community. It is uncertain if these 7% had cancer-related pain. The estimate would then be that 8% to 15% of the audited cohort with pain scores of 4 to 10 had non– cancer-related pain. Only two patients had documentation that they declined opioids. In the original study, 9,826 patients had pain scores of 4 to 10. Applying the observations above, 786 to 1,474 patients had pain unrelated to cancer. If none of these patients received opioids and they are removed from the denominator, then the proportion of untreated cancer-related pain improves to 35% to 40%, suggesting that pain is still undertreated in a significant proportion of patients with cancer. The observations from the audit are limited because the criteria for chart selection may not have been applied uniformly at each center, and chart abstractors were not centrally trained. There may also be ambiguity in medical charts around the possible reasons for lack of opioid treatment. However, the data resulting from the audit suggest that non– cancer-related pain does not appear to make up a significant proportion of the pain being described by patients with cancer. Additional work is required to better understand reasons for undertreatment of pain in Ontario to facilitate possible interventions to improve patient care.
Normal Flow (TIMI-3) Before Mechanical Reperfusion Therapy Is an Independent Determinant of Survival in Acute Myocardial Infarction
Authors: Gregg W. Stone, David Cox, Eulogio Garcia, Bruce R. Brodie, Marie-Claude Morice, John Griffin, Luiz Mattos, Alexandra J. Lansky, William W. O’Neill, Cindy L. Grines
Journal: Circulation (2001)

Background — Whereas survival after lytic therapy for myocardial infarction is strongly dependent on early administration, it is unknown whether the otherwise excellent outcomes in patients undergoing primary PTCA for acute myocardial infarction, in whom TIMI-3 flow rates of &gt;90% may be achieved, can be further improved by early reperfusion. Methods and Results — Among 2507 patients enrolled in 4 PAMI trials undergoing primary PTCA, spontaneous reperfusion (TIMI-3 flow) was present in 16% at initial angiography. Compared with patients without TIMI-3 flow, those with TIMI-3 flow before PTCA had greater left ventricular ejection fraction (57±10% versus 53±11%, P =0.003) and were less likely to present in heart failure (7.0% versus 11.6%, P =0.009). Patients with initial TIMI-3 flow had significantly lower in-hospital rates of mortality, new-onset heart failure, and hypotension and had a shorter hospital stay. Cumulative 6-month mortality was 0.5% in patients with initial TIMI-3 flow, 2.8% with TIMI-2 flow, and 4.4% with initial TIMI-0/1 flow ( P =0.009). By multivariate analysis, TIMI-3 flow before PTCA was an independent determinant of survival (odds ratio 2.1, P =0.04), even when corrected for by postprocedural TIMI-3 flow. Conclusions — Patients undergoing primary PTCA in whom TIMI-3 flow is present before angioplasty present with greater clinical and angiographic evidence of myocardial salvage, are less likely to develop complications related to left ventricular failure, and have improved early and late survival. These data warrant prospective randomized trials of pharmacological strategies to promote early reperfusion before definitive mechanical intervention in acute myocardial infarction.
Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial
Authors: Gilles Montalescot, Stephen D Wiviott, Eugene Braunwald, Sabina A Murphy, C Michael Gibson, Carolyn H McCabe, Elliott M Antman
Journal: The Lancet (2009)
Prediction of abstinence from ethanol in alcoholic recipients following liver transplantation
Authors: P F Foster, F Fabrega, S Karademir, H N Sankary, D Mital, J W Williams
Journal: Hepatology (1997)

The prediction of abstinence from ethanol may be crucial to the optimal selection of liver transplantation candidates with alcoholism. Of 84 consecutive end-stage alcoholic patients who underwent transplantation (1986-1994) at our institution, we analyzed 63 long-surviving recipients for pretransplantation variables to predict posttransplantation abstinence (follow-up: 49.3 ± 21 mo). Thirty-three pretransplantation variables were reviewed from our transplantation data base and supplemented and confirmed with interviews with recipients. The psycho-social inclusion criteria included the following: patient recognition of alcoholism, a domicile, an occupation, and at least one close personal relationship. The incidence of abstinence from ethanol was (50/63) 79%. A logistic regression of the 33 variables in conjunction with our above inclusion criteria accurately predicted abstinence (90% accuracy, χ 2 model, P &lt; .00001) based on the absence of previous history of any illicit drug use (Drug Use: yes = 1/no = 0), the presence of an active, personal life insurance policy (Life Ins: yes = 1/no = 0), number of alcoholic sisters (ETOH-SIS), and the length of pretransplantation abstinence (PRE-TRANS-ABS, mos): Prob. of abstinence = 1/1 + e(-F), F = -0.33 ± 0.89 (DRUG USE) -1.02 (LIFE INS) -1.68 (ETOH-SIS) +0.24 (PRE-TRANS-ABS). In contrast, receiver-operating characteristic curve analysis found that 7 and 9 months of pretransplantation abstinence were the best cut-off points in predicting subsequent abstinence, but poor utility was noted at these points with this specific value alone (sensitivity 61-84%, specificity 64-68%). A separate analysis of high-risk patients with poly-drug use (n = 15, alcohol recidivism 8/15, 53%) and the remaining low-risk group of purely alcohol dependent patients (n = 48, alcohol recidivism 5/48, 10%) found no combination of variables was predictive of abstinence in either group. The length of pretransplantation abstinence is a relatively poor predictor of posttransplantation abstinence. Variables of comorbid substance use, social function, and possibly family history are more predictive in conjunction with our standard criteria and might be useful as tools in evaluating liver transplantation candidates whose primary diagnosis is alcohol-induced cirrhosis.
Hepatocyte specific deletion of c-Met leads to the development of severe non-alcoholic steatohepatitis in mice
Authors: Daniela C Kroy, Fabienne Schumacher, Pierluigi Ramadori, Maximilian Hatting, Ina Bergheim, Nikolaus Gassler, Mark V Boekschoten, Michael Müller, Konrad L Streetz, Christian Trautwein
Journal: Journal of Hepatology (2014)
Antibody Responses to Polysaccharide and Polysaccharide-Conjugate Vaccines after Treatment of Hodgkin Disease
Authors: Deborah C. Molrine
Journal: Annals of Internal Medicine (1995)

Objective: To compare the immunogenicity of polysaccharide-conjugate vaccines with that of polysaccharide vaccines in patients previously treated for Hodgkin disease. Design: All patients were immunized with Haemophilus influenzae type b (HIB)-conjugate and 4-valent meningococcal polysaccharide vaccines. Subgroups of patients were randomly assigned to receive either 23-valent pneumococcal polysaccharide vaccine or a 7-valent pneumococcal-conjugate vaccine that links seven pneumococcal serotypes to the outer membrane protein complex of Neisseria meningitidis. Patients: 144 patients who had completed treatment for Hodgkin disease, which had been diagnosed at least 2 years before the study. Measurements: Antigen-specific antibody concentrations before and 3 to 6 weeks after immunization; number of persons who achieved anti-HIB antibody concentrations considered to be in the protective range. Results: The geometric mean anti-HIB antibody concentration increased from 1.79 µg/mL before immunization to 54.1 µg/mL after; the percentage of persons with antibody concentrations in the protective range increased from 62% before immunization to 99% after. Patients immunized with 23-valent pneumococcal vaccine had a geometric mean pneumococcal antibody concentration after immunization (9.15 µg/mL) that was similar to that of healthy controls (10.0 µg/mL) for the seven serotypes measured. In contrast, patients who received 7-valent pneumococcal-conjugate vaccine had a significantly lower mean response compared with patients who received 23-valent vaccine; their geometric mean antibody concentration after immunization was 4.95 µg/mL (P = 0.005). Conclusion: A single dose of HIB-conjugate vaccine was immunogenic in patients who had completed treatment for Hodgkin disease diagnosed at least 2 years before immunization. In addition, responses to the 23-valent pneumococcal and 4-valent meningococcal vaccines were equivalent to those seen in healthy controls. Finally, patients had a significantly lower response to a single dose of 7-valent pneumococcal-conjugate vaccine than to 23-valent vaccine.
Depression and anxiety in women with early breast cancer: five year observational cohort study
Authors: Caroline Burgess, Victoria Cornelius, Sharon Love, Jill Graham, Michael Richards, Amanda Ramirez
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To examine the prevalence of, and risk factors for, depression and anxiety in women with early breast cancer in the five years after diagnosis. <b>Design</b> Observational cohort study. <b>Setting</b> NHS breast clinic, London. <b>Participants</b> 222 women with early breast cancer: 170 (77%) provided complete interview data up to either five years after diagnosis or recurrence. <b>Main outcome measures</b> Prevalence of clinically important depression and anxiety (structured psychiatric interview with standardised diagnostic criteria) and clinical and patient risk factors, including stressful life experiences (Bedford College life events and difficulties schedule). <b>Results</b> Nearly 50% of the women with early breast cancer had depression, anxiety, or both in the year after diagnosis, 25% in the second, third, and fourth years, and 15% in the fifth year. Point prevalence was 33% at diagnosis, falling to 15% after one year. 45% of those with recurrence experienced depression, anxiety, or both within three months of the diagnosis. Previous psychological treatment predicted depression, anxiety, or both in the period around diagnosis (one month before diagnosis to four months after diagnosis). Longer term depression and anxiety, were associated with previous psychological treatment, lack of an intimate confiding relationship, younger age, and severely stressful non-cancer life experiences. Clinical factors were not associated with depression and anxiety, at any time. Lack of intimate confiding support also predicted more protracted episodes of depression and anxiety. <b>Conclusion</b> Increased levels of depression, anxiety, or both in the first year after a diagnosis of early breast cancer highlight the need for dedicated service provision during this time. Psychological interventions for women with breast cancer who remain disease free should take account of the broader social context in which the cancer occurs, with a focus on improving social support.
Health-Related Quality of Life in Patients With Advanced Colorectal Cancer Treated With Cetuximab: Overall and <i>KRAS</i>-Specific Results of the NCIC CTG and AGITG CO.17 Trial
Authors: Heather-Jane Au, Christos S. Karapetis, Chris J. O'Callaghan, Dongsheng Tu, Malcolm J. Moore, John R. Zalcberg, Hagen Kennecke, Jeremy D. Shapiro, Sheryl Koski, Nick Pavlakis, Danielle Charpentier, David Wyld, Michael Jefford, Gregory J. Knight, Nadine M. Magoski, Michael D. Brundage, Derek J. Jonker
Journal: Journal of Clinical Oncology (2009)

National Cancer Institute of Canada Clinical Trials Group CO.17 demonstrated the antiepidermal growth factor receptor (anti-EGFR) monoclonal antibody cetuximab improves overall and progression-free survival in patients with advanced, chemotherapy-refractory colorectal cancer (CRC), particularly in patients with wild-type KRAS tumors. This article reports the health-related quality-of-life (HRQL) outcomes from CO.17.Patients (N = 572) with pretreated EGFR-detectable advanced CRC were randomly assigned to cetuximab and best supportive care (BSC) or to BSC alone. HRQL primary end points assessed by the EORTC QLQ-C30 were physical function (PF) and global health status (GHS); mean changes from baseline to 8 and 16 weeks were assessed. Post hoc analysis by KRAS mutation status was performed.Questionnaire compliance was 94% at baseline, but it declined differentially (67% v 47% for cetuximab v BSC at 16 weeks). PF change scores were -3.9 for cetuximab and -8.6 for BSC (P = .046) at 8 weeks and were -5.9 and -12.5 for cetuximab and BSC, respectively, (P = .027) at 16 weeks. GHS change scores were -0.5 and -7.1 (P = .008) at 8 weeks and were -3.6 and -15.2 (P = .008) at 16 weeks for cetuximab and BSC, respectively. In patients who had tumors with wild-type KRAS status, cetuximab resulted in less PF deterioration at 8 weeks (-0.7 v -7.2; P = .11) and 16 weeks (-3.4 v -13.8; P = .008) compared with BSC. Patients with wild-type status who received cetuximab experienced improved GHS at 8 weeks, whereas patients who received BSC alone deteriorated (3.2 v -7.7; P = .002). Cetuximab preserved GHS at 16 weeks (-0.2 v -18.1; P < .001). No significant differences were noted between study arms for patients with mutated KRAS tumors.Cetuximab offers important HRQL and survival benefits for pretreated patients with advanced, wild-type KRAS CRC.
Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial
Authors: Young-Suk Lim, Kwan Soo Byun, Byung Chul Yoo, So Young Kwon, Yoon Jun Kim, Jihyun An, Han Chu Lee, Yung Sang Lee
Journal: Gut (2015)

<h3>Objective</h3> Little clinical data are available regarding the optimal treatment of patients who harbour entecavir (ETV)-resistant HBV. <h3>Design</h3> In this multicentre randomised trial, patients who had HBV with ETV resistance-associated mutations and serum HBV DNA concentrations &gt;60 IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n=45) or TDF and ETV (1 mg/day) combination therapy (n=45) for 48 weeks. <h3>Results</h3> Baseline characteristics were comparable between groups, including HBV DNA levels (median, 4.02 log<sub>10</sub> IU/mL) and hepatitis B e antigen-positivity (89%). All patients had at least one ETV-resistance mutation: rtT184A/C/F/G/I/L/S (n=49), rtS202G (n=43) and rtM250L/V (n=7), in addition to rtM204V/I (n=90). All except one patient in the TDF group completed 48 weeks of treatment. At week 48, the proportion of patients with HBV DNA &lt;15 IU/mL, the primary efficacy endpoint, was not significantly different between the TDF and TDF+ETV groups (71% vs 73%; p&gt;0.99). The mean change in HBV DNA levels from baseline was not significantly different between groups (−3.66 vs −3.74 log<sub>10</sub> IU/mL; p=0.81). Virological breakthrough occurred in one patient on TDF, which was attributed to poor drug adherence. At week 48, six and three patients in the TDF and TDF+ETV groups, respectively, retained their baseline resistance mutations (p&gt;0.99). None developed additional resistance mutations. Safety profiles were comparable in the two groups. <h3>Conclusions</h3> TDF monotherapy for 48 weeks provided a virological response comparable to that of TDF and ETV combination therapy in patients infected with ETV-resistant HBV. <h3>Trial registration number</h3> ClinicalTrials.gov ID NCT01639092.