tbuckley/cabot-search huggingface dataset:
Efficacy and Bleeding Complications Among Patients Randomized to Enoxaparin or Unfractionated Heparin for Antithrombin Therapy in Non–ST-Segment Elevation Acute Coronary Syndromes
Authors: John L. Petersen, Kenneth W. Mahaffey, Vic Hasselblad, Elliott M. Antman, Marc Cohen, Shaun G. Goodman, Anatoly Langer, Michael A. Blazing, Anne Le-Moigne-Amrani, James A. de Lemos, Christopher C. Nessel, Robert A. Harrington, James J. Ferguson, Eugene Braunwald, Robert M. Califf
Journal: JAMA (2004)

Antithrombin therapy has become a guidelines-recommended standard of care in the treatment of acute coronary syndromes (ACS), but recent trials comparing use of enoxaparin and unfractionated heparin in ACS have yielded less robust efficacy and safety results than have earlier trials of these antithrombin therapies.To systematically evaluate the end points of all-cause death and nonfatal myocardial infarction (MI), transfusion, and major bleeding observed in the 6 randomized controlled trials comparing enoxaparin and unfractionated heparin in treatment of ACS.The primary data sets for ESSENCE, A to Z, and SYNERGY were available at the Duke Clinical Research Institute. Baseline characteristics and event frequencies for TIMI 11B, ACUTE II, and INTERACT were provided by the principal investigator of each study.All 6 randomized controlled trials comparing enoxaparin and unfractionated heparin in non-ST-segment elevation ACS were selected for analysis.Efficacy and safety end points were extracted from the overall trial populations and the subpopulation receiving no antithrombin therapy prior to randomization.Systematic evaluation of the outcomes for 21 946 patients was performed using a random-effects empirical Bayes model. No significant difference was found in death at 30 days for enoxaparin vs unfractionated heparin (3.0% vs 3.0%; odds ratio [OR], 1.00; 95% confidence interval [CI], 0.85-1.17). A statistically significant reduction in the combined end point of death or nonfatal MI at 30 days was observed for enoxaparin vs unfractionated heparin in the overall trial populations (10.1% vs 11.0%; OR, 0.91; 95% CI, 0.83-0.99; number needed to treat, 107). A statistically significant reduction in the combined end point of death or MI at 30 days was also observed for enoxaparin in the populations receiving no prerandomization antithrombin therapy (8.0% vs 9.4%; OR, 0.81; 95% CI, 0.70-0.94; number needed to treat, 72). No significant difference was found in blood transfusion (OR, 1.01; 95% CI, 0.89-1.14) or major bleeding (OR, 1.04; 95% CI, 0.83-1.30) at 7 days after randomization in the overall safety population or in the population of patients receiving no prerandomization antithrombin therapy.In a systematic overview of approximately 22 000 patients across the spectrum of ACS, enoxaparin is more effective than unfractionated heparin in preventing the combined end point of death or MI.
Method to Our Madness or Madness in Our Methods? Pitfalls in Trial Methodology
Authors: Mark N. Levine, Rosalyn Juergens
Journal: Journal of Clinical Oncology (2012)

In the article that accompanies this editorial, the results of three clinical trials in patients with non–small-cell lung cancer (NSCLC) are reported. An important aim of an editorial can be to evaluate whether the design of the trial and the methods used to analyze the results permit readers to draw definitive conclusions that inform clinical practice or guide the development of future clinical trials. Each of these articles raises important issues about trial methodology that the reader may not have had the time to think about and that could influence the interpretation of the results. Ipilimumab is an exciting new targeted agent which specifically blocks the binding of cytotoxic T-lymphocyte antigen-4 (CTLA-4) to its ligands. This blockade augments T-cell activation leading to tumor regression. Ipilimumab was recently shown to improve survival in patients with advanced melanoma. 1,2 Lynch et al 3 conducted a randomized phase II trial in patients with NSCLC to estimate the additional activity of ipilimumab over chemotherapy alone using immune-related progression-free survival (irPFS) as an outcome measure. The use of a placebo for ipilimumab and the double-blind design strengthened the comparison of carboplatin and paclitaxel plus the immune-targeted agent with chemotherapy alone. Another important objective of the trial was to address the scheduling of ipilimumab and chemotherapy. Two schedules were tested: (1) ipilimumab administered concurrently with chemotherapy (concurrent), and (2) two cycles of chemotherapy followed by four cycles of chemotherapy and ipilimumab together (phased). The authors reported that the phased regimen improved irPFS significantly compared with the control regimen (hazard ratio [HR] 0.72; 95% CI, 0.50 to1.06; P .05), but the concurrent regimen did not (HR 0.81; CI, 0.55 to 1.17,P .13). It is the choice of the optimal regimen that we want to comment on. Not only is the phased regimen active but so is the concurrent one. Note that both HRs are less than 1 and in the Kaplan-Meier plots, the curves for both the phased and concurrent regimens are above that of the chemotherapy control (Fig 2 in publication). A larger sample size could well have resulted in the concurrent approach being significant too. It did not appear that the rules for selecting the optimum schedule were specified a priori. Nonetheless, the conclusion to support further investigation of phased-ipilimumab plus paclitaxel/carboplatin over the concurrent-ipilimumab chemotherapy regimen seems sensible given that the “phased” arm is consistently the best for all the outcome measures, and clearly superior for the progression (PFS) outcomes.
US Senate committee investigates conflicts of interest in industry funded medical education
Authors: J. Hopkins Tanne
Journal: BMJ (2009)

Prominent academic doctors and a medical students’ leader have criticised continuing medical education funded by industry at a hearing of the US Senate Special Subcommittee on Aging.

However, a representative of the accrediting group defended its work. Murray Kopelow said that his group had recently put in place stronger guidelines on industry funding.

The Senate committee’s hearing, chaired by Herb Kohl, a Wisconsin Democrat, on 29 July 2009, focused on conflicts of interest in the continuing medical education courses that most US doctors have to take.

Industry funding for accredited continuing medical education increased from $302m (£180m; €210m) in 1998 to $1.2bn in 2006 and accounts for about half of the funding for continuing education.

“Large corporations do not typically spend …
Clinical and Pharmacodynamic Evaluation of Metronomic Cyclophosphamide, Celecoxib, and Dexamethasone in Advanced Hormone-refractory Prostate Cancer
Authors: Andrea Fontana, Luca Galli, Anna Fioravanti, Paola Orlandi, Costanza Galli, Lorenza Landi, Simona Bursi, Giacomo Allegrini, Eloise Fontana, Roberta Di Marsico, Andrea Antonuzzo, Manolo D'Arcangelo, Romano Danesi, Mario Del Tacca, Alfredo Falcone, Guido Bocci
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The aims of the present study were to evaluate the clinical activity and the pharmacodynamic profile of the novel schedule of a single i.v. standard dose of cyclophosphamide (CTX) immediately followed by an oral metronomic CTX regimen with celecoxib (CXB) and dexamethasone (DEX) in advanced hormone-refractory prostate cancer patients. Experimental Design: Twenty-eight patients (68% docetaxel-resistant) received 500 mg/m2 CTX i.v. bolus on day 1 and, from day 2, 50 mg/day CTX p.o. plus 200 mg/twice a day CXB p.o. and 1 mg/day DEX p.o. until disease progression. Plasma vascular endothelial growth factor (VEGF) and thrombospondin-1 were detected by ELISA, and real-time reverse transcription-PCR of VEGF and thrombospondin-1 gene expression on peripheral blood mononuclear cell and of VE-cadherin (VE-C) in blood samples was done. Results: A confirmed prostate-specific antigen decrease of ≥50% from baseline was observed in 9 of 28 patients (32%). Median progression-free survival and overall survival were 3 months (95% confidence interval, 2.2-4.2 months) and 21 months (95% confidence interval, 12.4-29.4 months), respectively. Toxicity was mild and no grade 3 to 4 toxicities occurred. A significant relationship was found between plasma VEGF and prostate-specific antigen values (r = 0.4223; P &amp;lt; 0.001). VEGF levels significantly increased in nonresponders, whereas the responder patients maintained significantly lower levels of VE-C gene expression after the beginning of the treatment if compared with nonresponder ones. Conclusion: Metronomic CTX plus CXB and DEX showed favorable toxicity and activity profile in patients. VE-C gene expression and VEGF levels represent potentially useful pharmacodynamic markers for the clinical response.
DNA Methylation in Inflammatory Genes among Children with Obstructive Sleep Apnea
Authors: Jinkwan Kim, Rakesh Bhattacharjee, Abdelnaby Khalyfa, Leila Kheirandish-Gozal, Oscar Sans Capdevila, Yang Wang, David Gozal
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Section:ChooseTop of pageAbstract <<Materials and MethodsResultsDiscussionReferencesCITING ARTICLES
Progressive Decrease of Left Superior Temporal Gyrus Gray Matter Volume in Patients With First-Episode Schizophrenia
Authors: Kiyoto Kasai, Martha E. Shenton, Dean F. Salisbury, Yoshio Hirayasu, Chang-Uk Lee, Aleksandra A. Ciszewski, Deborah Yurgelun-Todd, Ron Kikinis, Ferenc A. Jolesz, Robert W. McCarley
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Smaller temporal lobe cortical gray matter volumes, including the left superior temporal gyrus, have been reported in magnetic resonance imaging (MRI) studies of patients with chronic schizophrenia and, more recently, in patients with first-episode schizophrenia. However, it remains unknown whether there are progressive decreases in temporal lobe cortical gray matter volumes in patients with first-episode schizophrenia and whether similarly progressive volume decreases are present in patients with affective psychosis. METHOD: High-spatial-resolution MRI scans at initial hospitalization and 1.5 years later were obtained from 13 patients with first-episode schizophrenia, 15 patients with first-episode affective psychosis (mainly manic), and 14 healthy comparison subjects. MRI volumes were calculated for gray matter of superior temporal gyrus and for the amygdala-hippocampal complex. RESULTS: Patients with first-episode schizophrenia showed significant decreases in gray matter volume over time in the left superior temporal gyrus compared with patients with first-episode affective psychosis or healthy comparison subjects. This progressive decrease was more pronounced in the posterior portion of the left superior temporal gyrus (mean=9.6%) than in the anterior portions (mean=8.4%). No group differences in the rate of change over time were present in other regions. CONCLUSIONS: These findings demonstrate a progressive volume reduction of the left posterior superior temporal gyrus gray matter in patients with first-episode schizophrenia but not in patients with first-episode affective psychosis.
Identification of overlapping HLA class I-restricted cytotoxic T cell epitopes in a conserved region of the human immunodeficiency virus type 1 envelope glycoprotein: definition of minimum epitopes and analysis of the effects of sequence variation.
Authors: R P Johnson, A Trocha, T M Buchanan, B D Walker
Journal: The Journal of Experimental Medicine (1992)

Although the immunologic basis of protective immunity in human immunodeficiency virus type 1 (HIV-1) infection has not yet been defined, virus-specific cytotoxic T lymphocytes (CTL) are likely to be an important host defense and may be a critical feature of an effective vaccine. These observations, along with the inclusion of the HIV-1 envelope in the majority of vaccine candidates presently in clinical trials, underscore the importance of the precise characterization of the cellular immune responses to this protein. Although humoral immune responses to the envelope protein have been extensively characterized, relatively little information is available regarding the envelope epitopes recognized by virus-specific CTL and the effects of sequence variation within these epitopes. Here we report the identification of two overlapping CTL epitopes in a highly conserved region of the HIV-1 transmembrane envelope protein, gp41, using CTL clones derived from two seropositive subjects. An eight-amino acid peptide was defined as the minimum epitope recognized by HLA-B8-restricted CTL derived from one subject, and in a second subject, an overlapping nine-amino acid peptide was identified as the minimal epitope for HLA-B14-restricted CTL clones. Selected single amino acid substitutions representing those found in naturally occurring HIV-1 isolates resulted in partial to complete loss of recognition of these epitopes. These data indicate the presence of a highly conserved region in the HIV-1 envelope glycoprotein that is immunogenic for CTL responses. In addition, they suggest that natural sequence variation may lead to escape from immune detection by HIV-1-specific CTL. Since the region containing these epitopes has been previously shown to contain an immunodominant B cell epitope and also overlaps with a major histocompatibility complex class II T cell epitope recognized by CD4+ CTL from HIV-1 rgp160 vaccine recipients, it may be particularly important for HIV-1 vaccine development. Finally, the identification of minimal CTL epitopes presented by class I HLA molecules should facilitate the definition of allele-specific motifs.
c-<i>Kit/PDGFRA</i> Gene Status Alterations Possibly Related to Primary Imatinib Resistance in Gastrointestinal Stromal Tumors
Authors: Francesca="C"&gt; Miselli, Paola Casieri, Tiziana Negri, Marta Orsenigo, M. Stefania Lagonigro, Alessandro Gronchi, Marco Fiore, Paolo G. Casali, Rossella Bertulli, Antonino Carbone, Marco A. Pierotti, Elena Tamborini, Silvana Pilotti
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To correlate morphologic changes with molecular, biochemical, and cytogenetic profiles in gastrointestinal stromal tumor (GIST) patients before and after imatinib treatment. Experimental Design: We investigated 132 tumor samples obtained from 35 patients with advanced disease who underwent resective surgery after imatinib treatment according to the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group protocol. On the basis of imaging findings, 27 patients were responders and 8 progressors, and retaining this radiological subdivision, we analyzed posttreatment morphologic changes correlating them with molecular, biochemical, and cytogenetic analyses. Results: On the basis of morphology (residual viable cellularity/proliferation markers), three subgroups were identified showing high, moderate, or low response. All of the progressing cases clustered in the low-response subgroup, whereas the responding cases were distributed in all three subgroups. The correlation between morphology and the molecular findings showed that secondary mutations segregated with the low-response subgroup, whereas c-Kit primary resistance mutations were randomly distributed in the three subgroups. Fluorescence in situ hybridization analysis of c-Kit/PDGFRA genes showed that all of the progressing cases were disomic. Referring to morphology, among the responding cases, a disomic pattern was mainly restricted to the high responders, whereas the moderate and low responders were aneusomic. Comparison of post-imatinib genomic profiles with the 23 available primary tumors showed that 17 cases carried the same cytogenetic pattern. Overall, 12 of the 27 primary tumors presented a gain/loss of c-Kit/PDGFRA gene copy number. Conclusions: Our findings show that c-Kit/PDGFRA genomic alterations were present at disease onset in 1/3 of the examined cases. They therefore represent an early event possibly related to primary imatinib resistance in GISTs.
Very High Frequency of Hypermethylated Genes in Breast Cancer Metastasis to the Bone, Brain, and Lung
Authors: Jyoti Mehrotra, Mustafa Vali, Megan McVeigh, Scott L. Kominsky, Mary Jo Fackler, Jaana Lahti-Domenici, Kornelia Polyak, Nicoletta Sacchi, Elizabeth Garrett-Mayer, Pedram Argani, Saraswati Sukumar
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Most often it is not the primary tumor, but metastasis to distant organs that results in the death of breast cancer patients. To characterize molecular alterations in breast cancer metastasis, we investigated the frequency of hypermethylation of five genes (Cyclin D2, RAR-β, Twist, RASSF1A, and HIN-1) in metastasis to four common sites: lymph node, bone, brain, and lung. Experimental Design: Methylation-specific PCR for the five genes was performed on DNA extracted from archival paraffin-embedded specimens of paired primary breast cancer and its lymph nodes (LN) metastasis (n = 25 each); in independent samples of metastasis to the bone (n = 12), brain (n = 8), and lung (n = 10); and in normal bone, brain, and lung (n = 22). Results: No hypermethylation was detected in the five genes in the normal host tissues. In paired samples, LN metastasis had a trend of higher prevalence of methylation compared with the primary breast carcinoma for all five genes with significance for HIN-1 (P = 0.04). Compared with the primary breast carcinomas, all five genes had higher methylation frequencies in the bone, brain, and lung metastasis, with HIN-1 and RAR-β methylation being significantly higher (P &amp;lt; 0.01) in each group. Loss of expression of all five genes correlated, with a few exceptions, to hypermethylation of their promoter sequences in metastatic carcinoma cells microdissected from LNs. Conclusion: The frequent presence of hypermethylated genes in locoregional and distant metastasis could render them particularly susceptible to therapy targeted toward gene reactivation combining demethylating agents, histone deacetylase inhibitors, and/or differentiating agents.
Diabetes or Impaired Glucose Tolerance
Authors: Carmen Lara, Sergio Ponce de Leon, Hector Foncerrada, Martin Vega
Journal: Diabetes Care (2007)

Diagnosis has been considered a process of “labeling” with consequences that can be both positive (access to treatment) and negative (social rejection). The ultimate goal of making a diagnosis is to adequately inform the patient, thereby enhancing knowledge of the disorder, adherence to therapeutic advice, and the ability to manage illness effectively.

Impaired glucose tolerance and diabetes are terms that differentiate two metabolic carbohydrate abnormalities. Establishing the optimum diagnostic levels for glycemic thresholds, however, depends on balancing the medical, social, and economic costs of labeling a patient who is not at substantial risk for developing complications versus the corresponding costs of not diagnosing “true” diabetes cases (1).

Among patients who have alteration in metabolizing glucose, varying (in a controlled setting) the diagnostic criteria for diabetes and related carbohydrate disorders offers an opportunity to assess whether labeling, either as having “impaired glucose tolerance” or “diabetes,” influences patients’ knowledge of their disease, adherence to therapy, or mechanisms for coping and metabolic control. We used a clinical trial design to assess the effects of diagnostic labeling among participants randomly assigned to be informed that they had either impaired glucose tolerance or diabetes.

Participants were adults attending a primary care clinic, and inclusion criteria were fasting glucose level 100–140 mg/dl and glucose level >140 but <200 mg/dl 2-h post–75-g …
Prolonged Exposure vs Eye Movement Desensitization and Reprocessing vs Waiting List for Posttraumatic Stress Disorder in Patients With a Psychotic Disorder
Authors: David P. G. van den Berg, Paul A. J. M. de Bont, Berber M. van der Vleugel, Carlijn de Roos, Ad de Jongh, Agnes Van Minnen, Mark van der Gaag
Journal: JAMA Psychiatry (2015)

The efficacy of posttraumatic stress disorder (PTSD) treatments in psychosis has not been examined in a randomized clinical trial to our knowledge. Psychosis is an exclusion criterion in most PTSD trials.To examine the efficacy and safety of prolonged exposure (PE) therapy and eye movement desensitization and reprocessing (EMDR) therapy in patients with psychotic disorders and comorbid PTSD.A single-blind randomized clinical trial with 3 arms (N = 155), including PE therapy, EMDR therapy, and waiting list (WL) of 13 outpatient mental health services among patients with a lifetime psychotic disorder and current chronic PTSD. Baseline, posttreatment, and 6-month follow-up assessments were made.Participants were randomized to receive 8 weekly 90-minute sessions of PE (n = 53), EMDR (n = 55), or WL (n = 47). Standard protocols were used, and treatment was not preceded by stabilizing psychotherapeutic interventions.Clinician-rated severity of PTSD symptoms, PTSD diagnosis, and full remission (on the Clinician-Administered PTSD Scale) were primary outcomes. Self-reported PTSD symptoms and posttraumatic cognitions were secondary outcomes.Data were analyzed as intent to treat with linear mixed models and generalized estimating equations. Participants in the PE and EMDR conditions showed a greater reduction of PTSD symptoms than those in the WL condition. Between-group effect sizes were 0.78 (P < .001) in PE and 0.65 (P = .001) in EMDR. Participants in the PE condition (56.6%; odds ratio [OR], 3.41; P = .006) or the EMDR condition (60.0%; OR, 3.92; P < .001) were significantly more likely to achieve loss of diagnosis during treatment than those in the WL condition (27.7%). Participants in the PE condition (28.3%; OR, 5.79; P = .01), but not those in the EMDR condition (16.4%; OR, 2.87; P = .10), were more likely to gain full remission than those in the WL condition (6.4%). Treatment effects were maintained at the 6-month follow-up in PE and EMDR. Similar results were obtained regarding secondary outcomes. There were no differences in severe adverse events between conditions (2 in PE, 1 in EMDR, and 4 in WL). The PE therapy and EMDR therapy showed no difference in any of the outcomes and no difference in participant dropout (24.5% in PE and 20.0% in EMDR, P = .57).Standard PE and EMDR protocols are effective, safe, and feasible in patients with PTSD and severe psychotic disorders, including current symptoms. A priori exclusion of individuals with psychosis from evidence-based PTSD treatments may not be justifiable.isrctn.com Identifier: ISRCTN79584912.