tbuckley/cabot-search huggingface dataset:
Setting the standard for advanced pancreatic ductal adenocarcinoma (A-PDAC) in 2010: Meta-regression and power analysis of phase III randomized clinical trials (RCT) evaluating gemcitabine (GEM) in combination with cisplatin (CIS), oxaliplatin (L-OHP), or capecitabine (CAP).
Authors: I. Sperduti, E. Bria, D. Giannarelli, M. Di Maio, A. Gelibter, V. Vaccaro, F. Cuppone, F. Cognetti, M. Milella
Journal: Journal of Clinical Oncology (2010)

4049 Background: GEM-based doublets have had little impact on the dismal survival of A-PDAC. To evaluate differential effects of individual drugs combined with GEM, we conducted a literature-based meta-regression and power analysis of published phase III RCT. Methods: Hazard ratios (HR) with 95% confidence intervals (CI) were extracted for overall survival (OS), pooled using a random-effect model, and tested for heterogeneity. Sensitivity analyses according to the drug (CIS, L-OHP, or CAP) combined with GEM were performed. One-year absolute differences in OS (AD) and numbers of patients needed to treat (NNT) were calculated. A power analysis was conducted to evaluate if the number of pts included would be sufficient to reliably exclude a clinically meaningful 1-yr AD in any of the combination groups. Results: OS results for the 7 phase III RCT (2,422 pts) gathered are shown in the Table. Sensitivity analyses did not show any significant interaction with the different drugs combined with GEM (p=0.45). Meta-regression analysis using performance status (0-1), disease status (locally advanced) and gender (female) did not show any significant impact of the selected predictors on OS results. Power analysis indicated that, even in the best-case scenario of a 3% 1-year benefit (GEM/CAP), 2,910 pts per arm would have been required to ensure reliable results. Conversely, the present analysis allows to exclude that GEM doublets may improve 1-yr OS by ≥ 5% over GEM alone with 80% power and a 2-tailed α of 0.05. Conclusions: Single- agent GEM remains the standard of care for A-PDAC. L-OHP and CAP combinations appear to provide a statistically significant benefit; that is, however, negligible in absolute terms and does not support the routine use of GEM doublets in clinical practice. RCT (pts) HR (95% CI) p value Het. (p) 1-yr AD (%) NNT CIS 3 (702) 0.94 (0.76, 1,17) 0.61 0.19 - - L-OHP 2 (868) 0.86 (0.74, 0.99) 0.041 0.65 2.6 38-39 CAP 2 (852) 0.86 (0.75, 0.99) 0.039 0.94 3.0 33-34 No significant financial relationships to disclose.
Cluster of human parechovirus infections as the predominant cause of sepsis in neonates and infants, Leicester, United Kingdom, 8 May to 2 August 2016
Authors: Julian W Tang, Christopher W Holmes, Fadwa A Elsanousi, Ayushi Patel, Fazila Adam, Rachel Speight, Savitha Shenoy, Daniel Bronnert, Gary Stiefel, Premkumar Sundaram, Suchandra Pande, Arani Sridhar, Venkatesh Kairamkonda, Srini Bandi
Journal: Eurosurveillance (2016)

We report an unusually high number of cases (n = 26) of parechovirus infections in the cerebrospinal fluid (CSF) of neonates and infants admitted with sepsis in the United Kingdom during 8 May to 2 August 2016. Although such infections in neonates and infants are well-documented, parechovirus has not been routinely included in many in-house and commercial PCR assays for CSF testing. Clinicians should consider routine parechovirus testing in young children presenting with sepsis.
HIF1α and metabolic reprogramming in inflammation
Authors: Sarah E. Corcoran, Luke A.J. O’Neill
Journal: Journal of Clinical Investigation (2016)

HIF1α is a common component of pathways involved in the control of cellular metabolism and has a role in regulating immune cell effector functions. Additionally, HIF1α is critical for the maturation of dendritic cells and for the activation of T cells. HIF1α is induced in LPS-activated macrophages, where it is critically involved in glycolysis and the induction of proinflammatory genes, notably Il1b. The mechanism of LPS-stimulated HIF1α induction involves succinate, which inhibits prolyl hydroxylases (PHDs). Pyruvate kinase M2 (PKM2) is also induced and interacts with and promotes the function of HIF1α. In another critical inflammatory cell type, Th17 cells, HIF1α acts via the retinoic acid-related orphan receptor-γt (RORγt) to drive Th17 differentiation. HIF1α is therefore a key reprogrammer of metabolism in inflammatory cells that promotes inflammatory gene expression.
Comparison of the effects of anti-EGFR and anti-VEGF antibody as first-line treatment for metastatic colorectal cancer
Authors: Yasuyuki Kawamoto, Masaki Inoue, Sachiko Shimizu, Mio Matsumoto, Shin Haba, Akiko Yokoyama, Shinji Yoshii, Nobuaki Akakura
Journal: Annals of Oncology (2015)
<i>Cannabis sativa</i>allergy: looking through the fog
Authors: I. I. Decuyper, A. L. Van Gasse, N. Cop, V. Sabato, M. A. Faber, C. Mertens, C. H. Bridts, M. M. Hagendorens, L. De Clerck, H. P. Rihs, D. G. Ebo
Journal: Allergy (2016)

IgE-mediated Cannabis (C. sativa, marihuana) allergy seems to be on the rise. Both active and passive exposure to cannabis allergens may trigger a C. sativa sensitization and/or allergy. The clinical presentation of a C. sativa allergy varies from mild to life-threatening reactions and often seems to depend on the route of exposure. In addition, sensitization to cannabis allergens can result in various cross-allergies, mostly for plant foods. This clinical entity, designated as the 'cannabis-fruit/vegetable syndrome', might also imply cross-reactivity with tobacco, natural latex and plant-food-derived alcoholic beverages. Hitherto, these cross-allergies are predominantly reported in Europe and appear mainly to rely upon cross-reactivity between nonspecific lipid transfer proteins or thaumatin-like proteins present in C. sativa and their homologues, ubiquitously distributed throughout plant kingdom. At present, diagnosis of cannabis-related allergies predominantly rests upon a thorough history completed with skin testing using native extracts from crushed buds and leaves. However, quantification of specific IgE antibodies and basophil activation tests can also be helpful to establish correct diagnosis. In the absence of a cure, treatment comprises absolute avoidance measures. Whether avoidance of further use will halt the extension of related cross-allergies remains uncertain.
139P Neuroendocrine neoplasms of the esophagus - emerging clinicopathological trends and outcomes of a rare entity
Authors: M.P. Kamath, L. D, K. Lakshmaiah, L.A. Jacob, R.V. Kumar, S. Babu, G. Babu, A.S. Komaranchath, A. S
Journal: Annals of Oncology (2015)
The Roles of Mutation, Selection, and Expression in Determining Relative Rates of Evolution in Mitochondrial versus Nuclear Genomes
Authors: Justin C. Havird, Daniel B. Sloan
Journal: Molecular Biology and Evolution (2016)

Eukaryotes rely on proteins encoded by the nuclear and mitochondrial (mt) genomes, which interact within multisubunit complexes such as oxidative-phosphorylation enzymes. Although selection is thought to be less efficient on the asexual mt genome, in bilaterian animals the ratio of nonsynonymous to synonymous substitutions (ω) is lower in mt- compared with nuclear-encoded OXPHOS subunits, suggesting stronger effects of purifying selection in the mt genome. Because high levels of gene expression constrain protein sequence evolution, one proposed resolution to this paradox is that mt genes are expressed more highly than nuclear genes. To test this hypothesis, we investigated expression and sequence evolution of mt and nuclear genes from 84 diverse eukaryotes that vary in mt gene content and mutation rate. We found that the relationship between mt and nuclear ω values varied dramatically across eukaryotes. In contrast, transcript abundance is consistently higher for mt genes than nuclear genes, regardless of which genes happen to be in the mt genome. Consequently, expression levels cannot be responsible for the differences in ω. Rather, 84% of the variance in the ratio of ω values between mt and nuclear genes could be explained by differences in mutation rate between the two genomes. We relate these findings to the hypothesis that high rates of mt mutation select for compensatory changes in the nuclear genome. We also propose an explanation for why mt transcripts consistently outnumber their nuclear counterparts, with implications for mitonuclear protein imbalance and aging.
Lowering Blood Pressure in Patients With Diabetes
Authors: Min Li, Zhenyu Tang
Journal: JAMA (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
A single-arm, phase II, multicenter trial of sunitinib maleate (SU) in locally advanced or metastatic pheochromocytoma/paraganglioma (PC/PG): Interim results.
Authors: Raya Leibowitz-Amit, Anthony Michael Joshua, Shereen Ezzat, Isabelle Bourdeau, Harold Olney, Sjoukje Oosting, Joseph D. Ruether, Soo Chin, Cristina Palmieri, Jo-An Seah, Sylvia L Assa, Monika Krzyzanowska, Jennifer J. Knox
Journal: Journal of Clinical Oncology (2014)

431 Background: Metastatic PC/PG is rare and may be sporadic or have a genetic basis. Treatment remains challenging in the absence of well-controlled randomized trials. Case reports suggest clinical activity of SU in this setting. We aim to prospectively evaluate radiological and biochemical response to SU, and assess its toxicity profile in PC/PG. Methods: This is an ongoing single-arm, phase II, multicenter, investigator-initiated clinical trial, enrolling patients (pts) with metastatic or unresectable locally advanced malignant PG or PC with ECOG PS 0-2, no previous treatment with tyrosine kinase inhibitors, and evidence of radiological progression or disease-related symptoms. All pts receive 50mg SU daily at standard dosing, following blood pressure stabilization, and are assessed for radiological and biochemical response (with urine metanephrines, catecholamines or serum chromogranin A) q12 weeks until disease progression, unacceptable toxicity or pts withdrawal. Futility was defined as no documented responses within the first 14 patients and would have led to trial cessation. Results: Since May 2009, 14 pts enrolled in 3 academic hospitals (Canada and the Netherlands). Interim results of 10 pts are presented (pts characteristics are tabulated). Two pts had symptoms related to hormonal-excess and both had clinical improvement on SU. All 10 pts had biochemical evidence of hormonal excess, of which 5 had biochemical response (50%). Best radiological responses achieved were partial response (3/10 pts; 30%, 1 unconfirmed), stable disease &gt; 3 months (6/10; 60%) and progressive disease (1/10; 10%). Adverse events were consistent with known side-effects of SU. Seven pts had toxicity-related dose reductions, contributing to treatment cessation in two. Conclusions: This trial surpassed the pre-specified futility stopping rule with the current documented responses on SU and with durable patient benefit seen. Updated data will be presented and discussed. Clinical trial information: NCT00843037. [Table: see text]
Prevalence and incidence of toxoplasmosis: a retrospective analysis of mother-child examinations, Styria, Austria, 1995 to 2012
Authors: Christian Berghold, Sereina Annik Herzog, Heidelinde Jakse, Andrea Berghold
Journal: Eurosurveillance (2016)

In Austria, mandatory screening for the prevention of congenital toxoplasmosis stipulates a serological test for antibodies against Toxoplasma gondii as early as possible in pregnancy. In the case of a seronegative result, subsequent tests at intervals of 8 weeks are requested. We analysed serological data from Styria, an Austrian federal state, to determine the seroprevalence and incidence of Toxoplasma infections. The study included 353,599 tests from 103,316 women during 158,571 pregnancies from 1995 to 2012. The age-adjusted seroprevalence decreased from 43.3% in 1995 to 31.5% in 2012, with a yearly decline of 0.84% (95% confidence interval (CI): 0. 79 -0.88). The intergravid incidence showed an annual decrease of 4.2%. The average yearly incidence of intragravid and intergravid seroconversions was 0.52% (95% CI 0.45–0.61) and 0.72% (95% CI 0.67–0.77), respectively. If the difference between these rates (p &lt; 0.001) can be explained by the effect of primary prevention such as avoiding raw meat and taking hygiene precautions when encountering cats or preparing vegetables, only ca two of seven (28%) infections were avoided by hygiene measures taken by pregnant women. Primary prevention may therefore have its limits.
Effectiveness of Right Heart Catheterization: Time for a Randomized Trial
Authors: Owen Boyd
Journal: JAMA (1997)

<h3>To the Editor.</h3> —Dr Connors and the SUPPORT Investigators<sup>1</sup>provide thought-provoking information regarding apparent harm from the use of the RHC. The accompanying Editorial<sup>2</sup>provides thought-provoking reading, and the ripples from this article have already been felt around the world.<sup>3</sup>However, the investigators emphasize that this is not a randomized controlled trial, and the comparisons made within it rely totally on the accuracy of the propensity score, derived to predict the likelihood of placement of an RHC. Sensitivity analysis showed that for a single missing covariate in the propensity score to have misrepresented a true beneficial effect as harmful it would have to increase estimates of risk of death and likelihood of RHC 6-fold. Is this possible? There does seem to have been a missing<i>x</i>factor. The 2016 patients in the study had almost identical propensity scores and disease categories, but only half received an RHC. This was unlikely
Statistical Considerations in Evaluating a Biosimilar Product in an Oncology Clinical Study
Authors: Kun He, Huanyu Chen, Thomas Gwise, Sandra Casak, Steven Lemery, Patricia Keegan, Richard Pazdur, Rajeshwari Sridhara
Journal: Clinical Cancer Research (2016)

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) established an abbreviated approval pathway for biosimilar and interchangeable biological products that was intended to balance innovation and consumer interests. The FDA has published several guidance documents to facilitate implementation of the BPCI Act. Here we discuss the role of comparative clinical studies in the assessment of clinically meaningful differences and illustrate the underlying scientific concepts with a hypothetical example of a clinical study comparing a product to US-licensed bevacizumab. Clin Cancer Res; 22(21); 5167-70. ©2016 AACR.
A phase I, dose-escalation, safety, pharmacokinetic, pharmacodynamic study of thioureidobutyronitrile, a novel p53 targeted therapy, in patients with advanced solid tumors.
Authors: Geoffrey Shapiro, Jeffrey G Supko, Daniel C. Cho, John Frederick Hilton, Matthew Hadfield, Solida Pruitt-Thompson, Eveline Bordoli-Trachsela, Nela Zvereva, Andrew Wolanski, Aya Sato-DiLorenzo, Susan Gotthardt, Edward A. Fox, Sigitas Jonas Verselis, Ashok Kumar, Sylvia A. Holden, Siya Ram, Karima Chafai-Fadela, Kimberly Harding, Krishna E. Menon
Journal: Journal of Clinical Oncology (2013)

TPS2627 Background: Thioureidobutyronitrile, kevetrin, has demonstrated anti-tumor activity in several wild type and mutant p53 human tumor xenografts without evidence of genotoxicity. In wild type p53 models, kevetrin induces cell cycle arrest and apoptosis through activation and stabilization of wild type p53, resulting in increased expression of p53 target genes p21 and PUMA. Kevetrin also alters processivity of MDM2, and induces monoubiquitination of wild type p53, enhancing its stability (AACR 2011 abstract 4470). Mutant p53 is a complex target since it is an array of mutant proteins with oncogenic properties. Kevetrin induces degradation of oncogenic mutant p53 and induces apoptosis (AACR 2012 abstract 2874). Kevetrin therefore has the unique ability to target both wild type and mutant p53 tumors thereby controlling tumor growth in a wide range of preclinical tumor models. Methods: Adults with refractory locally advanced or metastatic solid tumors, acceptable liver and kidney function, and hematological status were eligible. Objectives include determination of DLT, MTD, recommended phase 2 dose, pharmacokinetics (PK), pharmacodynamics (PD), and evaluating preliminary evidence of antitumor activity. Kevetrin is given as a 1-hour intravenous infusion once weekly for 3 weeks in 28-day cycles. The starting dose was 10 mg/m 2 . In a 3+3 design, groups of 3-6 patients are evaluated for toxicity at each dose level. Dose escalation is based upon the number and intensity of adverse events in cycle 1. Kevetrin PK is characterized for the first and last doses given in cycle 1. Kevetrin induced expression of p21 in lymphocytes in preclinical studies; therefore p21 expression in peripheral blood mononuclear cells will be measured as a PD biomarker. Antitumor activity by RECIST 1.1 criteria and serum tumor markers will be assessed. The p53 status of tumors of selected patients will be determined. The second cohort is currently under evaluation. Conclusion: In preclinical models, Kevetrin has activity against tumors harboring both wild type and mutant p53 by diverse mechanisms. A first-in-human dose escalation trial is underway. Clinical trial information: NCT01664000.
Phase I Study of Forodesine (BCX1777), An Oral PNP Inhibitor In Patients with Relapsed or Refractory T/NK Malignancies.
Authors: Kunihiro Tsukasaki, Michinori Ogura, Hirokazu Nagai, Jun Taguchi, Tatsuya Suzuki, Dai Maruyama, Uchida Toshiki, Takashi Oyama, Tomomitsu Hotta, Kensei Tobinai
Journal: Blood (2010)
219P Phase I study of sorafenib in combination with uracil-tegafur in patients with unresectable advanced hepatocellular carcinoma in Japan
Authors: S. Itoh, K. Shirabe, K. Kimura, H. Okabe, N. Harimoto, T. Ikegami, H. Uchiyama, T. Yoshizumi, T. Ikeda, Y. Maehara
Journal: Annals of Oncology (2015)
Tobacco Advertising and Promotional Expenditures in Sports and Sporting Events — United States, 1992–2013
Authors: Israel T. Agaku, Satomi Odani, Stephanie Sturgis, Charles Harless, Rebecca Glover-Kudon
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Smokeless tobacco has been actively promoted by tobacco companies using endorsements by major sport figures, and research indicates that tobacco advertising can lead to youth initiation of tobacco use (1,2). Television and radio advertisements for cigarettes and smokeless tobacco have been prohibited since 1969,* and the 1998 Master Settlement Agreement(†) further prohibited tobacco companies from targeting youths with tobacco product advertisements in specified areas. In 2010, the Food and Drug Administration (FDA), under authority of the 2009 Family Smoking Prevention and Tobacco Control Act (FSPTCA), prohibited tobacco-brand sponsorship (i.e., sponsorship of sports and entertainment events or other social or cultural events using the tobacco brand name or anything identifiable with any brand of cigarettes or smokeless tobacco).(§) However, corporate-name tobacco sponsorship (i.e., sponsorship using the name of the corporation that manufactures regulated tobacco products) is still permitted under certain conditions.(¶) To monitor tobacco advertising and promotional activities in sports in the United States, CDC analyzed trends in sports-related marketing expenditures for cigarettes and smokeless tobacco during 1992-2013 using data from the Federal Trade Commission (FTC). During 1992-2013, sports-related marketing expenditures, adjusted by the consumer price index to constant 2013 dollars, decreased significantly for both cigarettes (from $136 million in 1992 to $0 in 2013) and smokeless tobacco (from $34.8 million in 1992 to $2.1 million in 2013). During 2010-2013, after the prohibition of tobacco-brand sponsorship in sports under the FSPTCA, cigarette manufacturers reported no spending (i.e., $0) on sports-related advertising and promotional activities; in contrast, smokeless tobacco manufacturers reported expenditures of $16.3 million on advertising and promoting smokeless tobacco in sports during 2010-2013. These findings indicate that despite prohibitions on brand sponsorship, smokeless tobacco products continue to be marketed in sports in the United States, potentially through other indirect channels such as corporate-name sponsorship. Enhanced measures are warranted to restrict youth-oriented tobacco marketing and promotional activities that could lead to tobacco initiation and use among children and adolescents (2). Reducing tobacco industry promotion through sponsorship of public and private events is an evidence-based strategy for preventing youth initiation of tobacco use (3). In addition, other proven interventions (e.g., tobacco price increases, anti-tobacco mass media campaigns, tobacco-free policies inclusive of smokeless tobacco, and barrier-free access to cessation services), could help reduce smokeless tobacco use in the United States (1).
The Hyposulphites in Infectious Diseases.
Authors: E. Chenery.
Journal: JAMA (1894)

<h3>Dear Sir:</h3> —I have just received theJournal of the AmericanMedical Associationof February 3, containing your article on the sulphites and hyposulphites of sodium in relation to some of the zymotic diseases. I was to lecture to-day on diphtheria and had only a moment to run over your points, and so was not so prepared to use your statements as I should have gladly done. I saw Professor Polli's statement as early as 1862 or '3, I think, and began the use of the hyposulphite of sodium as early as 1863 in diphtheria. I had an urgent case in an only daughter who was scrofulous, her tonsils quite meeting together. I was at my wits' end for a remedy and resolved to try the bisulphite and sent for it but could not obtain it. The apothecary, however, sent me the hyposulphite, saying that he thought I could use it. I
Choice of non-medic to run radiology school was “ill conceived,” says royal college
Authors: Gareth Iacobucci
Journal: BMJ (2016)

The Royal College of Radiologists (RCR) has criticised Health Education England’s decision to appoint a non-medic to lead a regional training school for radiologists.

The college voiced its concerns after the national education and training body offered the post of head of the Yorkshire and the Humber School of Radiology to a radiographer.

The college said that it had not been consulted about the appointment process and described the decision as “ill informed and ill conceived.”

“We understand …
Cost-Effectiveness of Once-Daily Oral Chelation Therapy with Deferasirox (Exjade®, ICL670) Versus Infusional Deferoxamine in Transfusion-Dependent Thalassemic Patients.
Authors: Thomas E. Delea, Oleg Sofrygin, Simu K. Thomas, Jean-Francois Baladi, Pradyumna D. Phatak, Thomas D. Coates
Journal: Blood (2005)