tbuckley/cabot-search huggingface dataset:
Evaluation of disease-free survival as surrogate endpoint for overall survival using two individual patient data meta-analyses of adjuvant chemotherapy in operable non-small cell lung cancer.
Authors: S. Michiels, A. Mauguen, D. Fisher, S. Burdett, R. Paulus, S. J. Mandrekar, C. P. Belani, F. A. Shepherd, T. Eisen, H. Pang, L. Collette, C. Le Pechoux, J. Pignon
Journal: Journal of Clinical Oncology (2011)

7004 Background: The gold standard endpoint in clinical trials of adjuvant chemotherapy (CT) in lung cancer is overall survival (OS), which while a reliant and simple-to-measure outcome, takes a long time to observe in this setting. This study aimed to evaluate disease-free survival (DFS) as a potential surrogate endpoint for OS in adjuvant CT trials, which could lead to more rapid conclusion of trials. Methods: This analysis was based on individual patient data of 7,626 patients (pts) and 25 randomized trials from two large meta-analyses of adjuvant CT: surgery alone versus surgery + CT and surgery + radiotherapy (RT) versus surgery + RT + CT. DFS was defined as the time from randomization to the first event (local or distant recurrence or death from any cause). A correlation approach was used to assess individual and trial level surrogacy: at the individual level, to estimate association between distributions of DFS and OS (ρ), and at trial level, to estimate association between treatment effects on DFS and OS (R). Values of ρ and R closer to 1.0 would indicate strong surrogacy. Results: Analysis 1 (without RT) included 18 trials (5,379 pts, 2,525 DFS events and 2,163 deaths); analysis 2 (with RT) included 7 trials (2,247 pts, 1,673 DFS events and 1,566 deaths). 79% and 84% of DFS events, respectively, occurred in the first three years. Correlations between DFS and OS were very strong, both at the individual (ρ=0.91 in trials without RT and 0.93 in trials with RT) and trial level (R=0.96, 95% confidence interval [0.92-1.00] and 0.99 [0.98-1.00], respectively). Considering only events occurring in the first three years and deaths in the first five years, trial-level correlation remained strong (R=0.94 [0.88-1.00] and 0.98 [0.95-1.01] respectively). Conclusions: Our large database provides good evidence that disease-free survival is a valid surrogate endpoint for overall survival in operable non-small cell lung cancer in the adjuvant CT setting. Supported by French Cancer League, PHRC and British Medical Research Council.
Abstract 20973: The Impact of Independent Statistical Analysis on Reported Outcomes in Cardiovascular Clinical Trials
Authors: Ricardo Esquitin, Rupa L Iyengar, Kshitij A Shah, Louai Razzouk, Sameer Bashee, Ashish Aneja, Verghese Mathew, Michael E Farkouh
Journal: Circulation (2010)

Background: The influence of independent statistical analysis on the outcomes of cardiovascular trials has not been well documented. While, industry sponsored cardiovascular trials are more likely ...
Antimicrobial resistance is a social problem requiring a social solution
Authors: R. Smith
Journal: BMJ (2015)

We need to reverse our dependency on antibiotics, whether or not new ones are discovered Antimicrobial resistance has reasserted itself on the national and international agenda as a critical threat to public health and health systems. It undermines the very foundations of modern healthcare, from joint replacements to chemotherapy, threatens to reverse the decline in mortality and morbidity from infectious diseases, jeopardises animal health and welfare, and poses potentially crippling financial effects.1 2 It is intrinsically a biological phenomenon, which has, perhaps naturally, led to much of the discussion on tackling it being driven from a biological, and broader scientific, perspective. However, the conditions promoting, or militating against, the biological mechanisms of antimicrobial resistance are deeply social, shaped by cultural, political, and economic processes. Such social aspects include:
Distribution, properties, and functional characteristics of three classes of histamine receptor.
Authors: S J Hill
Journal: Pharmacological Reviews (1990)

It is clear from the preceding overview of histamine receptor pharmacology that research into the pharmacology of histamine receptors is at an exciting stage of development. The rapid advance of molecular biology should soon see the structural identification and cloning of all three of the major vertebrate histamine receptors. Further work will continue toward enhancing our understanding of the control by histamine of intracellular signaling via H1- and H2-receptors, and the rapid explosion of work on the H3-receptor should begin to unravel the mechanisms underlying its actions, perhaps via effects on ionic channels. The potential role of histamine as an intracellular second messenger raises exciting possibilities, as does the search for a histamine receptor analogous to the ligand-gated ion channel in the invertebrate nervous system.
John Hedley Cule
Authors: J. Blair
Journal: BMJ (2015)

This doctor’s life is a remarkable one and merits recognition and recording. John Hedley Cule was born in Ton Pentre in the Rhondda Valley. His father, Walter Edwards Cule, was a very successful draper in Ystrad Road, Pentre. John was at school first at the Rhondda Intermediate School for boys, and then at Porth County School, where he was a chorister in the local chapel. His father later sent him to Kingswood School in Bath, a Methodist school founded by John Wesley. Here his headmaster, A Barrett Sackett, kindled his interest in Wesley’s medical work, and it was this which stimulated his interest in history of medicine. In 1938 John went to Trinity Hall at Cambridge University to study medicine. During the London blitz of 1940, he and other students went to London to treat injured people. John recalled those days of fear, as the German bombs fell, and his early experience in seeing seriously injured people of all ages, of running along streets with houses on fire and crumbling after a bomb had done its huge damage. “But we all knew it had to be done, we used to say”—like all British people in those days. These young students did not flinch. They had the benefit of release from the bombing as they went back to the quietness of Cambridge, after their several days of …
Is there a relationship between walk distance and lung function parameters in different disease groups? Can we predict walk distance?
Authors: Jennifer Colbourne, Matthew Rutter, Karl Sylvester
Journal: European Respiratory Journal (2012)

Limited data exists which specifies whether certain respiratory physiological characteristics in lung disease groups are associated with exercise response and functional ability.    AIMS   1) To determine whether relationships exist between the outcomes of exercise (six-minute walk test (6mwt)) and results of lung function in patients with specific lung disease. 2) Will relationships allow generation of equations to accurately predict walk distance?    METHOD   Retrospective analysis of lung function and concomitant 6mwt data from individuals who attended the lung function department between 2009-2011. Validation of generated predicted equations in separate classified cohort of subjects and comparison to Enright equations (1998).    SUBJECTS   352 patient9s data collected. 5 classified with mixed lung disease excluded from analysis due to small sample size. Of the remaining 347 patients; 38 (10.9%) identified as restrictive, 158 (43.5%) obstructive and 151 (43.5%) normal as per ATS/ERS interpretation guidelines.   RESULTS   Significant correlations exist between lung function and walk distance. Regression equations generated for restrictive (r=0.509 p=    CONCLUSION   The regression equations demonstrated better predictive capability when compared to Enrights equations, thus supporting the requirement for disease specific regression equations.
Comparison of content of FDA letters not approving applications for new drugs and associated public announcements from sponsors: cross sectional study
Authors: P. Lurie, H. S. Chahal, D. W. Sigelman, S. Stacy, J. Sclar, B. Ddamulira
Journal: BMJ (2015)

<b>Objectives </b>To describe the content of non-public complete response letters issued by the US Food and Drug Administration (FDA) when they do not approve marketing applications from sponsors (drug companies) and to compare them with the content any subsequent press releases issued by those sponsors <b>Design</b> Cross sectional study. <b>Data sources </b>All applications for which FDA's Center for Drug Evaluation and Research initially issued complete response letters (n=61) from 11 August 2008 to 27 June 2013. Complete response letters and press releases were divided into discrete statements related to seven domains and 64 subdomains and assessed to determine whether they matched. <b>Results</b> 48% (29) of complete response letters cited deficiencies in both the safety and efficacy domains, and only 13% cited neither safety nor efficacy deficiencies. No press release was issued for 18% (11) of complete response letters, and 21% (13) of press releases did not match any statements from the letters. Press release statements matched 93 of the 687 statements (14%), including 16% (30/191) of efficacy and 15% (22/150) of safety statements. Of 32 complete response letters that called for a new clinical trial for safety or efficacy, 59% (19) had matching press release statements. Seven complete response letters reported higher mortality rates in treated participants; only one associated press release mentioned this fact. <b>Conclusions</b> FDA generally issued complete response letters to sponsors for multiple substantive reasons, most commonly related to safety and/or efficacy deficiencies. In many cases, press releases were not issued in response to those letters and, when they were, omitted most of the statements in the complete response letters. Press releases are incomplete substitutes for the detailed information contained in complete response letters.
Cross-Reacting Tumor-Specific Transplantation Antigens in Methylcholanthrene-Induced Guinea Pig Sarcomas
Authors: E C Holmes, D L Morton, G Schidlovsky, E Trahan
Journal: JNCI Journal of the National Cancer Institute (1971)

Cross-reacting tumor-specific transplantation antigens were demonstrated in two of three methylcholanthrene-induced strain-2 guinea pig sarcomas. In addition, water-soluble extracts prepared from the two cross-reacting tumors contained cross-reacting tumor-specific transplantation antigens. Electron microscopic studies revealed virus-like particles similar to those previously described in strain-2 guinea pig leukemias in two of the three tumors examined, but the cross reactions between these tumors could not be correlated with the presence of these viral particles.
Radio-clinic aspect of multifocal hydatidosis
Authors: Regis Gothard Bopaka, W. Elkhattabi, H. Afif, A. Aichane, Z. Bouayad
Journal: European Respiratory Journal (2013)

Hydatidosis is a cosmopolitan endemic parasitosis in Morocco caused by man being infected with tapeworm larva. Hydatidosis can affect many organs; lung is the more affected area after liver. We are reporting a retrospective research over 5 years (2007-2011), related to 82 lung hydatid cyst cases among which 30 cases with another infection associated. They are 17 men and 13 women. Hydatid contagium was found in 12 cases. Hydatid cist antecedent of liver formerly operated in 4 cases.Hydatidoptysia is outlined in 4 cases. Tele-thorax displayed round opacity among 22 cases, a Hydroaric image with floating membrane aspect in 8 cases plus a pleural infringement in 10 cases. Tomodensitometry objectified in addition of pulmonary localization, a pleural infringement in 13 cases, mediastinal in one case, inner hepatorenal in another one and cardiac as showed up by cardiac echography abdominal echography objectified hepatic localization in 14 cases. Bronchoscopy visualized a typical aspect of hydatic membrane in one case. Hydatic serology is positive regarding 18 cases (60%). Surgical treatment was suggested within 24 cases firstly for pulmonary infringement then spread to other organs. Morocco stands for being a hydatic endemic country. Hydatidosis is a benign infection but can turn critical due to its multiple localizations. Surgery treatment remains to be the only one which absolutely heals. As it stands for, this should be taken in consideration with all cases.
Effects of medical and surgical therapy on postinfarction mortality rates.
Authors: P Peduzzi, K Detre, M L Murphy, J Thomsen, H Hultgren, T Takaro
Journal: Circulation (1991)

We are writing to express concern about the misinterpretation of our data that appeared in a recent article by Kahn and colleagues' and the accompanying editorial by Meier.2These articles addressed primary angioplasty for treatment of acute myocardial infarction, a strategy in which the guide wire and balloon catheter are used as a direct method to achieve myocardial reperfusion.Both papers allude to our recent report of complications in patients undergoing "rescue" coronary angioplasty of the right coronary artery3; this represents a distinctly different, de- layed application of angioplasty as a fallback means to restoring infarct vessel patency.4With respect to relative lack of complications in the series presented by Kahn et al compared with our experience, these authors state that "explanations for these major differences are not readily apparent."'Meier takes this further by stating: "The poor outcome of acute angioplasty in right coronary artery infarc- tion reported recently, however, was not confirmed ... as the reasons were hard to understand in the first place."2Our explanation for the discordance in results of right coronary artery intervention lies in the critical difference in patient characteristics.Patients who undergo primary angioplasty are at considerably less risk for mortality or major cardiac events than those who prove resistant to thrombolysis since they are relatively unselected and are having a first attempt at reperfusion.On the other hand, the rescue patients have had more protracted isch- emia, a higher likelihood of deep plaque rupture, propagation of coronary artery thrombus with aging, cross-linked fibrin increasing platelet content, and worse left ventricular function.4 6One cannot justifiably compare data between the two strategies as has been done in these articles.Furthermore, the complications and results from our center for rescue angioplasty of the right coronary artery have recently been confirmed in a much larger multicenter experience by Abbottsmith and colleagues.6For example, in the recent study of 165 patients, those with rescue of the right versus the left coronary had a marked increase in ventricular fibrillation (16% versus 9%) and secondor third-degree atrioventricular block (12% versus 1%), abrupt closure (11% versus 4%), and subsequent reocclusion (31% versus 17%), respectively.6It is quite clear that patients who acutely fail pharmacological thrombolysis of the right coronary artery have an increased periprocedural complication rate of rescue angioplasty.While the mechanism for this observation is not fully understood, it is important to acknowledge potential pitfalls of reperfusion therapies, especially when lack of judicious use can lead to key deleterious outcomes.
Asbestos-related cancer
Authors: James F. Gerrits, Philip J. Landrigan
Journal: CA A Cancer Journal for Clinicians (1996)

To the Editor: In the Guest Editorial on occupational cancer by Dr. Philip Landrigan in the March/April issue,1 I can't believe the statement that “more than 50 percent of asbestos workers die of asbestos-related cancer.” There are varying degrees of asbestos exposure depending on the workplace. Also, there are several types of asbestos and some have no association with cancer. Author's Reply: Asbestos is a proven human carcinogen. It has been declared carcinogenic by the US Environmental Protection Agency, the International Agency for Research on Cancer of the World Health Organization, and regulatory bodies in nations around the world.1,1 Asbestos can cause a variety of different cancers. These include malignant mesothelioma, lung cancer, cancer of the throat, cancer of the larynx, and gastrointestinal cancer.2 The relationship between asbestos and cancer was first recognized among workers who had been occupationally exposed as miners, shipbuilders, and insulation workers. Among these workers who labored directly with asbestos, the risk of asbestos-related cancer has been fearsome. More than 50 percent of the workers in some of these groups have subsequently died of lung cancer, malignant mesothelioma, and other asbestos-related diseases. These are the high-risk groups to whom I refer in my editorial. The high rate of malignancy observed among these groups illustrates the point that risks of occupational cancer are not distributed evenly across the American population. Instead, these risks are highly concentrated in those segments of our population who are most heavily exposed to carcinogens.3 Any degree of exposure to a proven carcinogen such as asbestos invovles some risk; no safe threshold level of exposure has been established. Clearly, however, the degree of risk is related to the degree of exposure. Risk increases with the extent and severity of exposure. Dr. Gerrits is quite correct in noting that the risk of asbestos exposure depends upon the degree of exposure. Dr. Gerrits is incorrect in asserting that some types of asbestos are safe. Contrary to Dr. Gerrits' claim, extensive clinical and epidemiologic research inde-icates that all forms of asbestos are fully capable of causing human malignancy.1,1 All three major types of asbestos—chrysotile, crocidolite, and amosite—have been shown in epidemiologic studies to cause lung cancer, malignant mesothelioma, and other cancers. Also in experimental studies, all forms of asbestos have been shown capable of inducing malignancy in laboratory animals. To be sure the asbestos industry, particularly the producers of Canadian chrysotile asbestos, the form of asbestos most commonly used in the United States, have claimed that certain forms of asbestos present little hazard to human health. The manufacturers have used those claims as the basis for extensive marketing campaigns overseas, particularly in developing countries.4,5 However, those claims are without factual basis. They resemble similar false claims made even to this day by the tobacco industry.
Upregulation of Xanthine Oxidase by Lipopolysaccharide, Interleukin-1, and Hypoxia
Authors: PAUL M. HASSOUN, FENG-SHENG YU, CLAUDIA G. COTE, JAVIER J. ZULUETA, RANEETA SAWHNEY, KELLY A. SKINNER, HENRY B. SKINNER, DALE A. PARKS, JOSEPH J. LANZILLO
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

LPS and selected cytokines upregulate xanthine dehydrogenase/xanthine oxidase (XDH/XO) in cellular systems. However, the effect of these factors on in vivo XDH/XO expression, and their contribution to lung injury, are poorly understood. Rats were exposed to normoxia or hypoxia for 24 h after treatment with LPS (1 mg/kg) and IL-1beta (100 microg/kg) or sterile saline. Lungs were then harvested for measurement of XDH/XO enzymatic activity and gene expression, and pulmonary edema was assessed by measurement of the wet/dry lung weight ratio (W/D). Although treatment with LPS + IL-1beta or hypoxia independently produced a 2-fold elevation (p < 0. 05 versus exposure to normoxia and treatment with saline) in lung XDH/XO activity and mRNA, the combination of LPS + IL-1beta and hypoxia caused a 4- and 3.5-fold increase in these values, respectively. XDH/XO protein expression was increased 2-fold by hypoxia alone and 1.3-fold by treatment with LPS + IL-1beta alone or combination treatment. Compared with normoxic lungs, W/D was significantly increased by exposure to hypoxia, LPS + IL-1beta, or combination treatment. This increase was prevented by treatment of the animals with tungsten, which abrogated lung XDH/XO activity. In conclusion, LPS, IL-1beta, and hypoxia significantly upregulate lung XDH/XO expression in vivo. The present data support a role for this enzyme in the pathogenesis of acute lung injury.
NY-ESO-1–specific TCR–engineered T cells mediate sustained antigen-specific antitumor effects in myeloma
Authors: Aaron P Rapoport, Edward A Stadtmauer, Gwendolyn K Binder-Scholl, Olga Goloubeva, Dan T Vogl, Simon F Lacey, Ashraf Z Badros, Alfred Garfall, Brendan Weiss, Jeffrey Finklestein, Irina Kulikovskaya, Sanjoy K Sinha, Shari Kronsberg, Minnal Gupta, Sarah Bond, Luca Melchiori, Joanna E Brewer, Alan D Bennett, Andrew B Gerry, Nicholas J Pumphrey, Daniel Williams, Helen K Tayton- Martin, Lilliam Ribeiro, Tom Holdich, Saul Yanovich, Nancy Hardy, Jean Yared, Naseem Kerr, Sunita Philip, Sandra Westphal, Don L Siegel, Bruce L Levine, Bent K Jakobsen, Michael Kalos, Carl H June
Journal: Nature Medicine (2015)
Bronchiolitis in children: summary of NICE guidance
Authors: Valentina Ricci, Vanessa Delgado Nunes, M Stephen Murphy, Steve Cunningham, Technical Team
Journal: BMJ (2015)

#### The bottom line

#### How patients were involved in the creation of this article

Committee members involved in the development of this guideline included two lay members who actively contributed to the formulation of the recommendations summarised here. 

Bronchiolitis is the most common lower respiratory tract infection in the first year of life: one in five infants is affected and 2-3% are admitted to hospital.1 The diagnosis is made on clinical evidence and clinicians need to be confident with their decision. An initial coryzal illness progresses over three to five days to troublesome cough, increased work of breathing, and difficulty feeding. Mild cases can be managed at home, but infants with severe respiratory distress, difficulty taking adequate oral fluids, or with apnoea require secondary care. There are no effective treatments and hospitals provide supportive care with oxygen and hydration. Parents should be told about red flag symptoms that need prompt clinical review and should be aware that symptoms (mostly cough) may persist for weeks after the acute illness.2

This article summarises the most recent recommendations from the National Institute for Health and Care Excellence (NICE) on how to diagnose and manage infants and children with bronchiolitis.3

NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the guideline development group’s experience and opinion of what constitutes good practice. …