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Lockstone H.E.,University of Oxford | Sanderson S.,Weatherall Institute of Molecular Medicine | Kulakova N.,Weatherall Institute of Molecular Medicine | Baban D.,University of Oxford | And 6 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2010

Rationale: Approximately 60 to 70% of patients with pulmonary sarcoidosis have disease that resolves spontaneously; the rest follow a chronic course with varying levels of fibrosis. It is unclear why some patients progress and if treatment affects outcome. Objectives: To determine differential gene expression profile in lungs of patients with self-limiting sarcoidosis compared to those with progressive-fibrotic disease, and to analyze the biological relevance of these differentially expressed genes. Methods: We examined microarray expression of 26,626 genes in transbronchial biopsies of granulomatous areas in lungs of patients with active but self-limiting (n = 8) versus those with active, progressive (± fibrotic) pulmonary disease (n = 7). Measurements and Main Results: Three hundred thirty-four genes were differentially expressed between the two groups (P < 0.01, Bayesian moderated t test). Gene Set Enrichment Analysis showed over-representation of gene-sets (defined by Gene Ontology) related to host immune activation, proliferation, and defense, among genes up-regulated in the progressive-fibrotic group (FDR q < 0.0001 for the top 43 gene sets), and a marked enrichment of, and similarity in gene expression profiles between, progressive-fibrotic sarcoidosis and hypersensitivity pneumonitis (HP), (q < 0.001), but not idiopathic pulmonary fibrosis (IPF). Conclusions: The findings suggest that patients with progressive/fibrotic pulmonary sarcoidosis have intense immune activity related to host defense in their lungs, with processes more similar to HP than IPF. The study also demonstrates that transbronchial lung biopsy samples can provide good-quality RNA for gene expression profiling, supporting its potential use as a prognostic classifier for pulmonary sarcoidosis.


Denney L.,Weatherall Institute of Molecular Medicine | Aitken C.,Gartnavel General Hospital | Li C.K.-F.,Weatherall Institute of Molecular Medicine | Wilson-Davies E.,Gartnavel General Hospital | And 9 more authors.
PLoS ONE | Year: 2010

Background: The cause of severe disease in some patients infected with pandemic influenza A virus is unclear. Methodology/Principal Findings: We present the cellular immunology profile in the blood, and detailed clinical (and postmortem) findings of three patients with rapidly progressive infection, including a pregnant patient who died. The striking finding is of reduction in natural killer (NK) cells but preservation of activated effector CD8 T lymphocytes; with viraemia in the patient who had no NK cells. Comparison with control groups suggests that the reduction of NK cells is unique to these severely ill patients. Conclusion/Significance: Our report shows markedly reduced NK cells in the three patients that we sampled and raises the hypothesis that NK may have a more significant role than T lymphocytes in controlling viral burden when the host is confronted with a new influenza A virus subtype. © 2010 Denney et al.


Gunatilake S.,Portsmouth Hospitals NHS Trust | Brims F.J.H.,Sir Charles Gairdner Hospital | Fogg C.,University of Portsmouth | Lawrie I.,University of Manchester | And 9 more authors.
Trials | Year: 2014

Background: Malignant pleural mesothelioma is an incurable cancer caused by exposure to asbestos. The United Kingdom has the highest death rate from mesothelioma in the world and this figure is increasing. Median survival is 8 to 12 months, and most patients have symptoms at diagnosis. The fittest patients may be offered chemotherapy with palliative intent. For patients not fit for systemic anticancer treatment, best supportive care remains the mainstay of management. A study from the United States examining advanced lung cancer showed that early specialist palliative care input improved patient health related quality of life and depression symptoms 12 weeks after diagnosis. While mesothelioma and advanced lung cancer share many symptoms and have a poor prognosis, oncology and palliative care services in the United Kingdom, and many other countries, vary considerably compared to the United States. The aim of this trial is to assess whether regular early symptom control treatment provided by palliative care specialists can improve health related quality of life in patients newly diagnosed with mesothelioma. Methods: This multicentre study is an non-blinded, randomised controlled, parallel group trial. A total of 174 patients with a new diagnosis of malignant pleural mesothelioma will be minimised with a random element in a 1:1 ratio to receive either 4weekly regular early specialist symptom control care, or standard care. The primary outcome is health related quality of life for patients at 12 weeks. Secondary outcomes include health related quality of life for patients at 24 weeks, carer health related quality of life at 12 and 24 weeks, patient and carer mood at 12 and 24 weeks, overall survival and analysis of healthcare utilisation and cost. Discussion: Current practice in the United Kingdom is to involve specialist palliative care towards the final weeks or months of a life-limiting illness. This study aims to investigate whether early, regular specialist care input can result in significant health related quality of life gains for patients with mesothelioma and if this change in treatment model is cost-effective. The results will be widely applicable to many institutions and patients both in the United Kingdom and internationally. Trial registration: Current controlled trials ISRCTN18955704.Date ISRCTN assigned: 31 January 2014. © 2014 Gunatilake et al.; licensee BioMed Central Ltd.


Kohler M.,University of Zürich | Stradling J.R.,Oxford Center for Respiratory Medicine
Expert Opinion on Investigational Drugs | Year: 2011

The standard treatment for obstructive sleep apnoea (OSA) is continuous positive airway pressure (CPAP). Depending on selection criteria and quality of care, up to 50% of patients with OSA do not tolerate CPAP. For patients who cannot tolerate CPAP despite good quality care, pharmacological treatment would be a desirable alternative. The mechanisms by which pharmacological treatment is supposed to improve OSA include, amongst others, an augmentation in pharyngeal dilator muscle tone, an increase in ventilatory drive, a reduction in airway resistance and alterations in pharyngeal surface tension forces. In humans, most recent pharmacological approaches to the treatment of OSA in clinical trials have focused on modulating serotoninergic and cholinergic activities, as both have been shown to augment pharyngeal dilator muscle tone. However, currently there is not enough evidence to recommend any particular drug treatment for OSA. Methodological issues of published clinical trials on pharmacological OSA treatment make it difficult to draw definitive conclusions and inform further drug developments in this area. In this article, the pitfalls of clinical trials on pharmacological OSA therapy are summarised and potential solutions and directions for future studies are given. © 2011 Informa UK, Ltd.


Kahan B.C.,Queen Mary, University of London | Cro S.,University College London | Dore C.J.,University College London | Bratton D.J.,University College London | And 4 more authors.
Trials | Year: 2015

Background: Blinded outcome assessment is recommended in open-label trials to reduce bias, however it is not always feasible. It is therefore important to find other means of reducing bias in these scenarios. Methods: We describe two randomised trials where blinded outcome assessment was not possible, and discuss the strategies used to reduce the possibility of bias. Results: TRIGGER was an open-label cluster randomised trial whose primary outcome was further bleeding. Because of the cluster randomisation, all researchers in a hospital were aware of treatment allocation and so could not perform a blinded assessment. A blinded adjudication committee was also not feasible as it was impossible to compile relevant information to send to the committee in a blinded manner. Therefore, the definition of further bleeding was modified to exclude subjective aspects (such as whether symptoms like vomiting blood were severe enough to indicate the outcome had been met), leaving only objective aspects (the presence versus absence of active bleeding in the upper gastrointestinal tract confirmed by an internal examination). Conclusions: When blinded outcome assessment is not possible, it may be useful to modify the outcome definition or method of assessment to reduce the risk of bias. Trial registration: TRIGGER: ISRCTN85757829. Registered 26 July 2012. © 2014 Kahan et al.; licensee BioMed Central Ltd.


Simoff M.J.,Ford Motor Company | Lally B.,University of Miami | Slade M.G.,Oxford Center for Respiratory Medicine | Goldberg W.G.,Ford Motor Company | And 4 more authors.
Chest | Year: 2013

Background: Many patients with lung cancer will develop symptoms related to their disease process or the treatment they are receiving. These symptoms can be as debilitating as the disease progression itself. To many physicians these problems can be the most difficult to manage. Methods: A detailed review of the literature using strict methodologic review of article quality was used in the development of this article. MEDLINE literature reviews, in addition to Cochrane reviews and other databases, were used for this review. The resulting article lists were then reviewed by experts in each area for quality and finally interpreted for content. Results: We have developed recommendations for the management of many of the symptom complexes that patients with lung cancer may experience: pain, dyspnea, airway obstruction, cough, bone metastasis, brain metastasis, spinal cord metastasis, superior vena cava syndrome, hemoptysis, tracheoesophageal fistula, pleural effusions, venous thromboembolic disease, depression, fatigue, anorexia, and insomnia. Some areas, such as dyspnea, are covered in considerable detail in previously created high-quality evidence-based guidelines and are identified as excellent sources of reference. The goal of this guideline is to provide the reader recommendations based on evidence supported by scientific study. Conclusions: Improved understanding and recognition of cancer-related symptoms can improve management strategies, patient compliance, and quality of life for all patients with lung cancer. Copyright © by the American College of Chest Physicians 2013.


Hallifax R.J.,Oxford Center for Respiratory Medicine | Hallifax R.J.,University of Oxford | Corcoran J.P.,Oxford Center for Respiratory Medicine | Corcoran J.P.,University of Oxford | And 12 more authors.
Chest | Year: 2014

BACKGROUND: Definitive diagnosis of pleural disease (particularly malignancy) depends upon histologic proof obtained via pleural biopsy or positive pleural fluid cytology. Image-guided sampling is now standard practice. Local anesthetic thoracoscopy has a high diagnostic yield for malignant and nonmalignant disease, but is not always possible in frail patients, if pleural fluid is heavily loculated, or where the lung is adherent to the chest wall. Such cases can be converted during the same procedure as attempted thoracoscopy to cutting-needle biopsy. Th is study aimed to determine the diagnostic yield of a physician-led service in both planned biopsies and cases of failed thoracoscopy.METHODS: Th is study was a retrospective review of all ultrasound-guided, cutting-needle biopsies performed at the Oxford Centre for Respiratory Medicine between January 2010 and July 2013. Histologic results were assessed for the yield of pleural tissue, final diagnosis, and clinical follow-up in nonmalignant cases.RESULTS: Fift y ultrasound-guided biopsies were undertaken. Overall, 47 (94.0%) successfully obtained sufficient tissue for histologic diagnosis. Of the 50 biopsy procedures, 13 were conducted aft er failed thoracoscopy (5.2% of 252 attempted thoracoscopies over the same time period); of these 13, 11 (84.6%) obtained sufficient tissue. Th irteen of 50 biopsy specimens (26.0%) demonstrated pleural malignancy on histology (despite previous negative pleural fluid cytology), while 34 specimens (68.0%) were diagnosed as benign. Of the benign cases, 10 were pleural TB, two were sarcoidosis, and 22 were benign pleural thickening. There was one "false negative" of mesothelioma (median follow-up, 16 months).CONCLUSIONS: Within this population, physician-based, ultrasound-guided, cutting-needle pleural biopsy obtained pleural tissue successfully in a high proportion of cases, including those of failed thoracoscopy. © 2014 American College of Chest Physicians.

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