Scholarly Works - Medicine - Clinical Pharmacology Unit


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  • ItemPublished versionOpen Access
    Quantitative analysis of dynamic 18F-FDG PET/CT for measurement of lung inflammation
    (Springer, 2017-05-25) Coello, C; Fisk, M; Mohan, D; Wilson, FJ; Brown, AP; Polkey, MI; Wilkinson, I; Tal-Singer, R; Murphy, PS; Cheriyan, J; Gunn, RN; Fisk, Marie [0000-0002-1292-7642]; Wilkinson, Ian [0000-0001-6598-9399]; Cheriyan, Joseph [0000-0001-6921-1592]
    $\textbf{Background:}$ An inflammatory reaction in the airways and lung parenchyma, comprised mainly of neutrophils and alveolar macrophages, is present in some patients with chronic obstructive pulmonary disease (COPD). Thoracic fluorodeoxyglucose $^{18}$F-FDG) positron emission tomography (PET) has been proposed as a promising imaging biomarker to assess this inflammation. We sought to introduce a fully quantitative analysis method and compare this with previously published studies based on the Patlak approach using a dataset comprising $^{18}$F-FDG PET scans from COPD subjects with elevated circulating inflammatory markers (fibrinogen) and matched healthy volunteers (HV). Dynamic $^{18}$F-FDG PET scans were obtained for high-fibrinogen (>2.8 g/l) COPD subjects (N = 10) and never smoking HV (N = 10). Lungs were segmented using co-registered computed tomography images and subregions (upper, middle and lower) were semi-automatically defined. A quantitative analysis approach was developed, which corrects for the presence of air and blood in the lung (qABL method), enabling direct estimation of the metabolic rate of FDG in lung tissue. A normalised Patlak analysis approach was also performed to enable comparison with previously published results. Effect sizes (Hedge's g) were used to compare HV and COPD groups. $\textbf{Results:}$ The qABL method detected no difference (Hedge's g = 0.15 [-0.76 1.04]) in the tissue metabolic rate of FDG in the whole lung between HV (μ = 6.0 ± 1.9 × 10$^{-3}$ ml cm$^{-3}$ min$^{-1}$) and COPD (μ = 5.7 ± 1.7 × 10$^{-3}$ ml cm$^{-3}$ min$^{-1}$). However, analysis with the normalised Patlak approach detected a significant difference (Hedge's g = -1.59 [-2.57 -0.48]) in whole lung between HV (μ = 2.9 ± 0.5 × 10$^{-3}$ ml cm$^{-3}$ min$^{-1}$) and COPD (μ = 3.9 ± 0.7 × 10$^{-3}$ ml cm$^{-3}$ min$^{-1}$). The normalised Patlak endpoint was shown to be a composite measure influenced by air volume, blood volume and actual uptake of $^{18}$F-FDG in lung tissue. $\textbf{Conclusions:}$ We have introduced a quantitative analysis method that provides a direct estimate of the metabolic rate of FDG in lung tissue. This work provides further understanding of the underlying origin of the $^{18}$F-FDG signal in the lung in disease groups and helps interpreting changes following standard or novel therapies.
  • ItemOpen Access
    Monotherapy versus dual therapy for the initial treatment of hypertension (PATHWAY-1): a randomised double-blind controlled trial.
    (BMJ, 2015-08-07) MacDonald, Thomas M; Williams, Bryan; Caulfield, Mark; Cruickshank, J Kennedy; McInnes, Gordon; Sever, Peter; Webb, David J; Mackenzie, Isla S; Salsbury, Jackie; Morant, Steve; Ford, Ian; Brown, Morris J
    INTRODUCTION: Previous studies have suggested that more intensive initial therapy for hypertension results in better long-term blood pressure (BP) control. We test this hypothesis comparing initial monotherapy with dual therapy in the management of essential hypertension. METHODS AND ANALYSIS: The study is a prospective, multicentre, double-blind, active-controlled trial in patients with essential hypertension. Around 50% of patients studied will be newly diagnosed and the others will be known hypertensives who previously received only monotherapy. The trial is divided into three phases as follows: Phase 1 (Week 0-Week 16): Randomised, parallel-group, masked assignation to either combination or monotherapy. Phase 2 (Week 17-Week 32): Open-label combination therapy. Phase 3 (Week 33-Week 52): Open-label combination therapy plus open-label add-on (if BP is above 140/90 mm Hg). Hierarchical primary end points are: a comparison of home BP (home systolic blood pressure (HSBP)) averaged over the duration of phase 1 and 2 in the combination versus monotherapy arms. If combination is superior in this analysis, then the averaged mean HSBP between initial monotherapy and initial combination therapy at the end of phase 2 will be compared. Secondary end points include: BP control at 1 year; the role of age, baseline renin, sodium status, plasma volume, haemodynamic compensation and peripheral resistance on BP control; validation of the National Institute for Clinical Excellence/British Hypertension Society joint guideline algorithm; safety and tolerability of combination therapy; and the impact of combination versus monotherapy on left ventricular mass and aortic pulse wave velocity. A sample size of 536 (268 in each group) will have 90% power to detect a difference in means of 4 mm Hg. ETHICS AND DISSEMINATION: PATHWAY 1 was approved by UK ethics (REC Reference 09/H0308/132). Trial results will be published and all participating subjects will be informed of the results. TRIAL REGISTRATION NUMBER: UKCRN 4499 and EudraCT number 2008-007749-29 registered 27/08/2009.