Kevin G. Blyth

Changes in Right Ventricular Function Measured by Cardiac Magnetic Resonance Imaging in Patients Receiving Pulmonary Arterial Hypertension–Targeted Therapy The EURO-MR Study

Background—Most measures that predict survival in pulmonary hypertension (PH) relate directly to, or correlate with, right ventricular (RV) function. Direct assessment of RV function using noninvasive techniques such as cardiac MRI may therefore be an appropriate way of determining response to therapy and monitoring disease progression in PH. Methods and Results—In this pan-European study, 91 patients with PH (mean pulmonary arterial pressure 46±15 mm Hg) underwent clinical and cardiac MRI assessments at baseline and after 12 months of disease-targeted therapy (predominantly endothelin receptor antagonists [47.3%] or phosphodiesterase type-5 inhibitors [25.3%]). At month 12, functional class had improved in 21 patients, was unchanged in 63 patients, and had deteriorated in 7 patients. Significant improvements were achieved in RV and left ventricular ejection fraction (P<0.001 and P=0.0007, respectively), RV stroke volume index (P<0.0001), and left ventricular end-diastolic volume index (P=0.0015). Increases in 6-minute walk distance were significant (P<0.0001) and correlated with change in RV ejection fraction and left ventricular end-diastolic volume, although correlation coefficients were low (r=0.28, P=0.01 and r=0.26, P=0.02, respectively). Conclusions—On-treatment changes in cardiac MRI–derived variables from left and right sides of the heart reflected changes in functional class and survival in patients with PH. Direct measurement of RV function using cardiac MRI can fully assess potential benefits of treatment in PH.

Imaging in pleural mesothelioma: a review of the 13th International Conference of the International Mesothelioma Interest Group

Imaging plays an important role in the detection, diagnosis, staging, response assessment, and surveillance of malignant pleural mesothelioma. The etiology, biology, and growth pattern of mesothelioma present unique challenges for each modality used to capture various aspects of this disease. Clinical implementation of imaging techniques and information derived from images continue to evolve based on active research in this field worldwide. This paper summarizes the imaging-based research presented orally at the 2016 International Conference of the International Mesothelioma Interest Group (iMig) in Birmingham, United Kingdom, held May 1-4, 2016. Presented topics included intraoperative near-infrared imaging of mesothelioma to aid the assessment of resection completeness, an evaluation of tumor enhancement improvement with increased time delay between contrast injection and image acquisition in standard clinical magnetic resonance imaging (MRI) scans, the potential of early contrast enhancement analysis to provide MRI with a role in mesothelioma detection, the differentiation of short- and long-term survivors based on MRI tumor volume and histogram analysis, the response-assessment potential of hemodynamic parameters derived from dynamic contrast-enhanced computed tomography (DCE-CT) scans, the correlation of CT-based tumor volume with post-surgical tumor specimen weight, and consideration of the need to update the mesothelioma tumor response assessment paradigm.

Malignant pleural mesothelioma: an update on investigation, diagnosis and treatment.

Malignant pleural mesothelioma is an aggressive malignancy of the pleural surface, predominantly caused by prior asbestos exposure. There is a global epidemic of malignant pleural mesothelioma underway, and incidence rates are predicted to peak in the next few years. This article summarises the epidemiology and pathogenesis of malignant pleural mesothelioma, before describing some key factors in the patient experience and outlining common symptoms. Diagnostic approaches are reviewed, including imaging techniques and the role of various biomarkers. Treatment options are summarised, including the importance of palliative care and methods of controlling pleural effusions. The evidence for chemotherapy, radiotherapy and surgery is reviewed, both in the palliative setting and in the context of trimodality treatment. An algorithm for managing malignant pleural effusion in malignant pleural mesothelioma patients is presented. Finally new treatment developments and novel therapeutic approaches are summarised. This article on mesothelioma describes pathogenesis, symptoms, diagnostic approaches and treatment options http://ow.ly/cjkb305aQGz

Measurement of Pulse Wave Velocity using Magnetic Resonance Imaging

Arterial stiffness has a strong relationship with cardiovascular disease. Pulse wave velocity (PWV) is increasingly used as a measure of arterial stiffness. The calculation of PWV requires accurate measurement of blood flow velocity and aortic length. Using magnetic resonance imaging (MRI), we are able to accurately acquire blood flow velocity and to virtually measure the aortic length inside the central aorta. Manual measurement of aorta length is inaccurate and subjective. In this study, we set out to develop a method which automatically locates the thoracic aorta and measures aortic length, allowing noninvasive measurement of PWV derived from the aortic flow. Our method is novel, efficient and robust. This offers a reliable and convenient tool for PWV measurement allowing detailed non invasive assessment of cardiovascular risk.

Dose de-escalation of intrapleural tissue plasminogen activator therapy for pleural infection the alteplase dose assessment for pleural infection therapy project

Rationale: Intrapleural therapy with a combination of tissue plasminogen activator (tPA) 10 mg and DNase 5 mg administered twice daily has been shown in randomized and open‐label studies to successfully manage over 90% of patients with pleural infection without surgery. Potential bleeding risks associated with intrapleural tPA and its costs remain important concerns. The aim of the ongoing Alteplase Dose Assessment for Pleural infection Therapy (ADAPT) project is to investigate the efficacy and safety of dose de‐escalation for intrapleural tPA. The first of several planned studies is presented here. Objectives: To evaluate the efficacy and safety of a reduced starting dose regimen of 5 mg of tPA with 5 mg of DNase administered intrapleurally for pleural infection. Methods: Consecutive patients with pleural infection at four participating centers in Australia, the United Kingdom, and New Zealand were included in this observational, open‐label study. Treatment was initiated with tPA 5 mg and DNase 5 mg twice daily. Subsequent dose escalation was permitted at the discretion of the attending physician. Data relating to treatment success, radiological and systemic inflammatory changes (blood C‐reactive protein), volume of fluid drained, length of hospital stay, and treatment complications were extracted retrospectively from the medical records. Results: We evaluated 61 patients (41 males; age, 57 ± 16 yr). Most patients (n = 58 [93.4%]) were successfully treated without requiring surgery for pleural infection. Treatment success was corroborated by clearance of pleural opacities visualized by chest radiography (from 42% [interquartile range, 22‐58] to 16% [8‐31] of hemithorax; P < 0.001), increase in pleural fluid drainage (from 175 ml in the 24 h preceding treatment to 2,025 ml [interquartile range, 1,247‐2,984] over 72 h of therapy; P < 0.05) and a reduction in blood C‐reactive protein (P < 0.05). Seven patients (11.5%) had dose escalation of tPA to 10 mg. Three patients underwent surgery. Three patients (4.9%) received blood transfusions for gradual pleural blood loss; none were hemodynamically compromised. Pain requiring escalation of analgesia affected 36% of patients; none required cessation of therapy. Conclusions: These pilot data suggest that a starting dose of 5 mg of tPA administered intrapleurally twice daily in combination with 5 mg of DNase for the treatment of pleural infection is safe and effective. This regimen should be tested in future randomized controlled trials.

Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma (DIAPHRAGM) study: protocol of a prospective, multicentre, observational study.

Introduction Malignant pleural mesothelioma (MPM) is an asbestos-related cancer, which is difficult to diagnose. Thoracoscopy is frequently required but is not widely available. An accurate, non-invasive diagnostic biomarker would allow early specialist referral, limit diagnostic delays and maximise clinical trial access. Current markers offer insufficient sensitivity and are not routinely used. The SOMAmer proteomic classifier and fibulin-3 have recently demonstrated sensitivity and specificity exceeding 90% in retrospective studies. DIAPHRAGM (Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma) is a suitably powered, multicentre, prospective observational study designed to determine whether these markers provide clinically useful diagnostic and prognostic information. Methods and analysis Serum and plasma (for SOMAscan and fibulin-3, respectively) will be collected at presentation, prior to pleural biopsy/pleurodesis, from 83 to 120 patients with MPM, at least 480 patients with non-MPM pleural disease and 109 asbestos-exposed controls. Final numbers of MPM/non-MPM cases will depend on the incidence of MPM in the study population (estimated at 13–20%). Identical sampling and storage protocols will be used in 22 recruiting centres and histological confirmation sought in all cases. Markers will be measured using the SOMAscan proteomic assay (SomaLogic) and a commercially available fibulin-3 ELISA (USCN Life Science). The SE in the estimated sensitivity and specificity will be <5% for each marker and their performance will be compared with serum mesothelin. Blood levels will be compared with paired pleural fluid levels and MPM tumour volume (using MRI) in a nested substudy. The prognostic value of each marker will be assessed and a large bioresource created. Ethics and dissemination The study has been approved by the West of Scotland Research Ethics Committee (Ref: 13/WS/0240). A Trial Management Group meets on a monthly basis. Results will be published in peer-reviewed journals, presented at international meetings and disseminated to patient groups. Trial registration number ISRCTN10079972, Pre-results.

The diagnostic performance of routinely acquired and reported computed tomography imaging in patients presenting with suspected pleural malignancy

Highlights • The sensitivity of routinely performed CT for pleural malignancy was only 58%.• Nearly half of the malignant cases had a benign CT (negative predictive value 54%).• CTPA and non-specialist radiology reporting were associated with lower sensitivity.• CT specificity was 80%, and was not affected by use of CTPA or specialist reporting.• Pleural malignancy is frequently occult on routinely acquired CT imaging.

Inconsistent results or inconsistent methods? A plea for standardisation of biomarker sampling in mesothelioma studies

Reproducibility is a quality that all biomarkers must demonstrate before entering the clinical arena. In Octobers issue of Thorax , Creaney et al 1 reported important diagnostic performance data regarding fibulin-3 in malignant pleural mesothelioma (MPM). Their results (plasma area under the curve (AUC) 0.671, sensitivity 21%) are remarkably discordant with those reported by Pass et al ,2 using the same assay in a similarly designed study (plasma AUC 0.974–0.997, sensitivity 97%). Although some discordance is expected, this pattern is common in the MPM biomarker …

Assessment of the Presence of Occult Myocardial Infarction in Chronic Obstructive Pulmonary Disease Using Contrast-Enhanced Cardiac Magnetic Resonance Imaging

Background: Chronic obstructive pulmonary disease (COPD) has been identified as a risk factor for ischaemic heart disease, independent of smoking history, and inflammation is thought to play a role. Objectives: We sought to ascertain whether occult myocardial infarction (MI) was present in the COPD population, and to assess its relationship with inflammation and natriuretic peptides. Method: We recruited 25 patients with moderate/severe COPD and 17 control smokers without lung disease. All participants had no known cardiac disease. Contrast-enhanced cardiac magnetic resonance imaging was performed and analysed for delayed contrast enhancement (DE), indicative of previous MI. All participants had venous blood samples taken for assessment of NT-proBNP and inflammatory markers. Results: DE was not found in any participant. Right ventricular ejection fraction was lower in COPD patients. Other cardiac measurements and NT-proBNP levels were similar in the 2 groups. C-reactive protein, IL-8, GM-CSF, IL-1β and TNF-α were all significantly higher in the COPD group. Conclusion: DE, indicating previous MI, was not found in patients with moderate/severe COPD. Occult MI does not appear to be common in this population, but a larger study would be needed to conclusively test this.

S21 Early Contrast Enhancement: A Perfusion-based Magnetic Resonance Imaging Biomarker of Pleural Malignancy

Introduction and objectives Radiological detection of pleural malignancy (PM) remains challenging. In early-stage Malignant Pleural Mesothelioma (MPM) a pleural effusion may be the only significant abnormality, indistinguishable from benign asbestos-related pleural effusion (BAPE). PM is associated with neovascularisation. We report the diagnostic performance of a novel perfusion-based Magnetic Resonance Imaging (MRI) biomarker of PM – Early Contrast Enhancement (ECE). Methods 24 patients with suspected PM were recruited prospectively. All underwent contrast-enhanced Computed Tomography (CT) scanning, 3T Pleural MRI and Thoracoscopy. 18/24 had complete MRI examinations: T1-weighted 3D-spoiled-gradient-echo sequences acquired at baseline, 40 s, 80 s and 4.5, 9 and 13.5 min after intravenous Gadobutrol contrast. Mean signal intensity (SI) of representative parietal pleura was derived from 15 regions of interest placed by two respiratory physicians. ECE was defined objectively by an early peak in mean SI (≤4.5 min) on the resulting SI/time curve (Figure 1). Morphology suggestive of PM on CT and MRI was recorded by two thoracic radiologists. Diagnostic performance and inter-observer agreement for ECE, MRI and CT morphology were compared. All analyses were blinded. Pleural SI data were correlated against Microvessel Density (MVD) measured in paraffin-embedded pleural biopsies stained with CD34 and Factor VIII immunostains. Results Mean patient age was 73 (SD 8) years. 18/24 were asbestos-exposed and 12/18 had pleural thickening ≤5 mm. ECE was present in 10/11 patients with PM (MPM (n = 10); lung cancer (n = 1)). The false negative case had MPM. ECE was absent in 6/7 patients with benign pleural disease (BAPE (n = 4), fibrothorax (n = 2), TB (n = 1)). The false positive case had TB. Overall diagnostic accuracy of ECE, MRI and CT morphology: sensitivity 91%, 91%, 90%; specificity 86%, 71%, 50%; negative predictive value 86%, 83%, 80%; positive predictive value 91%, 83%, 69% respectively. Inter-observer agreement was 0.766 for ECE, 0.727 for MRI and 0.753 for CT. Figure 1 shows the relationship between MVD and Pleural SI.Abstract S21 Figure 1 Example of 3D T1-weighted Pleural MR images acquired 4.5 minutes post-Gadobutrol in 2 different patients – one with BAPE (Panel A) and one with early-satge MPM (Panel B). Panels C and D show the accompanying partietal pleura SI/time curves for each patient (Panel C: patient with BAPE – ECE absent, panel D: patient with MPM – ECE present). Panels E and F demonstrate the relationship between peak signal intensity gradient in patients with pleural malignancy and Microvessel Density measured in diseased tissue with CD34 immunostain (Panel E) and Factor VIII immunostain (Panel F) Conclusions ECE appears an accurate and reproducible, perfusion-based, objective biomarker of PM, out-performing subjectively-defined CT and MR morphology. ECE assessment can be performed in patients with minimal pleural thickening, suggesting potential utility as a biomarker of early-stage MPM or low-volume metastatic PM.