Selina Tsim

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

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.

British Thoracic Society Guideline for the investigation and management of malignant pleural mesothelioma

Section 3: Clinical features which predict the presence of mesothelioma Recommendations Section 4: Staging systems Recommendation Section 5: Imaging modalities for diagnosing and staging Recommendations Section 6: Pathological diagnosis Recommendations

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.

Early Contrast Enhancement: a novel Magnetic Resonance Imaging biomarker of pleural malignancy

Highlights • A novel MRI biomarker of pleural malignancy is described – Early Contrast Enhancement.• Early Contrast Enhancement is a semi-objective, perfusion-based biomarker.• Early Contrast Enhancement can be measured in patients with minimal pleural thickening.

BTS guideline for the investigation and management of malignant pleural mesothelioma

The full guideline for the investigation and management of malignant pleural mesothelioma is published in Thorax. The following is a summary of the recommendations and good practice points. The sections referred to in the summary refer to the full guideline.

S26 Identification and prognostic importance of non-expansile lung following drainage of suspected malignant pleural effusion

Introduction Malignant Pleural Effusion (MPE) is common and often Results in disabling breathlessness. Non-expansile lung (NEL) frequently complicates pleural drainage, resulting in talc pleurodesis failure. Reliable detection of NEL would allow better clinical decision-making and more rational design of MPE trials. We developed 2 semi-objective definitions of NEL, which we hypothesised might prove more accurate and more consistent than the currently used subjective British Thoracic Society (BTS) method. Materials and Methods A retrospective cohort study was performed, involving 93 consecutive patients who underwent local anaesthetic thoracoscopy at our centre (July 2010- January 2015). NEL was defined prospectively at 3 month follow-up in all. Post-drainage chest radiographs were retrospectively classified as ‘NEL’ or ‘expansile’ by 2 independent assessors using the subjective BTS method and the 2 semi-objective methods (Re-expansion Proportion (REP) and Lateral Apposition Ratio (LAR), shown in figure 1). Sensitivity, Specificity and Inter-observer Agreement (Cohen’s Kappa, k) for NEL by each method were compared. Overall Survival (OS) based on expansion status by each method was compared using Kaplan-Meier methodology (MPE cases only). Results 65/93 patients had MPE. Sensitivity (0.81 (95%CI 0.71–0.89)) and specificity (0.87 (95%CI 0.81–1.00)) by the BTS method were highest. REP (sensitivity 0.61 (95%CI 0.49–0.72), specificity 0.94 (95%CI 0.73–1.00)) and LAR (sensitivity 0.56 (95%CI 0.44–0.67), specificity 0.94 (95%CI 0.73–1.00)) were less accurate. Inter-rater agreement (k) for BTS, REP, LAR were 0.68, 0.46 and 0.53, respectively. In MPE patients, NEL was consistently associated with a 2–4-fold lower median OS by all methods. Discussion The subjective BTS method appeared more accurate in predicting NEL than REP or LAR in this retrospective study, however all methods were subject to significant inter-observer variation. NEL is strongly associated with mortality. Our data highlight the clinical importance of NEL and its potential impact on MPE trial design, but do not strongly support any of these reported end-points as reliable clinical decision-making tools, trial end-points, or entry/stratification criteria. Further prospective research is needed to standardise the definition of NEL for these purposes, ideally prior to pleural drainage, and link this to patient-centred end-points. Abstract S26 Figure 1 Semi-objective definitions of non-expansile lung (NEL) including worked examples and screenshots from Vue PACS v13 (Carestream Health Inc., Rochester, NY).

Pre-EDIT: protocol for a randomised feasibility trial of elastance-directed intrapleural catheter or talc pleurodesis (EDIT) in malignant pleural effusion

Introduction Non-expansile lung (NEL) is a common cause of talc pleurodesis (TP) failure in malignant pleural effusion (MPE), but is often occult prior to drainage. Reliable detection of NEL would allow patients to be allocated between intrapleural catheter (IPC) and TP. High pleural elastance (PEL) has been associated with NEL in observational studies. Pre-EDIT is a randomised feasibility trial of elastance-directed IPC or TP (EDIT) management using a novel, purpose-built digital pleural manometer (Rocket Medical, UK). Methods and analysis Consecutive patients with MPE without prior evidence of NEL or preference for IPC will be randomised 1:1 between EDIT management and standard care (an attempt at TP). The primary objective is to determine whether sufficient numbers of patients (defined as 30 within 12 months (or 15 over 6 months)) can be recruited and randomised to justify a subsequent phase III trial testing the efficacy of EDIT management. Secondary objectives include safety, technical feasibility and validation of study design elements, including the definition of PEL using 4D pleural MRI before and after fluid aspiration. EDIT involves PEL assessment during a large volume pleural fluid aspiration, followed by an attempt at TP or placement of an IPC within 24 hours. Patients will be allocated to IPC if the rolling average PEL sustained over at least 250 mL fluid aspirated (PEL250) is ≥ 14.5 cm H2O/L. Ethics and dissemination Pre-EDIT was approved by the West of Scotland Regional Ethics Committee on 8 March 2017 (Ref: 17/WS/0042). Results will be presented at scientific meetings and published in peer-reviewed journals. Trial registration number NCT03319186; Pre-results.