Fully automated volumetric measurement of malignant pleural mesothelioma by deep learning AI: validation and comparison with modified RECIST response criteria.

BACKGROUND: In malignant pleural mesothelioma (MPM), complex tumour morphology results in inconsistent radiological response assessment. Promising volumetric methods require automation to be practical. We developed a fully automated Convolutional Neural Network (CNN) for this purpose, performed blinded validation and compared CNN and human response classification and survival prediction in patients treated with chemotherapy. METHODS: In a multicentre retrospective cohort study; 183 CT datasets were split into training and internal validation (123 datasets (80 fully annotated); 108 patients; 1 centre) and external validation (60 datasets (all fully annotated); 30 patients; 3 centres). Detailed manual annotations were used to train the CNN, which used two-dimensional U-Net architecture. CNN performance was evaluated using correlation, Bland-Altman and Dice agreement. Volumetric response/progression were defined as ≤30%/≥20% change and compared with modified Response Evaluation Criteria In Solid Tumours (mRECIST) by Cohen's kappa. Survival was assessed using Kaplan-Meier methodology. RESULTS: Human and artificial intelligence (AI) volumes were strongly correlated (validation set r=0.851, p<0.0001). Agreement was strong (validation set mean bias +31 cm3 (p=0.182), 95% limits 345 to +407 cm3). Infrequent AI segmentation errors (4/60 validation cases) were associated with fissural tumour, contralateral pleural thickening and adjacent atelectasis. Human and AI volumetric responses agreed in 20/30 (67%) validation cases κ=0.439 (0.178 to 0.700). AI and mRECIST agreed in 16/30 (55%) validation cases κ=0.284 (0.026 to 0.543). Higher baseline tumour volume was associated with shorter survival. CONCLUSION: We have developed and validated the first fully automated CNN for volumetric MPM segmentation. CNN performance may be further improved by enriching future training sets with morphologically challenging features. Volumetric response thresholds require further calibration in future studies.

Intrapleural Fibrinolytics and Deoxyribonuclease for Treatment of Indwelling Pleural Catheter-Related Pleural Infection: A Multi-Center Observational Study.

BACKGROUND: Indwelling pleural catheters (IPC) are increasingly used for management of recurrent (especially malignant) effusions. Pleural infection associated with IPC use remains a concern. Intrapleural therapy with tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) significantly reduces surgical referrals in non-IPC pleural infection, but data on its use in IPC-related pleural infection are scarce. OBJECTIVE: To assess the safety and efficacy of intrapleural tPA and DNase in IPC-related pleural infection. METHODS: Patients with IPC-related pleural infection who received intrapleural tPA/DNase in five Australian and UK centers were identified from prospective databases. Outcomes on feasibility of intrapleural tPA/DNase delivery, its efficacy and safety were recorded. RESULTS: Thirty-nine IPC-related pleural infections (predominantly Staphylococcus aureus and gram-negative organisms) were treated in 38 patients; 87% had malignant effusions. In total, 195 doses (median 6 [IQR = 3-6]/patient) of tPA (2.5 mg-10 mg) and DNase (5 mg) were instilled. Most (94%) doses were delivered via IPCs using local protocols for non-IPC pleural infections. The mean volume of pleural fluid drained during the first 72 h of treatment was 3,073 (SD = 1,685) mL. Most (82%) patients were successfully treated and survived to hospital discharge without surgery; 7 required additional chest tubes or therapeutic aspiration. Three patients required thoracoscopic surgery. Pleurodesis developed post-infection in 23/32 of successfully treated patients. No major morbidity/mortality was associated with tPA/DNase. Four patients received blood transfusions; none had systemic or significant pleural bleeding. CONCLUSION: Treatment of IPC-related pleural infection with intrapleural tPA/DNase instillations via the IPC appears feasible and safe, usually without additional drainage procedures or surgery. Pleurodesis post-infection is common.

Inter-observer variation in image interpretation and the prognostic importance of non-expansile lung in malignant pleural effusion.

BACKGROUND AND OBJECTIVE: Non-expansile lung (NEL) frequently complicates management of malignant pleural effusion (MPE) and is an important factor in clinical practice and trials. NEL is frequently diagnosed on a single radiographic observation, but neither the inter-observer agreement of this approach nor the prognostic importance of NEL in MPE has been reported. METHODS: A multicentre retrospective cohort study was performed in two UK pleural centres. NEL was defined as <50% pleural re-apposition on post-drainage radiographs by primary and secondary assessors at each site. Inter-observer agreement was assessed by Cohen's kappa (κ). Kaplan-Meier methodology and multivariate Cox models were used to assess the prognostic impact of NEL versus no NEL and 'complete NEL' versus 'complete expansion', based on a single assessor's results from each site. RESULTS: NEL was identified by the primary assessor in 33 of 97 (34%) in Cohort 1 and 15 of 86 (17%) in Cohort 2. Inter-observer agreement between assessors was only fair-to-moderate (Cohort 1 κ: 0.38 (95% CI: 0.21-0.55), Cohort 2 κ: 0.51 (95% CI: 0.30-0.72)). In both cohorts, NEL was associated with shorter median overall survival (Cohort 1: 188 vs 371 days, Cohort 2: 192 vs 412 days). This prognostic association was independent in Cohort 1 (hazard ratio (HR): 2.19, 95% CI: 1.31-3.66) but not in Cohort 2 (HR: 1.42, 95% CI: 0.71-2.87). Survival was inferior in both cohorts in cases of complete NEL versus complete expansion. CONCLUSION: Radiographic NEL is common but inter-observer agreement is only fair-to-moderate. NEL is associated with adverse survival. These data do not support the use of single radiographic assessments to classify NEL.

Results of the Meso-ORIGINS feasibility study regarding collection of matched benign-mesothelioma tissue pairs by longitudinal surveillance.

OBJECTIVES: To assess key elements of the design for Meso-ORIGINS (Mesothelioma Observational study of RIsk prediction and Generation of paired benign-meso tissue samples, Including a Nested MRI Substudy), an ambitious, UK-wide, prospective study that will collect ≥63 matched benign-mesothelioma tissue pairs through longitudinal surveillance and repeat biopsy of patients with asbestos-associated pleural inflammation (AAPI). DESIGN: A multicentre, mixed-methods feasibility study, comprising a prospective observational element, evaluating recruitment feasibility, technical feasibility of repeat local anaesthetic thoracoscopy (LAT) and patient acceptability, and a retrospective cohort study focused on AAPI-mesothelioma evolution rate, informing sample size. SETTING: 4 UK pleural disease centres (February 2019-January 2020). PARTICIPANTS: Patients with AAPI (history or typical imaging plus appropriate pleural histology) were eligible for both elements. In August 2019, eligibility for the prospective element was broadened, including addition of radiological AAPI for technical feasibility and patient acceptability endpoints only. Retrospective cases required ≥2 years follow-up. OUTCOME MEASURES: A prospective recruitment target was set a priori at 27 histological AAPI cases (or 14 in any 6 months). Technical feasibility and patient acceptability were determined at 6-month follow-up by thoracic ultrasound surrogates and questionnaires, respectively. Retrospective malignant pleural mesothelioma evolution rate was defined by proportion (95% CI). Baseline predictors of evolution were identified using logistic regression. RESULTS: 296 patients with AAPI (39 prospective, 257 retrospective) were recruited/selected. 21/39 prospective recruits were histologically diagnosed (target n=27). Repeat LAT was technically feasible and acceptable in 13/28 (46%) and 24/36 (67%) cases with complete follow-up data. Mesothelioma evolution was confirmed histologically in 36/257 retrospective cases (14% (95% CI 10.3% to 18.8%)) and associated with malignant CT features (OR 4.78 (95% CI 2.36 to 9.86)) and age (OR 1.06 (95% CI 1.02 to 1.12)). CONCLUSIONS: Our initial eligibility criteria were too narrow. Meso-ORIGINS will recruit a broader cohort, including prevalent cases, any biopsy type and patients with malignant CT features. A range of rebiopsy techniques will be allowed, accounting for technical and patient factors. The sample size has been reduced to 500. TRIAL REGISTRATION NUMBER: ISRCTN12840870.

Staging by Thoracoscopy in potentially radically treatable Lung Cancer associated with Minimal Pleural Effusion (STRATIFY): protocol of a prospective, multicentre, observational study.

INTRODUCTION: Recurrence rate following radical therapy for lung cancer remains high, potentially reflecting occult metastatic disease, and better staging tools are required. Minimal pleural effusion (mini-PE) is associated with particularly high recurrence risk and is defined as an ipsilateral pleural collection (<1/3 hemithorax on chest radiograph), which is either too small to safely aspirate fluid for cytology using a needle, or from which fluid cytology is negative. Thoracoscopy (local anaesthetic thoracoscopy (LAT) or video-assisted thoracoscopic surgery (VATS)) is the gold-standard diagnostic test for pleural malignancy in patients with larger symptomatic effusions. Staging by Thoracoscopy in potentially radically treatable Lung Cancer associated with Minimal Pleural Effusion (STRATIFY) will prospectively evaluate thoracoscopic staging in lung cancer associated-mini-PE for the first time. METHODS AND ANALYSIS: STRATIFY is a prospective multicentre observational study. Recruitment opened in January 2020. The primary objective is to determine the prevalence of detectable occult pleural metastases (OPM). Secondary objectives include assessment of technical feasibility and safety, and the impact of thoracoscopy results on treatment plans, overall survival and recurrence free survival. Inclusion criteria are (1) suspected/confirmed stages I-III lung cancer, (2) mini-PE, (3) Performance Status 0-2 (4), radical treatment feasible if OPM excluded, (5) ≥16 years old and (6) informed consent. Exclusion criteria are any metastatic disease or contraindication to the chosen thoracoscopy method (LAT/VATS). All patients have LAT or VATS within 7 (±5) days of registration, with results returned to lung cancer teams for treatment planning. Following an interim analysis, the sample size was reduced from 96 to 50, based on a lower-than-expected OPM rate. An MRI substudy was removed in November 2022 due to pandemic-related site setup/recruitment delays. These also necessitated a no-cost recruitment extension until October 2023. ETHICS AND DISSEMINATION: Protocol approved by the West of Scotland Research Ethics Committee (Ref: 19/WS/0093). Results will be published in peer-reviewed journals and presented at international meetings. TRIAL REGISTRATION NUMBER: ISRCTN13584097.

Impact on quality of life from multimodality treatment for lung cancer: a randomised controlled feasibility trial of surgery versus no surgery as part of multimodality treatment in potentially resectable stage III-N2 NSCLC (the PIONEER trial).

INTRODUCTION: Optimal treatment for 'potentially resectable' stage III-N2 non-small cell lung cancer (NSCLC) requires multimodality treatment: local treatment (surgery or radiotherapy) and systemic anticancer therapy. There is no clear evidence of superiority for survival between the two approaches and little research has explored quality of life (QOL). This study will inform the design of a phase III randomised trial of surgery versus no surgery as part of multimodality treatment for stage III-N2 NSCLC with QOL as a primary outcome. METHODS AND ANALYSIS: Patient participants will be randomised to receive multimodality treatment (1) with surgery OR (2) without surgery. The Quintet Recruitment Intervention will be used to maximise recruitment. Eligible patients will have 'potentially resectable' N2 NSCLC and have received a multidisciplinary team recommendation for multimodality treatment. Sixty-six patients and their carers will be recruited from 8 UK centres. Patient/carer QOL questionnaires will be administered at baseline, weeks 6, 9, 12 and month 6. Semistructured interviews will be conducted. Quantitative data will be analysed descriptively and qualitative data will be analysed using framework analysis. ETHICS AND DISSEMINATION: Ethical approval has been obtained. Results will be disseminated via publications, national bodies and networks, and patient and public involvement groups. TRIAL REGISTRATION: NCT04540757.

Serum Proteomics and Plasma Fibulin-3 in Differentiation of Mesothelioma From Asbestos-Exposed Controls and Patients With Other Pleural Diseases.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory. METHODS: A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure. RESULTS: A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557-0.664], p = 0.0015) and 0.516 [0.443-0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume. CONCLUSIONS: SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.

A comparison between MRI and CT in the assessment of primary tumour volume in mesothelioma.

INTRODUCTION: Primary tumour staging in Malignant Pleural Mesothelioma (MPM) using Computed Tomography (CT) imaging is confounded by perception errors reflecting low spatial resolution between tumour and adjacent structures. Augmentation using perfusion CT is constrained by radiation dosage. In this study, we evaluated an alternative tumour staging method using perfusion-tuned Magnetic Resonance Imaging (MRI). METHODS: Consecutive patients with suspected MPM were recruited to a prospective observational study. All had MRI (T1-weighted, isotropic, contrast-enhanced 3-Tesla perfusion imaging) and CT (contrast-enhanced) pre-biopsy. Patients diagnosed with MPM underwent MRI and CT volumetry, with readers blinded to clinical data. MRI volumetry was semi-automated, using signal intensity limits from perfusion studies to grow tumour regions within a pleural volume. A similar CT method was not possible, therefore all visible tumour was manually segmented. MRI and CT volumes were compared (agreement, correlation, analysis time, reproducibility) and associations with survival examined using Cox regression. RESULTS: 58 patients were recruited and had MRI before biopsy. 31/58 were diagnosed with MPM and these scans were used for volumetry. Mean (SD) MRI and CT volumes were 370 cm3 and 302 cm3, respectively. MRI volumes were larger (average bias 61.9 cm3 (SD 116), 95 % limits (-165.5 - 289 cm3), moderately correlated with CT (r = 0.56, p = 0.002) and independently associated with survival (HR 4.03 (95 % CI 1.5-11.55), p = 0.006). CT volumes were not associated with survival, took longer to compute than MRI volumes (mean (SD) 151 (19) v 14 (2) minutes, p=<0.0001) and were less reproducible (inter-observer ICC 0.72 for CT, 0.96 for MRI). CONCLUSIONS: MRI and CT generate different tumour volumes in MPM. In this study, MRI volumes were larger and were independently associated with survival. MRI volumetry was quicker and more reproducible than CT.

Chest drain aerosol generation in COVID-19 and emission reduction using a simple anti-viral filter.

INTRODUCTION: The COVID-19 pandemic has been characterised by significant in-hospital virus transmission and deaths among healthcare workers. Sources of in-hospital transmission are not fully understood, with special precautions currently reserved for procedures previously shown to generate aerosols (particles <5 µm). Pleural procedures are not currently considered AGPs (Aerosol Generating Procedures), reflecting a lack of data in this area. METHODS: An underwater seal chest drain bottle (R54500, Rocket Medical UK) was set up inside a 60-litre plastic box and connected via an airtight conduit to a medical air supply. A multichannel particle counter (TSI Aerotrak 9310 Aerosol Monitor) was placed inside the box, allowing measurement of particle count/cubic foot (pc/ft3) within six channel sizes: 0.3-0.5, 0.5-1, 1-3, 3-5, 5-10 and >10 µm. Stabilised particle counts at 1, 3 and 5 L/min were compared by Wilcoxon signed rank test; p values were Bonferroni-adjusted. Measurements were repeated with a simple anti-viral filter, designed using repurposed materials by the study team, attached to the drain bottle. The pressure within the bottle was measured to assess any effect of the filter on bottle function. RESULTS: Aerosol emissions increased with increasing air flow, with the largest increase observed in smaller particles (0.3-3 µm). Concentration of the smallest particles (0.3-0.5 µm) increased from background levels by 700, 1400 and 2500 pc/ft3 at 1, 3 and 5 L/min, respectively. However, dispersion of particles of all sizes was effectively prevented by use of the viral filter at all flow rates. Use of the filter was associated with a maximum pressure rise of 0.3 cm H2O after 24 hours of flow at 5 L/min, suggesting minimal impact on drain function. CONCLUSION: A bubbling chest drain is a source of aerosolised particles, but emission can be prevented using a simple anti-viral filter. These data should be considered when designing measures to reduce in-hospital spread of SARS-CoV-2.

Baseline predictors of negative and incomplete pleural cytology in patients with suspected pleural malignancy - Data supporting 'Direct to LAT' in selected groups.

OBJECTIVES: Negative effusion cytology is more common in certain forms of Malignant Pleural Effusion (MPE) and results in pathway delay. Local Anaesthetic Thoracoscopy (LAT) is extremely sensitive and safe but cannot be offered to all. A stratified pathway, including 'Direct to LAT' in selected cases could enhance patient experience but requires reliable baseline predictors of unhelpful cytology, including both negative (no malignant cells) and incomplete results (malignant cells identified but predictive markers failed), since pleural biopsies will be required in the latter for optimal management. This retrospective analysis of a prospective multi-centre study, sought to identify baseline features for pathway rationalization. MATERIALS AND METHODS: 363/638 (57%) of patients recruited to the DIAPHRAGM study (ISRCTN10079972) were included. Prospective data, including final diagnoses, asbestos exposure and fluid cytology results were supplemented by retrospective Computed Tomography (CT) and predictive marker reports. Independent predictors of negative and incomplete cytology were determined by multivariable logistic regression. Contingency tables were used to assess diagnostic value of cytology in associated phenotypes. RESULTS: 238/363 (66%) patients were diagnosed with MPE (18 tumour types). Fluid cytology was negative in 151/238 (63%) and independently associated with asbestos-exposure (Odds Ratio (OR) 5.34) and a malignant CT (OR 2.25). When both features were recorded the sensitivity and negative predictive value of fluid cytology were 19% (95% CI 11-30%) and 9% (95% CI 4-20%)), respectively. Cytology was incomplete in 34/238 (14%), i.e. 47% of positive cytology cases) but was not associated with any baseline feature. ORs for incomplete cytology in Ovarian, Breast, Renal and Lung Cancer were 83, 22, 21 and 9, respectively. CONCLUSION: Negative cytology is extremely likely in patients with asbestos exposure and a malignant CT report. A 'Direct-to-LAT' approach may be appropriate in this setting. No baseline predictors of incomplete cytology were identified.

Pre-EDIT: A Randomized Feasibility Trial of Elastance-Directed Intrapleural Catheter or Talc Pleurodesis in Malignant Pleural Effusion.

BACKGROUND: Talc slurry pleurodesis (TSP) prevents recurrence of symptomatic malignant pleural effusion (MPE) in 71% to 78% patients. Nonexpansile lung (NEL) frequently accounts for TSP failure but is often occult predrainage, impairing selection of patients. NEL is associated with high pleural elastance (PEL), but technical limitations have hampered the development of PEL as a predictive NEL marker. We performed a single-center, randomized, controlled, open-label feasibility trial of EDIT (elastance-directed indwelling pleural catheter or TSP) management, using a novel digital manometer and a new definition of high PEL. METHODS: Patients with symptomatic MPE were randomized 1:1 between EDIT and standard care (TSP). EDIT involved PEL assessment during large-volume thoracentesis; patients with high PEL (maximum PEL sustained over 250 mL [MaxPEL250] ≥ 14.5 cm H2O/L) were allocated to immediately receive an indwelling pleural catheter; the remainder underwent immediate drain placement for TSP. The primary outcome measure was recruitment feasibility, defined a priori as 30 patients over 12 months. Secondary outcomes included safety, technical reliability, and the aspiration volume required to detect high PEL. The accuracy of the PEL definition for NEL was analyzed post hoc. RESULTS: Thirty-one patients were randomized (one allocation failure) over 12 months. PEL assessment (mean duration, 33 minutes) was successful in 13 of 15 patients (87%). No directly attributable serious adverse events occurred. High PEL was detected in seven of 13 patients (54%), associated with 100% sensitivity and 67% specificity for NEL, and was first detected at a median volume of 325 mL (range, 250-800 mL). CONCLUSIONS: A phase 3 trial testing the effect of EDIT management on symptomatic MPE recurrence following TSP is feasible. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03319186; URL: www.clinicaltrials.gov.

Survival prediction in mesothelioma using a scalable Lasso regression model: instructions for use and initial performance using clinical predictors.

INTRODUCTION: Accurate prognostication is difficult in malignant pleural mesothelioma (MPM). We developed a set of robust computational models to quantify the prognostic value of routinely available clinical data, which form the basis of published MPM prognostic models. METHODS: Data regarding 269 patients with MPM were allocated to balanced training (n=169) and validation sets (n=100). Prognostic signatures (minimal length best performing multivariate trained models) were generated by least absolute shrinkage and selection operator regression for overall survival (OS), OS <6 months and OS <12 months. OS prediction was quantified using Somers DXY statistic, which varies from 0 to 1, with increasing concordance between observed and predicted outcomes. 6-month survival and 12-month survival were described by area under the curve (AUC) scores. RESULTS: Median OS was 270 (IQR 140-450) days. The primary OS model assigned high weights to four predictors: age, performance status, white cell count and serum albumin, and after cross-validation performed significantly better than would be expected by chance (mean DXY0.332 (±0.019)). However, validation set DXY was only 0.221 (0.0935-0.346), equating to a 22% improvement in survival prediction than would be expected by chance. The 6-month and 12-month OS signatures included the same four predictors, in addition to epithelioid histology plus platelets and epithelioid histology plus C-reactive protein (mean AUC 0.758 (±0.022) and 0.737 (±0.012), respectively). The <6-month OS model demonstrated 74% sensitivity and 68% specificity. The <12-month OS model demonstrated 63% sensitivity and 79% specificity. Model content and performance were generally comparable with previous studies. CONCLUSIONS: The prognostic value of the basic clinical information contained in these, and previously published models, is fundamentally of limited value in accurately predicting MPM prognosis. The methods described are suitable for expansion using emerging predictors, including tumour genomics and volumetric staging.

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.

Early Contrast Enhancement: A novel magnetic resonance imaging biomarker of pleural malignancy.

INTRODUCTION: Pleural Malignancy (PM) is often occult on subjective radiological assessment. We sought to define a novel, semi-objective Magnetic Resonance Imaging (MRI) biomarker of PM, targeted to increased tumour microvessel density (MVD) and applicable to minimal pleural thickening. MATERIALS AND METHODS: 60 consecutive patients with suspected PM underwent contrast-enhanced 3-T MRI then pleural biopsy. In 58/60, parietal pleura signal intensity (SI) was measured in multiple regions of interest (ROI) at multiple time-points, generating ROI SI/time curves and Mean SI gradient (MSIG: SI increment/time). The diagnostic performance of Early Contrast Enhancement (ECE; which was defined as a SI peak in at least one ROI at or before 4.5 min) was compared with subjective MRI and Computed Tomography (CT) morphology results. MSIG was correlated against tumour MVD (based on Factor VIII immunostain) in 31 patients with Mesothelioma. RESULTS: 71% (41/58) patients had PM. Pleural thickening was <10 mm in 49/58 (84%). ECE sensitivity was 83% (95% CI 61-94%), specificity 83% (95% CI 68-91%), positive predictive value 68% (95% CI 47-84%), negative predictive value 92% (78-97%). ECE performance was similar or superior to subjective CT and MRI. MSIG correlated with MVD (r = 0.4258, p = .02). DISCUSSION: ECE is a semi-objective, perfusion-based biomarker of PM, measurable in minimal pleural thickening. Further studies are warranted.

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.

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

OBJECTIVES: Contrast-enhanced computed tomography (CT) provides essential cross-sectional imaging data in patients with suspected pleural malignancy (PM). The performance of CT in routine practice may be lower than in previously reported research. We assessed this relative to 'real-life' factors including use of early arterial-phase contrast enhancement (by CT pulmonary angiography (CTPA)) and non-specialist radiology reporting. MATERIALS AND METHODS: Routinely acquired and reported CT scans in patients recruited to the DIAPHRAGM study (a prospective, multi-centre observational study of mesothelioma biomarkers) between January 2014 and April 2016 were retrospectively reviewed. CT reports were classified as malignant if they included specific terms e.g. "suspicious of malignancy", "stage M1a" and benign if others were used e.g. "indeterminate", "no cause identified". All patients followed a standard diagnostic algorithm. The diagnostic performance of CT (overall and based on the above factors) was assessed using 2×2 Contingency Tables. RESULTS: 30/345 (9%) eligible patients were excluded (non-contrast (n=13) or non-contiguous CT (n=4), incomplete follow-up (n=13)). 195/315 (62%) patients studied had PM; 90% were cyto-histologically confirmed. 172/315 (55%) presented as an acute admission, of whom 31/172 (18%) had CTPA. Overall, CT sensitivity was 58% (95% CI 51-65%); specificity was 80% (95% CI 72-87%). Sensitivity of CTPA (performed in 31/315 (10%)) was lower (27% (95% CI 9-53%)) than venous-phase CT (61% (95% CI 53-68%) p=0.0056). Sensitivity of specialist thoracic radiologist reporting was higher (68% (95% CI 55-79%)) than non-specialist reporting (53% (95% CI 44-62%) p=0.0488). Specificity was not significantly different. CONCLUSION: The diagnostic performance of CT in routine clinical practice is insufficient to exclude or confirm PM. A benign CT report should not dissuade pleural sampling where the presence of primary or secondary pleural malignancy would alter management. Sensitivity is lower with non-thoracic radiology reporting and particularly low using CTPA.

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.

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.