PET-CT-guided versus CT-guided biopsy in suspected malignant pleural thickening: a randomised trial.

BACKGROUND: Pleural biopsy is the gold standard for diagnosis of pleural malignancy but a significant proportion will have an inconclusive biopsy despite ongoing clinical suspicion of malignancy. We investigated whether positron emission tomography-computed tomography (PET-CT) targeted pleural biopsy is superior to standard CT-guided pleural biopsy following an initial non-diagnostic biopsy. METHODS: The TARGET trial was a multicentre, parallel group randomised trial. Patients with a previous inconclusive pleural biopsy but an ongoing suspicion of pleural malignancy were randomised (1:1) to receive either CT-guided biopsy (standard care) or PET-CT followed by a targeted CT biopsy (intervention). The primary outcome was pleural malignancy correctly identified from the trial biopsy. RESULTS: Between September 2015 and September 2018, 59 participants were randomised from eight UK hospital sites: 29 to CT-only followed by targeted biopsy and 30 to PET-CT followed by targeted biopsy. The proportion of pleural malignancy correctly identified was similar between the groups (risk ratio 1.03 (95% CI 0.83-1.29); p=0.77). The sensitivity of the trial biopsy to identify pleural malignancy was 79% (95% CI 54-94%) in the CT-only group versus 81% (95% CI 54-96%) in the PET-CT group. CONCLUSIONS: The results do not support the practice of PET-CT to guide pleural biopsies in patients with a previous non-diagnostic biopsy. The diagnostic sensitivity in the CT-only group was higher than anticipated and supports the practice of repeating a CT-guided biopsy following an inconclusive result if clinical suspicion of malignancy persists.

Reflecting real-world patients with mesothelioma in research: an interim report of baseline characteristics from the ASSESS-meso cohort.

Objective: Mesothelioma varies in clinical phenotype and survival. Clinical trials are unavoidably affected by selection bias, reducing generalisability. ASSESS-meso is a UK, multicentre, prospective, mesothelioma cohort study (ISRCTN61861764). This pre-specified interim analysis, conducted when recruitment reached 25% of target, summarised participant characteristics and evaluated external validity through comparison with real-world and clinical trial cohorts. Methods: The study took place at 14 hospitals across the UK. People diagnosed with mesothelioma, at any anatomical site, were eligible. Clinical, radiological and biochemical data were collected at enrolment. In this interim report, the external validity of the cohort was investigated through comparison of baseline demographic data with populations included in the 2020 UK National Mesothelioma Audit (real-world cohort), and CHECKMATE-743 and MAPS trials (clinical trial cohorts). Results: 244 patients were enrolled between 7 April 2017 and 1 March 2022. The cohort was predominantly male (195 out of 244; 80%) with a median age of 74 years. Pleural disease and epithelioid subtypes were most prevalent. ASSESS-meso participants were more similar to the real-world population with regard to age, performance status, disease site and stage than the clinical trial population. ASSESS-meso participants were more likely to be formally staged and less likely to have undifferentiated histology compared with the real-world cohort, possibly reflecting high rates of discussion of ASSESS-meso participants at regional mesothelioma multidisciplinary team meetings. As expected, poorer performance status, non-epithelioid histology and neutrophil-lymphocyte ratio were associated with shorter survival in the adjusted analysis. Conclusion: ASSESS-meso is representative of the UK mesothelioma population. Future outputs from the cohort will help characterise different mesothelioma phenotypes with high external validity.

A multidisciplinary approach to the diagnosis of antisynthetase syndrome.

Antisynthetase syndrome is a subtype of idiopathic inflammatory myopathy, strongly associated with the presence of interstitial lung disease. Diagnosis is made by identifying myositis-specific antibodies directed against aminoacyl tRNA synthetase, and relevant clinical and radiologic features. Given the multisystem nature of the disease, diagnosis requires the careful synthesis of subtle clinical and radiological features with the interpretation of specialized autoimmune serological testing. This is provided in a multidisciplinary environment with input from rheumatologists, respiratory physicians, and radiologists. Differentiation from other idiopathic interstitial lung diseases is key; treatment and prognosis differ between patients with antisynthetase syndrome and idiopathic interstitial lung disease. In this review article, we look at the role of the multidisciplinary team and its individual members in the initial diagnosis of the antisynthetase syndrome, including the role of physicians, radiologists, and the wider team.

Lymphocyte predominance in blood, pleural fluid, and tumour stroma; a prognostic marker in pleural mesothelioma.

BACKGROUND: As promising novel treatments develop for malignant pleural mesothelioma (MPM), early prognostication has become increasingly important. Circulating and local inflammatory cells are known to play a significant role in other tumour types. We assessed the proportion of lymphocyte populations within blood, pleural fluid and tumour stroma to prognosticate patients with MPM at diagnosis. METHODS: Consecutive patients diagnosed with biopsy-proven MPM were prospectively recruited to an observational cohort study and followed up for a minimum of 7.5 years. Blood and pleural fluid results at presentation were extracted from the medical records. Biopsy specimens were independently reviewed by 2 pathologists who scored the degree of lymphocytic and neutrophilic infiltration. RESULTS: Baseline results were available for 184 patients. The predominant pleural fluid cell type was calculable for 84 patients and 118 patients had biopsy specimens available for review. A low blood neutrophil/lymphocyte ratio (NLR < 4) inferred a better prognosis with a median survival of 420 days versus 301 days (p < 0.01). Survival was better for patients with a lymphocyte-predominant pleural effusion (430 vs 306 days, p < 0.01). Lymphocyte infiltration of tumour stroma was also associated with improved survival (n = 92, survival 430 days) compared with neutrophilic or acellular samples (n = 26, survival 342 days p < 0.01). In multivariable modelling lymphocyte predominance in blood, pleural fluid and tumour stroma were all associated with a better prognosis. CONCLUSIONS: Lymphocyte predominance within tumour stroma, pleural fluid or blood infers a better prognosis in patients with MPM.

Role of thoracic ultrasonography in pleurodesis pathways for malignant pleural effusions (SIMPLE): an open-label, randomised controlled trial.

BACKGROUND: Pleurodesis is done as an in-patient procedure to control symptomatic recurrent malignant pleural effusion (MPE) and has a success rate of 75-80%. Thoracic ultrasonography has been shown in a small study to predict pleurodesis success early by demonstrating cessation of lung sliding (a normal sign seen in healthy patients, lung sliding indicates normal movement of the lung inside the thorax). We aimed to investigate whether the use of thoracic ultrasonography in pleurodesis pathways could shorten hospital stay in patients with MPE undergoing pleurodesis. METHODS: The Efficacy of Sonographic and Biological Pleurodesis Indicators of Malignant Pleural Effusion (SIMPLE) trial was an open-label, randomised controlled trial done in ten respiratory centres in the UK and one respiratory centre in the Netherlands. Adult patients (aged ≥18 years) with confirmed MPE who required talc pleurodesis via either a chest tube or as poudrage during medical thorascopy were eligible. Patients were randomly assigned (1:1) to thoracic ultrasonography-guided care or standard care via an online platform using a minimisation algorithm. In the intervention group, daily thoracic ultrasonography examination for lung sliding in nine regions was done to derive an adherence score: present (1 point), questionable (2 points), or absent (3 points), with a lowest possible score of 9 (preserved sliding) and a highest possible score of 27 (complete absence of sliding); the chest tube was removed if the score was more than 20. In the standard care group, tube removal was based on daily output volume (per British Thoracic Society Guidelines). The primary outcome was length of hospital stay, and secondary outcomes were pleurodesis failure at 3 months, time to tube removal, all-cause mortality, symptoms and quality-of-life scores, and cost-effectiveness of thoracic ultrasonography-guided care. All outcomes were assessed in the modified intention-to-treat population (patients with missing data excluded), and a non-inferiority analysis of pleurodesis failure was done in the per-protocol population. This trial was registered with ISRCTN, ISRCTN16441661. FINDINGS: Between Dec 31, 2015, and Dec 17, 2019, 778 patients were assessed for eligibility and 313 participants (165 [53%] male) were recruited and randomly assigned to thoracic ultrasonography-guided care (n=159) or standard care (n=154). In the modified intention-to-treat population, the median length of hospital stay was significantly shorter in the intervention group (2 days [IQR 2-4]) than in the standard care group (3 days [2-5]; difference 1 day [95% CI 1-1]; p<0·0001). In the per-protocol analysis, thoracic ultrasonography-guided care was non-inferior to standard care in terms of pleurodesis failure at 3 months, which occurred in 27 (29·7%) of 91 patients in the intervention group versus 34 (31·2%) of 109 patients in the standard care group (risk difference -1·5% [95% CI -10·2% to 7·2%]; non-inferiority margin 15%). Mean time to chest tube removal in the intervention group was 2·4 days (SD 2·5) versus 3·1 days (2·0) in the standard care group (mean difference -0·72 days [95% CI -1·22 to -0·21]; p=0·0057). There were no significant between-group differences in all-cause mortality, symptom scores, or quality-of-life scores, except on the EQ-5D visual analogue scale, which was significantly lower in the standard care group at 3 months. Although costs were similar between the groups, thoracic ultrasonography-guided care was cost-effective compared with standard care. INTERPRETATION: Thoracic ultrasonography-guided care for pleurodesis in patients with MPE results in shorter hospital stay (compared with the British Thoracic Society recommendation for pleurodesis) without reducing the success rate of the procedure at 3 months. The data support consideration of standard use of thoracic ultrasonography in patients undergoing MPE-related pleurodesis. FUNDING: Marie Curie Cancer Care Committee.

European Respiratory Society statement on thoracic ultrasound.

Thoracic ultrasound is increasingly considered to be an essential tool for the pulmonologist. It is used in diverse clinical scenarios, including as an adjunct to clinical decision making for diagnosis, a real-time guide to procedures and a predictor or measurement of treatment response. The aim of this European Respiratory Society task force was to produce a statement on thoracic ultrasound for pulmonologists using thoracic ultrasound within the field of respiratory medicine. The multidisciplinary panel performed a review of the literature, addressing major areas of thoracic ultrasound practice and application. The selected major areas include equipment and technique, assessment of the chest wall, parietal pleura, pleural effusion, pneumothorax, interstitial syndrome, lung consolidation, diaphragm assessment, intervention guidance, training and the patient perspective. Despite the growing evidence supporting the use of thoracic ultrasound, the published literature still contains a paucity of data in some important fields. Key research questions for each of the major areas were identified, which serve to facilitate future multicentre collaborations and research to further consolidate an evidence-based use of thoracic ultrasound, for the benefit of the many patients being exposed to clinicians using thoracic ultrasound.

British Thoracic Society Training Standards for Thoracic Ultrasound (TUS).

INTRODUCTION: The British Thoracic Society (BTS) responded to a call from the pleural community to establish this new Training Standard to detail the capabilities in practice for thoracic ultrasound (TUS), which will build on the previous curricula and extend the remit to include training for the emergency provision of TUS. METHODS: BTS convened a working group to produce a set of Training Standards. RESULTS: This document provides a comprehensive Training Standard for TUS facilitating timely and improved management of patients with respiratory presentations, particularly (but not exclusively) pleural pathologies. DISCUSSION: The Training Standards document will be widely disseminated.

Investigation of a unilateral pleural effusion: What CT scan coverage is optimal?

The use of thoracic CT for patients presenting with a unilateral pleural effusion is well established. However, there is no consensus with regard to the inclusion of the entire abdomen and pelvis in the initial imaging protocol. In this prospective UK-based study, 249 patients presenting with a unilateral effusion had a CT thorax/abdomen/pelvis performed. The prevalence of malignancy on thoracic CT was 56% (140/249). Clinically significant findings below the diaphragm were identified in 59 patients (24%). Integrating this approach into standard practice allows more rapid identification of the primary malignancy, upstaging lesions or alternative sites for biopsy.

Lung Parenchymal and Tracheal CT Morphology: Evaluation before and after Bariatric Surgery.

Background There is significant pulmonary functional deficit related to obesity, but no prospective CT studies have evaluated the effects of obesity on the lungs and trachea. Purpose To evaluate lung parenchymal and tracheal CT morphology before and 6 months after bariatric surgery, with functional and symptomatic correlation. Materials and Methods A prospective longitudinal study of 51 consecutive individuals referred for bariatric surgery was performed (from November 2011 to November 2013). All individuals had undergone limited (three-location) inspiratory and end-expiratory thoracic CT before and after surgery, with concurrent pulmonary function testing, body mass index calculation, and modified Medical Research Council (mMRC) dyspnea scale and Epworth scoring. Two thoracic radiologists scored the CT extent of mosaic attenuation, end-expiratory air trapping, and tracheal shape. The inspiratory and end-expiratory cross-sectional areas of the trachea were measured. The paired t test or Wilcoxon signed-rank test was used for pre- and postsurgical comparisons. Spearman correlation and logistic regression were used to evaluate correlations between CT findings and functional and symptom indexes. Results A total of 51 participants (mean age, 52 years ± 8 [standard deviation]; 20 men) were evaluated. Before surgery, air trapping extent correlated most strongly with decreased total lung capacity (Spearman rank correlation coefficient [rs] = -0.40, P = .004). After surgery, there were decreases in percentage mosaic attenuation (0% [interquartile range {IQR}: 0%-2.5%] vs 0% [IQR: 0%-0%], P < .001), air trapping (9.6% [IQR: 5.8%-15.8%] vs 2.5% [IQR: 0%-6.7%], P < .001), and tracheal collapse (201 mm2 [IQR: 181-239 mm2] vs 229 mm2 [186-284 mm2], P < .001). After surgery, mMRC dyspnea score change correlated positively with air trapping extent change (rs = 0.46, P = .001) and end-expiratory tracheal shape change (rs = 0.40, P = .01). At multivariable analysis, air trapping was the main determinant for decreased dyspnea after surgery (odds ratio, 1.2; 95% confidence interval: 1.1, 1.2; P = .03). Conclusion Dyspnea improved in obese participants after weight reduction, which correlated with less tracheal collapse and air trapping at end-expiration chest CT. © RSNA, 2020 Online supplemental material is available for this article.

Effect of Thoracoscopic Talc Poudrage vs Talc Slurry via Chest Tube on Pleurodesis Failure Rate Among Patients With Malignant Pleural Effusions: A Randomized Clinical Trial.

Importance: Malignant pleural effusion (MPE) is challenging to manage. Talc pleurodesis is a common and effective treatment. There are no reliable data, however, regarding the optimal method for talc delivery, leading to differences in practice and recommendations. Objective: To test the hypothesis that administration of talc poudrage during thoracoscopy with local anesthesia is more effective than talc slurry delivered via chest tube in successfully inducing pleurodesis. Design, Setting, and Participants: Open-label, randomized clinical trial conducted at 17 UK hospitals. A total of 330 participants were enrolled from August 2012 to April 2018 and followed up until October 2018. Patients were eligible if they were older than 18 years, had a confirmed diagnosis of MPE, and could undergo thoracoscopy with local anesthesia. Patients were excluded if they required a thoracoscopy for diagnostic purposes or had evidence of nonexpandable lung. Interventions: Patients randomized to the talc poudrage group (n = 166) received 4 g of talc poudrage during thoracoscopy while under moderate sedation, while patients randomized to the control group (n = 164) underwent bedside chest tube insertion with local anesthesia followed by administration of 4 g of sterile talc slurry. Main Outcomes and Measures: The primary outcome was pleurodesis failure up to 90 days after randomization. Secondary outcomes included pleurodesis failure at 30 and 180 days; time to pleurodesis failure; number of nights spent in the hospital over 90 days; patient-reported thoracic pain and dyspnea at 7, 30, 90, and 180 days; health-related quality of life at 30, 90, and 180 days; all-cause mortality; and percentage of opacification on chest radiograph at drain removal and at 30, 90, and 180 days. Results: Among 330 patients who were randomized (mean age, 68 years; 181 [55%] women), 320 (97%) were included in the primary outcome analysis. At 90 days, the pleurodesis failure rate was 36 of 161 patients (22%) in the talc poudrage group and 38 of 159 (24%) in the talc slurry group (adjusted odds ratio, 0.91 [95% CI, 0.54-1.55]; P = .74; difference, -1.8% [95% CI, -10.7% to 7.2%]). No statistically significant differences were noted in any of the 24 prespecified secondary outcomes. Conclusions and Relevance: Among patients with malignant pleural effusion, thoracoscopic talc poudrage, compared with talc slurry delivered via chest tube, resulted in no significant difference in the rate of pleurodesis failure at 90 days. However, the study may have been underpowered to detect small but potentially important differences. Trial Registration: ISRCTN Identifier: ISRCTN47845793.

Zoledronic acid in the management of mesothelioma - a feasibility study (Zol-A Trial): study protocol for a randomised controlled trial.

BACKGROUND: Nitrogen containing bisphosphonates such as zoledronic acid (ZA) are known to contain certain anti-cancer properties. These have been investigated in the past in various cancers such as breast, prostate and colon. ZA in particular has shown promising results in pre-clinical studies. We propose a multicentre double-blind randomised controlled feasibility study to assess the recruitment and acceptability of ZA/placebo alongside chemotherapy in malignant pleural mesothelioma (MPM). METHODS: Patients will be recruited for a 13-month period from October 2016 to November 2017. Eligible patients will be identified via the regional mesothelioma multidisciplinary team meeting. Those who receive chemotherapy will be randomised to receive either ZA or placebo alongside their chemotherapy. Those who decline chemotherapy will be offered to join the trial on the non-randomised open-labelled arm of the trial. Patients will receive a maximum of six cycles of ZA/placebo, at three-weekly cycles. All patients will be followed up for six months from randomisation. Semi-structured interviews to gather data on acceptability of trial procedures, tolerability of ZA and other relevant information will take place after the participants have completed their six cycles of treatment. For a better understanding about non-participation in mesothelioma trials we also aim to interview those who decline to take part in the trial. DISCUSSION: The qualitative and quantitative data gathered in this feasibility trial will hopefully pave the way to designing a robust full phase III trial to investigate the potential synergistic effect of ZA and current standard treatment for MPM, cisplatin-pemetrexed combination chemotherapy. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN45536692 . Registered on 9 August 2016. EudraCT no. 2015-004433-26.

Randomised controlled trial to compare the diagnostic yield of positron emission tomography CT (PET-CT) TARGETed pleural biopsy versus CT-guided pleural biopsy in suspected pleural malignancy (TARGET trial).

INTRODUCTION: Pleural malignancy, particularly malignant pleural mesothelioma (MPM) is increasing in incidence due to the long latency period from exposure to asbestos to development of the disease. MPM can be challenging to diagnose. For patients presenting without a pleural effusion, CT-guided biopsy remains the primary choice of biopsy, but the diagnostic sensitivity of this investigation is 70%-75%. Therefore, a proportion of patients will go on to require further biopsies. If the first biopsy is non-diagnostic, the chances of further non-diagnostic biopsies are high in MPM. METHODS: Target is a multicentre randomised controlled trial, aiming to recruit 78 patients over a 30-month period, from 10 centres in the UK. Patients will be randomised to either the standard arm which is a second CT-guided biopsy, or the interventional arm, a positron emission tomography-CT scan followed by a targeted CT-guided biopsy. Patients will be followed up for 12 months (patients recruited in the last 6 months of recruitment will have 6 months of follow-up). MPM biomarker mesothelin will be checked at baseline, 6 month and 12 month follow-up appointments where patients are able to attend these appointments. ETHICS AND DISSEMINATION: Ethical approval for this trial was granted by the South West-Exeter research and ethics committee (reference number 15/SW/0156). Results of the trial will be published in a peer-reviewed journal and presented at an international conference. TRIAL REGISTRATION NUMBER: ISRCTN 14024829; Pre-results.

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.

A Pilot Feasibility Study in Establishing the Role of Ultrasound-Guided Pleural Biopsies in Pleural Infection (The AUDIO Study).

BACKGROUND: Pleural infection is a common complication of pneumonia associated with high mortality and poor clinical outcome. Treatment of pleural infection relies on the use of broad-spectrum antibiotics because reliable pathogen identification occurs infrequently. We performed a feasibility interventional clinical study assessing the safety and significance of ultrasound (US)-guided pleural biopsy culture to increase microbiological yield. In an exploratory investigation, the 16S ribosomal RNA technique was applied to assess its utility on increasing speed and accuracy vs standard microbiological diagnosis. METHODS: Twenty patients with clinically established pleural infection were recruited. Participants underwent a detailed US scan and US-guided pleural biopsies before chest drain insertion, alongside standard clinical management. Pleural biopsies and routine clinical samples (pleural fluid and blood) were submitted for microbiological analysis. RESULTS: US-guided pleural biopsies were safe with no adverse events. US-guided pleural biopsies increased microbiological yield by 25% in addition to pleural fluid and blood samples. The technique provided a substantially higher microbiological yield compared with pleural fluid and blood culture samples (45% compared with 20% and 10%, respectively). The 16S ribosomal RNA technique was successfully applied to pleural biopsy samples, demonstrating high sensitivity (93%) and specificity (89.5%). CONCLUSIONS: Our findings demonstrate the safety of US-guided pleural biopsies in patients with pleural infection and a substantial increase in microbiological diagnosis, suggesting potential niche of infection in this disease. Quantitative polymerase chain reaction primer assessment of pleural fluid and biopsy appears to have excellent sensitivity and specificity.