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Background Malignant pleural mesothelioma (MPM) is an aggressive thoracic malignancy with a poor prognosis. Systemic immunotherapy is an effective frontline treatment for MPM, and there is a scientific rationale supporting the possible efficacy of local, i.e. intra-pleural immune modulators. Trial of intra-pleural bacterial immunotherapy (TILT) investigated the feasibility of performing a randomised trial of intra-pleural bacterial immunotherapy in people with MPM, using the trials within cohorts (TwiC) methodology. Methods TILT was a multicentre, three-armed, randomised, feasibility TwiC of intra-pleural OK432, BCG, or usual care in people with MPM. Eligible participants were identified from within the ASSESS-meso study, a prospective, longitudinal, observational cohort study, and were randomly selected to be offered a single dose of OK432 or BCG, via an indwelling pleural catheter. The primary outcome was feasibility, evaluated against prespecified recruitment, attrition and data completeness targets. The acceptability of trial processes and interventions was assessed during qualitative interviews with participants and family members at the end of the trial. TILT was registered prospectively on the European Clinical Trials Registry (EudraCT number 2016–004,727-23) and the ISRCTN Register on 04 December 2017. Results Seven participants were randomised from a planned sample size of 12; thus, the 66% recruitment rate target was not met. Two participants withdrew after randomisation, breaching the pre-stated attrition threshold of 10%. It was not possible to maintain blinding of control participants, which negated a fundamental tenet of the TwiC design. The trial processes and methodology were generally acceptable to participants and relatives, despite several recipients of intra-pleural bacterial agents experiencing significant local and systemic inflammatory responses. Conclusion It was possible to design a clinical trial of an investigational medicinal product based on the TwiC design and to obtain the necessary regulatory approvals. However, whilst acceptable to participants and relatives, the TwiC design was not a feasible method of investigating intra-pleural bacterial immunotherapy in people with MPM. Future trials investigating this topic should consider the eligibility constraints and recruitment difficulties encountered. Trial registration TILT was registered prospectively on the European Clinical Trials Registry (EudraCT number 2016-004727-23) and the ISRCTN Register (10432197) on 04 December 2017.

RATIONALE: Parapneumonic effusions have a wide clinical spectrum. The majority settle with conservative management but some progress to complex collections requiring intervention. For decades, physicians have relied on pleural fluid pH to determine the need for chest tube drainage despite a lack of prospective validation and no ability to predict the requirement for fibrinolytics or thoracic surgery.OBJECTIVES: To study the ability of soluble urokinase Plasminogen Activator Receptor (suPAR), a potential biomarker of pleural fluid loculation, to predict the need for invasive management compared to conventional fluid biomarkers (pH, glucose, LDH) in parapneumonic effusions.METHODS: Patients presenting with pleural effusions were prospectively recruited to an observational study with biological samples stored at presentation. Pleural fluid and serum suPAR levels were measured using the suPARnosticTM double-monoclonal antibody sandwich ELISA on 93 patients with parapneumonic effusions and 47 controls (benign and malignant effusions).MEASUREMENTS AND MAIN RESULTS: Pleural suPAR levels were significantly higher in effusions that loculated versus non-loculated parapneumonic effusions (median 132ng/ml vs 22ng/ml, pCONCLUSIONS: Raised pleural suPAR was predictive of patients receiving more invasive management of parapneumonic effusions and added value to conventional biomarkers. These results need validation in a prospective multicenter 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

Background Malignant pleural effusion affects more than 750,000 persons each year across Europe and the United States. Pleurodesis with the administration of talc in hospitalized patients is the most common treatment, but indwelling pleural catheters placed for drainage offer an ambulatory alternative. We examined whether talc administered through an indwelling pleural catheter was more effective at inducing pleurodesis than the use of an indwelling pleural catheter alone. Methods Over a period of 4 years, we recruited patients with malignant pleural effusion at 18 centers in the United Kingdom. After the insertion of an indwelling pleural catheter, patients underwent drainage regularly on an outpatient basis. If there was no evidence of substantial lung entrapment (nonexpandable lung, in which lung expansion and pleural apposition are not possible because of visceral fibrosis or bronchial obstruction) at 10 days, patients were randomly assigned to receive either 4 g of talc slurry or placebo through the indwelling pleural catheter on an outpatient basis. Talc or placebo was administered on a single-blind basis. Follow-up lasted for 70 days. The primary outcome was successful pleurodesis at day 35 after randomization. Results The target of 154 patients undergoing randomization was reached after 584 patients were approached. At day 35, a total of 30 of 69 patients (43%) in the talc group had successful pleurodesis, as compared with 16 of 70 (23%) in the placebo group (hazard ratio, 2.20; 95% confidence interval, 1.23 to 3.92; P = 0.008). No significant between- group differences in effusion size and complexity, number of inpatient days, mortality, or number of adverse events were identified. No significant excess of blockages of the indwelling pleural catheter was noted in the talc group. Conclusions Among patients without substantial lung entrapment, the outpatient administration of talc through an indwelling pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an indwelling catheter alone, with no deleterious effects.

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Introduction For decades the management of parapneumonic effusions has relied on pleural fluid pH measurement. However, the eventual requirement for fibrinolytics or surgery is more often dictated by the development of loculations. soluble urokinase Plasminogen Activating Receptor (suPAR) is a novel biomarker released by pleural mesothelial cells in response to infection as part of the fibrinolysis cascade. This study assessed levels of suPAR in the pleural fluid (PF) and serum of patients with parapneumonic effusions. Methods We analysed stored serum and PF from a prospectively collected cohort of patients with effusions due to infection. Cases with frank pus on thoracentesis were excluded. Baseline pleural ultrasounds were performed to assess loculations, with routine bloods and pleural fluid analysis. Clinical outcomes and final diagnoses were confirmed at 12 months by two respiratory consultants. suPAR levels were analysed in duplicate using the suPARnostic® double monoclonal antibody sandwich ELISA assay. Binomial logistic regression was used to compare clinical outcomes to biochemical markers. Mann Whitney test was used to compare suPAR levels between groups. Results Between 2008 and 2016 there were 93 patients with parapneumonic effusions recruited (49 non-loculated and 44 loculated effusions). Median PF suPAR was 88ng/ml (9–614ng/ml). PF suPAR was significantly higher in loculated effusions (median 162ng/ml versus 22ng/ml, p The sensitivity and specificity of PF suPAR >35ng/ml to predict loculations was 100% and 91% respectively. 94% of patients (45/48) with a pf suPAR over 35ng/ml were managed with a chest tube. Using stepwise logistic regression (in a model that included PF pH) PF suPAR was an independent predictor of need for fibrinolytics and surgery (p Conclusion The development of loculations is an important differentiator in the management of parapneumonic effusions. suPAR is a novel biomarker and is part of the fibrinolysis cascade. This is the first study to assess the potential role of suPAR in parapneumonic effusions. PF suPAR was superior to PF pH and serum CRP at predicting loculations as well as requirement for fibrinolytics or surgery. Its true utility needs assessing in a larger prospective study.

BackgroundThe use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial.MethodsWe did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336.FindingsBetween Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19–1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy.InterpretationRoutine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified.FundingResearch for Patient Benefit Programme from the UK National Institute for Health Research.

Pleural infection is increasing in incidence. Despite optimal medical management, up to 30% of patients will die or require surgery. Case reports suggest that irrigation of the pleural space with saline may be beneficial.A randomised controlled pilot study in which saline pleural irrigation (three times per day for 3 days) plus best-practice management was compared with best-practice management alone was performed in patients with pleural infection requiring chest-tube drainage. The primary outcome was percentage change in computed tomography pleural fluid volume from day 0 to day 3. Secondary outcomes included surgical referral rate, hospital stay and adverse events.35 patients were randomised. Patients receiving saline irrigation had a significantly greater reduction in pleural collection volume on computed tomography compared to those receiving standard care (median (interquartile range) 32.3% (19.6–43.7%) reduction versus 15.3% (−5.5–28%) reduction) (pSaline irrigation improves pleural fluid drainage and reduces referrals for surgery in pleural infection. A large multicentre randomised controlled trial is now warranted to evaluate its effects further.

Introduction and Objectives Eosinophilic pleural effusions (EPE) are a relatively uncommon finding in the investigation of undifferentiated pleural effusions. Traditionally defined as a cell count ≥10% eosinophils, it was initially felt to be a marker of benign disease, however, subsequent studies found malignancy to be the commonest aetiology, 1 with other causes, including infection, blood/air and drug reactions less frequent. Our aim is to use prospective data to examine the relative incidence and aetiology of EPE, and its prognostic significance. Methods We recruited 803 consecutive patients presenting to a pleural service, between 03/2008 and 03/2015, with undiagnosed pleural effusions. Pleural biochemistry, cytology, thoracic USS, chest radiograph and CT scans were performed. Biopsies and thoracoscopy were performed as clinically indicated. Patients were followed-up for minimum duration of 12 months with final diagnosis decided by independent review by 2 respiratory consultants. Survival data was calculated from study entry to death and censored on 07/2017. Results Of the 803 patients, 398/803 (49.6%) had a malignant pleural effusion(MPE). 57 (7.1%) had eosinophil count (EC) ≥10%. With this threshold, MPE was the commonest cause, at 24/57 (42%), followed by infection 9 (16%) and inflammatory pleuritis (IP) 5 (9%). With higher thresholds of EC, the relative frequency of malignancy decreased. At ≥30% EC, malignancy accounted for 4/20 cases, infection 4/20, drug/toxin 3/20, unknown 3/20, benign asbestos pleural effusion 2/20, pulmonary embolism 2/20, IP 1/20 and heart failure 1/20. Mortality rates were lower in EPE relative to non-EPE, with 6 months and 1 year mortality rates for EPE 19%–33% respectively, with non-EPE 36%–50%. The higher the EC, the lower mortality, with hazard ratios compared to non-EPE at 0.6, 0.5, 0.3, 0.2, 0.2 for ≥10%,≥20%,≥30%,≥40% and ≥50% EC respectively (p Conclusion Higher eosinophil counts are associated with decreased mortality and lower rates of malignant vs benign effusions. The threshold ≥10% is not helpful in differentiating MPE from benign disease. We suggest a higher threshold of ≥30% would hold greater clinical significance and therefore be a more useful definition for clinicians. Reference Rubins JB, Rubins HB. Aetiology and prognostic significance of eosinophilic pleural effusions: A prospective study. Chest 1996;110(5):1271–4.

Background: Haematological malignancy is an important cause of pleural effusion. Pleural effusions secondary to haematological malignancy are usually lymphocyte predominant. However, several other conditions such as carcinoma, tuberculosis, and chronic heart failure also cause lymphocytic effusions. Lymphocyte subset (LS) analysis may be a useful test to identify haematological malignancy in patients with lymphocytic effusions. However, research into their utility in pleural effusion diagnostic algorithms has not yet been published. Objectives: We aimed to determine the clinical utility of pleural fluid LS analysis and whether it can be applied to a diagnostic algorithm to identify effusions secondary to haematological malignancy. The secondary aim was to evaluate the diagnostic value of pleural fluid differential cell count. Methods: Consecutive consenting patients presenting to our pleural service between 2008 and 2013 underwent thoracentesis and differential cell count analysis. We proposed an algorithm which selected patients with lymphocytic effusions (>50%) to have further fluid sent for LS analysis. Two independent consultants agreed on the cause of the original effusion after a 12-month follow-up period. Results: A total of 60 patients had samples sent for LS analysis. LS analysis had an 80% sensitivity (8/10) and a 100% specificity for the diagnosis of haematological malignancy. The positive and negative predictive values were 100 and 96.1%, respectively. Overall 344 differential cell counts were analysed; 16% of pleural effusions with a malignant aetiology were neutrophilic or eosinophilic at presentation. A higher neutrophil and eosinophil count was associated with benign diagnoses, whereas a higher lymphocyte count was associated with malignant diagnoses. Conclusions: LS analysis may identify haematological malignancy in a specific cohort of patients with undiagnosed pleural effusions. A pleural fluid differential cell count provides useful additional information to streamline patient pathway decisions.

Rationale: Evaluation of a pleural effusion has historically focused on establishing a single etiology. Pleural fluid may accumulate through multiple pathophysiological processes. The prevalence of multiple causes for pleural effusions has not been established. The identification of contributing processes may improve clinical outcomes. Objectives: The objective of this prospectively collected case series was to establish the prevalence and nature of multiple etiologies for a unilateral pleural effusion. Methods: Consecutive patients presenting with an undiagnosed unilateral pleural effusion were recruited at a tertiary pleural center. Patients underwent a comprehensive structured diagnostic clinical evaluation and were followed up for a minimum of 12 months, after which one or more diagnoses were recorded independently by two experienced clinicians. Measurements and Main Results: One hundred thirty patients were recruited to the study over a 24-month period, and 126 patients completed follow up. Altogether, 88 patients (70%) had a single cause for their pleural effusion, and 38 (30%) had multiple causes. Serum N-terminal pro-brain natriuretic peptide (NT-pro BNP) greater than or equal to 1,500 pg/ml was predictive of multiple etiologies. NT-pro BNP had a sensitivity and specificity of 79 and 88%, respectively, for establishing heart failure as a primary or contributory cause. Thirteen patients with a malignant pleural effusion also had an NT-pro BNP greater than or equal to 1,500 pg/ml. Conclusions: This study is the first to estimate the prevalence of more than one identifiable cause for a unilateral pleural effusion. Out of 130 study subjects, 38 (30%) had multiple causes for an effusion. The identification of multiple pathologies underlying an accumulation of fluid in the pleural space may be important in determining optimum treatment and improving patients' symptoms.

Introduction Previous studies have assessed the diagnostic ability of pleural fluid adenosine deaminase (pfADA) in detecting tuberculous pleural effusions, with good specificity and sensitivity reported. However, in North Western Europe pfADA is not routinely used in the investigation of a patient with an undiagnosed pleural effusion, mainly due to a lack of evidence as to its utility in populations with low mycobacterium tuberculosis (mTB) incidence. Methods Patients presenting with an undiagnosed pleural effusion to a tertiary pleural centre in South-West England over a 3 year period, were prospectively recruited to a pleural biomarker study. Pleural fluid from consecutive patients with robust 12-month follow up data and confirmed diagnosis were sent for pfADA analysis. Results Of 338 patients enrolled, 7 had confirmed tuberculous pleural effusion (2%). All mTB effusions were lymphocyte predominant with a median pfADA of 72.0 IU/L (range- 26.7 to 91.5) compared to a population median of 12.0 IU/L (range- 0.3 to 568.4). The optimal pfADA cut off was 35 IU/L, which had a negative predictive value (NPV) of 99.7% (95% CI; 98.2-99.9%) for the exclusion of mTB, and sensitivity of 85.7% (95% CI; 42.2-97.6%) with an area under the curve of 0.88 (95% CI; 0.732–1.000). Discussion This is the first study examining the diagnostic utility of pfADA in a low mTB incidence area. The chance of an effusion with a pfADA under 35 IU/L being of tuberculous aetiology was negligible. A pfADA of over 35 IU/L in lymphocyte-predominant pleural fluid gives a strong suspicion of mTB.

© 2015 Clive et al. Introduction: Animal studies have shown Zoledronic Acid (ZA) may diminish pleural fluid accumulation and tumour bulk in malignant pleural disease (MPD). We performed a pilot study to evaluate its effects in humans. Methods: We undertook a single centre, double-blind, placebo-controlled trial in adults with MPD. Patients were randomised (1:1) to receive 2 doses of intravenous ZA or placebo, 3 weeks apart and were followed-up for 6 weeks. The co-primary outcomes were change in Visual Analogue Scale (VAS) score measured breathlessness during trial follow-up and change in the initial area under the curve (iAUC) on thoracic Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) from randomisation to week 5. Multiple secondary endpoints were also evaluated. Results: Between January 2010 and May 2013, 30 patients were enrolled, 24 randomised and 4 withdrew after randomisation (1 withdrew consent; 3 had a clinical decline). At baseline, the ZA group were more breathless, had more advanced disease on radiology and worse quality of life than the placebo group. There was no significant difference between the groups with regards change in breathlessness (Adjusted mean difference (AMD) 4.16 (95%CI -4.7 to 13.0)) or change in DCE-MRI iAUC (AMD -15.4 (95%CI -58.1 to 27.3). Two of nine (22%) in the ZA arm had a >10% improvement by modified RECIST (vs 0/11 who received placebo). There was no significant difference in quality of life measured by the QLQ-C30 score (global QOL: AMD -4.1 (-13.0 to 4.9)), side effects or serious adverse event rates. Conclusions: This is the first human study to evaluate ZA in MPD. The study is limited by small numbers and imbalanced baseline characteristics. Although no convincing treatment effect was identified, potential benefits for specific subgroups of patients cannot be excluded. This study provides important information regarding the feasibility of future trials to evaluate the effects of ZA further. Trial Registration: UK Clinical Research Network ID 8877 ISRCTN17030426 www.isrctn.com.

BACKGROUND: Malignant pleural effusion (MPE) causes debilitating breathlessness and predicting survival is challenging. This study aimed to obtain contemporary data on survival by underlying tumour type in patients with MPE, identify prognostic indicators of overall survival and develop and validate a prognostic scoring system.METHODS: Three large international cohorts of patients with MPE were used to calculate survival by cell type (univariable Cox model). The prognostic value of 14 predefined variables was evaluated in the most complete data set (multivariable Cox model). A clinical prognostic scoring system was then developed and validated.RESULTS: Based on the results of the international data and the multivariable survival analysis, the LENT prognostic score (pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group (ECOG) performance score (PS), neutrophil-to-lymphocyte ratio and tumour type) was developed and subsequently validated using an independent data set. Risk stratifying patients into low-risk, moderate-risk and high-risk groups gave median (IQR) survivals of 319 days (228-549; n=43), 130 days (47-467; n=129) and 44 days (22-77; n=31), respectively. Only 65% (20/31) of patients with a high-risk LENT score survived 1 month from diagnosis and just 3% (1/31) survived 6 months. Analysis of the area under the receiver operating curve revealed the LENT score to be superior at predicting survival compared with ECOG PS at 1 month (0.77 vs 0.66, pCONCLUSIONS: The LENT scoring system is the first validated prognostic score in MPE, which predicts survival with significantly better accuracy than ECOG PS alone. This may aid clinical decision making in this diverse patient population.

Introduction Numerous studies have assessed the diagnostic ability of pleural adenosine deaminase (ADA) in detecting tuberculous pleural effusions, with good specificity and sensitivity reported. However, in the UK (UK) ADA is not routinely used in the investigation of a patient with a pleural effusion, mainly due to a lack of evidence as to its utility in areas where tuberculosis (TB) incidence is low. Methods Patients presenting with an undiagnosed pleural effusion to a tertiary pleural centre in South-West England over a 3 year period, were prospectively recruited to a pleural biomarker study, in which baseline pleural fluid samples were collected and stored. Samples from consecutive patients with robust 12-month follow up data and confirmed diagnoses were sent for ADA analysis. Results Of 338 patients enrolled, 7 had confirmed tuberculous pleural effusion (2%). All 7 TB effusions were lymphocyte predominant with a median ADA of 72.0 IU/L (range- 26.7 to 91.5) compared to a population median of 12.0 IU/L (range- 0.3 to 568.4). Using the established cut off of 35 IU/L, ADA was shown to have a negative predictive value (NPV) of 99.7% (95% CI; 98.2–99.9%) for the exclusion of TB, and sensitivity of 85.7% (95% CI; 42.2–97.6%) with an area under the curve of 0.88 (95% CI; 0.732–1.000). In the context of a lymphocytic effusion an ADA over 35 IU/L had a sensitivity and positive predictive value of 85.7% (95% CI; 42.2–97.6%), see figure. Bacterial pleural infection was the main alternative cause of raised ADA in our cohort. Discussion This is the first study examining the diagnostic utility of pleural fluid ADA in a low TB incidence area. The chance of an effusion with an ADA under 35 IU/L being of tuberculous aetiology was negligible and empirical anti-TB therapy could be avoided in such cases. A pleural ADA of over 35 IU/L in lymphocyte-predominant pleural fluid gives a strong suspicion of tuberculous aetiology. In patients who are unsuitable for more invasive procedures this could be used as an indication to start therapy.