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.

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.

Outpatient Talc Administration by Indwelling Pleural Catheter for Malignant Effusion.

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. (Funded by Becton Dickinson; EudraCT number, 2012-000599-40 .).

Patient outcomes after hospitalisation with COVID-19 and implications for follow-up: results from a prospective UK cohort.

The longer-term consequences of SARS-CoV-2 infection are uncertain. Consecutive patients hospitalised with COVID-19 were prospectively recruited to this observational study (n=163). At 8-12 weeks postadmission, survivors were invited to a systematic clinical follow-up. Of 131 participants, 110 attended the follow-up clinic. Most (74%) had persistent symptoms (notably breathlessness and excessive fatigue) and limitations in reported physical ability. However, clinically significant abnormalities in chest radiograph, exercise tests, blood tests and spirometry were less frequent (35%), especially in patients not requiring supplementary oxygen during their acute infection (7%). Results suggest that a holistic approach focusing on rehabilitation and general well-being is paramount.

Standards of care in mesothelioma treatment.

The UK has the highest incidence of mesothelioma in the world, but services vary across the country partly due to uneven geographical distribution of cases. The Mesothelioma UK-funded national organisational audit has highlighted challenges in accessing diagnostic procedures such as thoracoscopy, as well as identifying examples of best practice, including access to clinical trials and specialist therapeutic procedures. To ensure equitable and optimal patient care, cancer alliances should have established referral pathways to specialist multidisciplinary team (MDT) services for discussion of all mesothelioma patients.

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.

Recurrence rates in primary spontaneous pneumothorax: a systematic review and meta-analysis.

Primary spontaneous pneumothorax (PSP) recurrence rates vary widely in the published literature, with limited data describing the factors that influence recurrence. The aims of this systematic review were to determine an estimation of PSP recurrence rates and describe risk factors for recurrence.A systematic review was conducted of all studies reporting PSP recurrence. Electronic searches were performed to identify English language publications of randomised trials and observational studies. The population was adults with PSP, who underwent conservative management, pleural aspiration or chest drainage. The outcome of interest was recurrence. Articles were screened and data extracted from eligible studies by two reviewers.Of 3607 identified studies, 29 were eligible for inclusion, comprising 13 548 patients. Pooled 1-year and overall recurrence rates were 29.0% (95% CI 20.9-37.0%) and 32.1% (95% CI 27.0-37.2%), respectively. Female sex was associated with increased recurrence (OR 3.03, 95% CI 1.24-7.41), while smoking cessation was associated with a four-fold decrease in risk (OR 0.26, 95% CI 0.10-0.63). I2 for random effects meta-analysis was 94% (p<0.0001), reflecting high heterogeneity between studies.This systematic review demonstrates a 32% PSP recurrence rate, with greatest risk in the first year. Female sex was associated with higher risk, suggesting possible sex-specific pathophysiology.

ERS/EACTS statement on the management of malignant pleural effusions.

Malignant pleural effusions (MPE) are a common pathology, treated by respiratory physicians and thoracic surgeons alike. In recent years, several well-designed randomised clinical trials have been published that have changed the landscape of MPE management. The European Respiratory Society (ERS) and the European Association for Cardio-Thoracic Surgery (EACTS) established a multidisciplinary collaboration of clinicians with expertise in the management of MPE with the aim of producing a comprehensive review of the scientific literature.Six areas of interest were identified, including the optimum management of symptomatic MPE, management of trapped lung in MPE, management of loculated MPE, prognostic factors in MPE, whether there is a role for oncological therapies prior to intervention for MPE and whether a histological diagnosis is always required in MPE.The literature revealed that talc pleurodesis and indwelling pleural catheters effectively manage the symptoms of MPE. There was limited evidence regarding the management of trapped lung or loculated MPE. The LENT score was identified as a validated tool for predicting survival in MPE, with Brims' prognostic score demonstrating utility in mesothelioma prognostication. There was no evidence to support the use of oncological therapies as an alternative to MPE drainage, and the literature supported the use of tissue biopsy as the gold standard for diagnosis and treatment planning.

Exploring the characteristics of patients with mesothelioma who chose active symptom control over chemotherapy as first-line treatment: a prospective, observational, single centre study.

BACKGROUND: Mesothelioma is an aggressive thoracic tumour with a poor prognosis. The only treatment that extends survival is chemotherapy. However, in the UK, up to 50% of patients who are suitable for chemotherapy choose not to receive it, opting for active symptom control instead. The aim of this prospective, single-centre observational study was to describe the characteristics of patients who chose active symptom control over chemotherapy and explore their reasons for doing so. METHODS: Two hundred consecutive patients with mesothelioma from one UK centre were included. Eligibility for chemotherapy and choice of first-line treatment were recorded prospectively. Patient characteristics and outcomes were compared using descriptive statistics, regression analysis and survival analysis. Reasons for choosing active symptom control over chemotherapy were extracted, retrospectively. RESULTS: People who chose active symptom control were older, more likely to be female and had worse performance statuses than patients who received front-line chemotherapy. Concern over side effects, the modest survival benefit and previous adverse experiences with chemotherapy were reported as reasons for the decision. Median survival was 13.9 months in the chemotherapy group compared with 6.7 months in the active symptom control group. CONCLUSIONS: This is the first study to describe the characteristics of patients with mesothelioma who chose active symptom control over chemotherapy, in the front-line setting. Important differences were seen between this group and patients who received chemotherapy, although confounding is likely to have affected some outcomes. Future research could use qualitative methods to explore patients' reasons for choosing active symptom control, and to further elucidate the decision-making process.

Pleural biopsies in undiagnosed pleural effusions; Abrams vs image-guided vs thoracoscopic biopsies.

PURPOSE OF REVIEW: Pleural biopsies are often necessary if a pleural effusion remains undiagnosed after radiological imaging and pleural fluid analysis. There are many methods of obtaining pleural biopsies, including blind or image-guided procedures, closed-bevel or cutting-edge needles, and percutaneous or thoracoscopic approaches. This article will review recent research relating to these methods, aiming to provide an overview of the strengths and limitations of each technique. RECENT FINDINGS: Historically pleural biopsies were undertaken using a blind closed 'Abrams' needle method. However, low diagnostic yields and high complication rates are seen with this technique compared with newer methods. Recent research compares image-guided, cutting-needle approaches to traditional Abrams biopsies, and evaluates the role of medical thoracoscopy in comparison to other techniques. SUMMARY: Thoracoscopic biopsies are the gold standard for investigating pleural disease. However, this service is not universally available and may be unsuitable for some patients. Image-guided cutting-needle biopsies under computed tomography or ultrasound guidance have high diagnostic rates and are useful in a wide patient population. The main role of Abrams biopsies is in the diagnosis of tuberculous pleuritis in resource-poor settings.

Nutritional management in chyle leaks and chylous effusions.

Chyle leaks occur when there is interruption to the lymphatic ducts that transport chyle around the body. The loss of this protein-rich, calorie-rich fluid can cause serious complications including dehydration, malnutrition and immunosuppression. Treatment of chyle leaks depends on the underlying cause, which may be surgical, secondary to malignant invasion or the result of a medical condition. Nutritional support is vital and leads to spontaneous leak closure in many cases. Nutritional management options include total bowel rest with parenteral nutrition, enteral feeding with specialized formula, or oral diet with supplementation. At present there is no consensus regarding which approach is superior. In reality, most patients with chyle leaks are managed with a combination or oral and enteral feeding, but further work is needed to clarify the optimum management strategy.

The mental health and well-being implications of a mesothelioma diagnosis: A mixed methods study.

PURPOSE: Mesothelioma is an incurable, asbestos-related cancer with a poor prognosis. There is scant evidence about the mental health and well-being impacts on patients and carers living with the illness. This study aimed to investigate mesothelioma's impact on mental health and well-being and the scale of mental health conditions in patients and informal carers. METHODS: A mixed-methods design was used: a cross-sectional survey of mesothelioma patients and informal carers plus semi-structured interviews with patients and carers. The survey used validated scales collecting data on mental health aspects of mesothelioma: the EQ5D to assess health-related quality-of-life; the Hospital Anxiety and Depression scale; the PCL-5 to assess Posttraumatic Stress; and the Posttraumatic Growth Inventory. The datasets were integrated during analysis. RESULTS: 96 useable survey responses were received. A clinical level of depression was reported by 29 participants (30.21%), of anxiety by 48 (50%), of posttraumatic distress disorder by 32 (33.33%), and of posttraumatic growth by 34 (35.42%). Carers had worse scores than patients. Three main themes were developed from interviews with 10 patients and 11 carers: 'Prognosis', 'Support from services', and 'Social connections and communication'. CONCLUSIONS: Healthcare professionals delivering a mesothelioma diagnosis require regular training in communication skills plus updating in current treatment options, so they provide an appropriate mix of realism and hope. Better signposting to mental health support is needed for patients and carers. Our introduction of posttraumatic growth into the mesothelioma literature is novel. We recommend specialist nurses are trained to recognise, understand, and foster posttraumatic growth.

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.

The priorities of people with mesothelioma and their carers: A qualitative interview study of trial participation and treatment decisions.

PURPOSE: Treatment options for mesothelioma are increasing, as are the number of clinical trials available to patients. However, little is known about patients' and relatives' priorities when making decisions about treatment and trial participation. The aim of this study was to provide insight into people's experiences of participating in clinical research and explore the factors influencing decision-making. METHODS: Face to face, semi-structured interviews were undertaken with mesothelioma patients who were participating in the TILT trial (a randomised trial of intra-pleural immunotherapy) and their relatives. Interviews were audio-recorded, transcribed and analysed thematically. RESULTS: Twelve people were interviewed, comprising five mesothelioma patients and seven relatives. Four themes were identified relating to the experience of mesothelioma: physicality, quality of life, uncertainty and risk, and planning for an unpredictable future. A further theme related to attitudes to research participation. PARTICIPANTS: valued physical strength and were careful not to jeopardise this with potential side effects of medication. Quality of life was important and was often prioritised over survival. Participants found ambiguity challenging and sought certainty, potentially in response to the uncertainty surrounding their future. The desire for certainty impacted on risk perception; an important factor in decision-making. Relatives often advocated on behalf of patients and were more reluctant about research participation due to concern about potential risks. CONCLUSION: The study confirmed previous qualitative findings around physicality, stoicism and uncertainty, building on these themes to highlight their influence on decision-making. Important findings for practice include the challenges associated with risk communication and the differing care needs and attitudes to research of relatives.

A trial of intra-pleural bacterial immunotherapy in malignant pleural mesothelioma (TILT) - a randomised feasibility study using the trial within a cohort (TwiC) methodology.

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.

Protocol for a prospective observational cohort study collecting data on demographics, symptoms and biomarkers in people with mesothelioma (ASSESS-meso).

INTRODUCTION: Mesothelioma is a heterogeneous disease that can be challenging to monitor and prognosticate. ASSESS-meso is a multicentre, prospective, longitudinal observational cohort study of patients with mesothelioma. The primary aim is to describe different clinical phenotypes and investigate predictive and prognostic factors, including biomarkers from blood and pleural fluid. The secondary aim is to provide a resource for future trials and substudies. METHODS AND ANALYSIS: We aim to recruit 700 patients with a histological, cytological or clinicopathological diagnosis of mesothelioma, at any anatomical site (pleural, peritoneal, pericardial, etc). Longitudinal data will be collected, including clinical information, radiological investigations, blood tests and patient-reported outcome measures for breathlessness, chest pain and sweats. Preplanned analyses will use Cox proportional hazards method to evaluate factors associated with survival, linear and logistic regression models to investigate associations with symptoms, and analysis of variance modelling to explore changes in symptoms over time. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Research Ethics Committee South West-Central Bristol (17-SW-0019) and Health Research Authority (IRAS ID 220360). A study steering committee has been established and results will be published OpenAccess in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN: 61861764.