Early Video-assisted Thoracoscopic Surgery or Intrapleural Enzyme Therapy in Pleural Infection: A Feasibility Randomized Controlled Trial. The Third Multicenter Intrapleural Sepsis Trial-MIST-3.

Rationale: Assessing the early use of video-assisted thoracoscopic surgery (VATS) or intrapleural enzyme therapy (IET) in pleural infection requires a phase III randomized controlled trial (RCT). Objectives: To establish the feasibility of randomization in a surgery-versus-nonsurgery trial as well as the key outcome measures that are important to identify relevant patient-centered outcomes in a subsequent RCT. Methods: The MIST-3 (third Multicenter Intrapleural Sepsis Trial) was a prospective multicenter RCT involving eight U.K. centers combining on-site and off-site surgical services. The study enrolled all patients with a confirmed diagnosis of pleural infection and randomized those with ongoing pleural sepsis after an initial period (as long as 24 h) of standard care to one of three treatment arms: continued standard care, early IET, or a surgical opinion with regard to early VATS. The primary outcome was feasibility based on >50% of eligible patients being successfully randomized, >95% of randomized participants retained to discharge, and >80% of randomized participants retained to 2 weeks of follow-up. The analysis was performed per intention to treat. Measurements and Main Results: Of 97 eligible patients, 60 (62%) were randomized, with 100% retained to discharge and 84% retained to 2 weeks. Baseline demographic, clinical, and microbiological characteristics of the patients were similar across groups. Median times to intervention were 1.0 and 3.5 days in the IET and surgery groups, respectively (P = 0.02). Despite the difference in time to intervention, length of stay (from randomization to discharge) was similar in both intervention arms (7 d) compared with standard care (10 d) (P = 0.70). There were no significant intergroup differences in 2-month readmission and further intervention, although the study was not adequately powered for this outcome. Compared with VATS, IET demonstrated a larger improvement in mean EuroQol five-dimension health utility index (five-level edition) from baseline (0.35) to 2 months (0.83) (P = 0.023). One serious adverse event was reported in the VATS arm. Conclusions: This is the first multicenter RCT of early IET versus early surgery in pleural infection. Despite the logistical challenges posed by the coronavirus disease (COVID-19) pandemic, the study met its predefined feasibility criteria, demonstrated potential shortening of length of stay with early surgery, and signals toward earlier resolution of pain and a shortened recovery with IET. The study findings suggest that a definitive phase III study is feasible but highlights important considerations and significant modifications to the design that would be required to adequately assess optimal initial management in pleural infection.The trial was registered on ISRCTN (number 18,192,121).

Thoracic ultrasound competence for ultrasound guided pleural procedures: The creation and validation of an assessment tool for use in the certification of basic thoracic ultrasound competence.

OBJECTIVES: Focused thoracic ultrasound (TUS) provides an increased safety profile when undertaking invasive pleural procedures. This has led to the requirement for defined curricula, high quality teaching and robust, validated assessment tools among physicians to ensure patient safety and clinical excellence. Current UK practice is based almost exclusively on expert consensus, but assessment methods employed have been shown to have low reliability and validity and are potentially open to bias. As a result, several assessment tools have been developed, although each has its own limitations. METHODS: This study aimed to develop and validate an assessment tool corresponding to those skills associated with the most basic level of practice, defined recently as an emergency level operator in the British Thoracic Society Training Standards for Thoracic Ultrasound. RESULTS: A total of 27 candidates were enrolled by two examiners based in Belfast and Oxford over a 10-month period between February and November 2019. Mean score of the inexperienced group was 44.3 (95% CI 39.2-49.4, range 28-54) compared with 74.9 (95% CI 72.8-77, range 64-80) in the experienced group providing an estimated mean difference of 30.7 between the two groups (95% CI 24.7-36.7; p < .001). CONCLUSIONS: This tool appears to discriminate between trainees with limited experience of TUS performance and those with no experience. It has the potential to form part of the assessment strategy for trainees in the United Kingdom and beyond, alongside well established assessment tools in postgraduate training.

Diagnostic Yield and Safety of Image-Guided Pleural Biopsy: A Systematic Review and Meta-Analysis.

BACKGROUND: Diagnostic yield (DY) and safety of computed tomography (CT)- and thoracic ultrasound (TUS)-guided biopsies in the diagnosis of pleural lesions have been investigated in a number of studies, but no synthesis of data from the literature has ever been performed. OBJECTIVES: We aimed to provide the first systematic review and meta-analysis on the DY and safety of CT- versus TUS-guided biopsy in the diagnosis of pleural lesions. METHOD: We searched MEDLINE and EMBASE for all studies reporting outcomes of interest published up to April 2018. Two authors reviewed all titles/abstracts and retrieved selected full text to identify studies according to predefined selection criteria. Summary estimates were derived using the random-effects model. Cumulative meta-analysis assessed the influence of increasing adoption of the procedures over time. RESULTS: Thirty original studies were included in the present review; the number of studies on TUS-guided biopsy was almost three-fold higher than those on CT-guided biopsy. The pooled DYs of the 2 procedures were overall excellent and differed <10%, being 84% for TUS-guided biopsy and 93% for CT-guided biopsy. Safety profiles were reassuring for both the techniques, being 7 and 3% for CT- and TUS-guided biopsy, respectively. DY of ultrasound technique significantly improved over time, while no time effect was observed for CT-guided biopsy. CONCLUSIONS: Data show that CT- and TUS-guided biopsies in the diagnosis of pleural lesions are both excellent procedures, without meaningful differences in DYs and safety. Considering that TUS is non-ionizing and easily performed at the bedside, it should be the preferred approach in presence of adequate skills.

Intercostal vessel screening prior to pleural interventions by the respiratory physician: a prospective study of real world practice.

INTRODUCTION: The rising incidence of pleural disease is seeing an international growth of pleural services, with physicians performing an ever-increasing volume of pleural interventions. These are frequently conducted at sites without immediate access to thoracic surgery or interventional radiology and serious complications such as pleural bleeding are likely to be under-reported. AIM: To assess whether intercostal vessel screening can be performed by respiratory physicians at the time of pleural intervention, as an additional step that could potentially enhance safe practice. METHODS: This was a prospective, observational study of 596 ultrasound-guided pleural procedures conducted by respiratory physicians and trainees in a tertiary centre. Operators did not have additional formal radiology training. Intercostal vessel screening was performed using a low frequency probe and the colour Doppler feature. RESULTS: The intercostal vessels were screened in 95% of procedures and the intercostal artery (ICA) was successfully identified in 53% of cases. Screening resulted in an overall site alteration rate of 16% in all procedures, which increased to 30% when the ICA was successfully identified. This resulted in procedure abandonment in 2% of cases due to absence of a suitable entry site. Intercostal vessel screening was shown to be of particular value in the context of image-guided pleural biopsy. CONCLUSION: Intercostal vessel screening is a simple and potentially important additional step that can be performed by respiratory physicians at the time of pleural intervention without advanced ultrasound expertise. Whether the widespread use of this technique can improve safety requires further evaluation in a multi-centre setting with a robust prospective study.

The role of imaging for the management of newly diagnosed glioblastoma in adults: a systematic review and evidence-based clinical practice guideline update.

TARGET POPULATION: These recommendations apply to adults with a newly diagnosed lesion with a suspected or histopathologically proven glioblastoma (GBM). QUESTION: What are the optimal imaging techniques to be used in the management of a suspected glioblastoma (GBM), specifically: which imaging sequences are critical for most accurately identifying or diagnosing a GBM and distinguishing this tumor from other tumor types? RECOMMENDATIONS: Critical Imaging for the Identification and Diagnosis of Glioblastoma Level II: In patients with a suspected GBM, it is recommended that the minimum magnetic resonance imaging (MRI) exam should be an anatomic exam with both T2 weighted, FLAIR and pre- and post-gadolinium contrast enhanced T1 weighted imaging. The addition of diffusion and perfusion weighted MR imaging can assist in the assessment of suspected GBM for the purposes of distinguishing GBM from other tumor types. Computed tomography (CT) can provide additional information regarding calcification or hemorrhage and also can be useful for subjects who are unable to undergo MR imaging. At a minimum, these anatomic sequences can help identify a lesion as well as its location, and potential for surgical intervention. Improvement of diagnostic specificity with the addition of non-anatomic (physiologic imaging) to anatomic imaging Level II: One blinded prospective study and a significant number of case series support the addition of diffusion and perfusion weighted MR imaging in the assessment of suspected GBM, for the purposes of distinguishing GBM from other tumor types (e.g., primary CNS lymphoma or metastases). Level III: It is suggested that magnetic resonance spectroscopy (MRS) and nuclear medicine imaging (PET 18F-FDG and 11C-MET) be used to provide additional support for the diagnosis of GBM.

A systematic review of comorbidities and outcomes of adult patients with pleural infection.

BACKGROUND: Pleural infection remains an important cause of mortality. This study aimed to investigate worldwide patterns of pre-existing comorbidities and clinical outcomes of patients with pleural infection. METHODS: Studies reporting on adults with pleural infection between 2000 and 2017 were identified from a search of Embase and MEDLINE. Articles reporting exclusively on tuberculous, fungal or post-pneumonectomy infection were excluded. Two reviewers assessed 20 980 records for eligibility. RESULTS: 211 studies met the inclusion criteria. 134 articles (227 898 patients, mean age 52.8 years) reported comorbidity and/or outcome data. The majority of studies were retrospective observational cohorts (n=104, 78%) and the most common region of reporting was East Asia (n=33, 24%) followed by North America (n=27, 20%). 85 articles (50 756 patients) reported comorbidity. The median (interquartile range (IQR)) percentage prevalence of any comorbidity was 72% (58-83%), with respiratory illness (20%, 16-32%) and cardiac illness (19%, 15-27%) most commonly reported. 125 papers (192 298 patients) reported outcome data. The median (IQR) length of stay was 19 days (13-27 days) and median in-hospital or 30-day mortality was 4% (IQR 1-11%). In regions with high-income economies (n=100, 74%) patients were older (mean 56.5 versus 42.5 years, p<0.0001), but there were no significant differences in prevalence of pre-existing comorbidity nor in length of hospital stay or mortality. CONCLUSION: Patients with pleural infection have high levels of comorbidity and long hospital stays. Most reported data are from high-income economy settings. Data from lower-income regions is needed to better understand regional trends and enable optimal resource provision going forward.

The microbiology of pleural infection in adults: a systematic review.

BACKGROUND AND OBJECTIVES: Pleural infection is a major cause of morbidity and mortality among adults. Identification of the offending organism is key to appropriate antimicrobial therapy. It is not known whether the microbiological pattern of pleural infection is variable temporally or geographically. This systematic review aimed to investigate available literature to understand the worldwide pattern of microbiology and the factors that might affect such pattern. DATA SOURCES AND ELIGIBILITY CRITERIA: Ovid MEDLINE and Embase were searched between 2000 and 2018 for publications that reported on the microbiology of pleural infection in adults. Both observational and interventional studies were included. Studies were excluded if the main focus of the report was paediatric population, tuberculous empyema or post-operative empyema. STUDY APPRAISAL AND SYNTHESIS METHODS: Studies of ≥20 patients with clear reporting of microbial isolates were included. The numbers of isolates of each specific organism/group were collated from the included studies. Besides the overall presentation of data, subgroup analyses by geographical distribution, infection setting (community versus hospital) and time of the report were performed. RESULTS: From 20 980 reports returned by the initial search, 75 articles reporting on 10 241 patients were included in the data synthesis. The most common organism reported worldwide was Staphylococcus aureus. Geographically, pneumococci and viridans streptococci were the most commonly reported isolates from tropical and temperate regions, respectively. The microbiological pattern was considerably different between community- and hospital-acquired infections, where more Gram-negative and drug-resistant isolates were reported in the hospital-acquired infections. The main limitations of this systematic review were the heterogeneity in the method of reporting of certain bacteria and the predominance of reports from Europe and South East Asia. CONCLUSIONS: In pleural infection, the geographical location and the setting of infection have considerable bearing on the expected causative organisms. This should be reflected in the choice of empirical antimicrobial treatment.

Malignant Pleural Effusions: Management Options.

Malignant pleural effusion (MPE) represents advanced metastatic malignancy and is associated with poor median survival. Incidence remains high and continues to rise, in part due to changing population demographics. This therefore represents a significant health care burden. Management is predominantly palliative in nature and multiple interventions are available within conventional treatment paradigms, all of which are proven to result in statistically significant patient benefit. This article further explores the methods available in the management of MPE along with the pitfalls, complications, and alternatives. Recent advances within the field are discussed with an exploration of likely future directions, including the role of ultrasound as a prospective predictor and the role of intrapleural fibrinolytic therapy.

Mapping and monitoring High Nature Value farmlands: challenges in European landscapes.

The importance of low intensity farming for the conservation of biodiversity throughout Europe was acknowledged early in the 1990s when the concept of 'High Nature Value farmlands' (HNVf) was devised. HNVf has subsequently been given high priority within the EU Rural Development Programme. This puts a requirement on each EU Member State not only to identify the extent and condition of HNVf within their borders but also to track trends in HNVf over time. However, the diversity of rural landscapes across the EU, the scarcity of (adequate) datasets on biodiversity, land cover and land use, and the lack of a common methodology for HNVf mapping currently represent obstacles to the implementation of the HNVf concept across Europe. This manuscript provides an overview of the characteristics of HNVf across Europe together with a description of the development of the HNVf concept. Current methodological approaches for the identification and mapping of HNVf across EU-27 and Switzerland are then reviewed, the main limitations of these approaches highlighted and recommendations made as to how the identification, mapping and reporting of HNVf state and trends across Europe can potentially be improved and harmonised. In particular, we propose a new framework that is built on the need for strategic HNVf monitoring based on a hierarchical, bottom-up structure of assessment units, coincident with the EU levels of political decision and devised indicators, and which is linked strongly to a collaborative European network that can provide the integration and exchange of data from different sources and scales under common standards. Such an approach is essential if the scale of the issues facing HNVf landscapes are to be identified and monitored properly at the European level. This would then allow relevant agri-environmental measures to be developed, implemented and evaluated at the scale(s) required to maintain the habitats and species of high nature conservation value that are intimately associated with those landscapes.

Improving the farmland biodiversity value of riparian buffer strips: conflicts and compromises.

The intensity of management of lowland grassland fields in the United Kingdom, coupled with the fact that such grasslands dominate much of the lowland landscape, means that there are now few opportunities for many plants, invertebrates, birds, or mammals to survive. The Scottish Agricultural College (SAC) has investigated whether fencing off the margins of such fields next to watercourses to control diffuse pollution has any positive impacts on biodiversity, based on assessments of vegetation composition and condition and structure of assemblages of invertebrates of importance as foodstuffs to farmland birds. Fencing watercourses increased the abundance of key groups of invertebrates. However, the invertebrate species diversity was not increased unless the margins were ≥ 5.4 m in width. Margins established in the study area to prevent access by livestock to watercourses or to enhance biodiversity are generally ≤ 2.6 m wide and are therefore unlikely to provide conditions for additional invertebrate species to use. The dense, tall swards within such margins are also unlikely to provide foraging opportunities for farmland birds. Management (such as low-intensity grazing by livestock in the margins) is essential to provide the conditions required for these groups, but this could conflict with the diffuse pollution mitigation aims. A compromise is proposed whereby limited autumn/winter grazing by livestock could be used to open the vegetation structure in the margins. Grazing by livestock at that time may be acceptable since it is not occurring in the period of main diffuse pollution concern (i.e., the fecal contamination of watercourses and bathing waters in the spring and summer). It is also essential that a landscape-scale approach is taken, driven by knowledge of the full needs of the species concerned, when deciding where best to target agri-environmental actions aimed at farmland bird conservation.

Turning on the light for brain tumor surgery: A 5-aminolevulinic acid story.

To aid surgeons in more complete and safe resection of brain tumors, adjuvant technologies have been developed to improve visualization of target tissue. Fluorescence-guided surgery relies on the use of fluorophores and specific light wavelengths to better delineate tumor tissue, inflammation, and areas of blood-brain barrier breakdown. 5-aminolevulinic acid (5-ALA), the first fluorophore developed specifically for brain tumors, accumulates within tumor cells, improving visualization of tumors both at the core, and infiltrative margin. Here, we describe the background of how 5-ALA integrated into the modern neurosurgery practice, clinical evidence for the current use of 5-ALA, and future directions for its role in neurosurgical oncology. Maximal safe resection remains the standard of care for most brain tumors. Gross total resection of high-grade gliomas (HGGs) is associated with greater overall survival and progression-free survival (PFS) in comparison to subtotal resection or adjuvant treatment therapies alone.1-3 A major challenge neurosurgeons encounter when resecting infiltrative gliomas is identification of the glioma tumor margin to perform a radical resection while avoiding and preserving eloquent regions of the brain. 5-aminolevulinic acid (5-ALA) remains the only optical-imaging agent approved by the FDA for use in glioma surgery and identification of tumor tissue.4 A multicenter randomized, controlled trial revealed that 5-ALA fluorescence-guided surgery (FGS) almost doubled the extent of tumor resection and also improved 6-month PFS.5 In this review, we will highlight the current evidence for use of 5-ALA FGS in brain tumor surgery, as well as discuss the future directions for its use.

Critical analysis of the utility of initial pleural aspiration in the diagnosis and management of suspected malignant pleural effusion.

INTRODUCTION: Current guidelines recommend an initial pleural aspiration in the investigation and management of suspected malignant pleural effusions (MPEs) with the aim of establishing a diagnosis, identifying non-expansile lung (NEL) and, at times, providing a therapeutic procedure. A wealth of research has been published since the guidelines suggesting that results and outcomes from an aspiration may not always provide sufficient information to guide management. It is important to establish the validity of these findings in a 'real world' population. METHODS: A retrospective analysis was conducted of all patients who underwent pleural fluid (PF) sampling, in a single centre, over 3 years to determine the utility of the initial aspiration. RESULTS: A diagnosis of MPE was confirmed in 230/998 (23%) cases, a further 95/998 (9.5%) were presumed to represent MPE. Transudative biochemistry was found in 3% of cases of confirmed MPE. Positive PF cytology was only sufficient to guide management in 45/140 (32%) cases. Evidence of pleural thickening on CT was associated with both negative cytology (χ2 1df=26.27, p<0.001) and insufficient samples (χ2 1df=10.39, p=0.001). In NEL 44.4% of patients did not require further procedures after pleurodesis compared with 72.7% of those with expansile lung (χ2 1df=5.49, p=0.019). In patients who required a combined diagnostic and therapeutic aspiration 106/113 (93.8%) required further pleural procedures. CONCLUSIONS: An initial pleural aspiration does not achieve either definitive diagnosis or therapy in the majority of patients. A new pathway prioritising symptom management while reducing procedures should be considered.

Pleural infection: a closer look at the etiopathogenesis, microbiology and role of antibiotics.

INTRODUCTION: Pleural infection is a condition that continues to pose a significant challenge to respiratory physicians. We hypothesize that the main barriers to progress include limited understanding of the etiopathogenesis, microbiology,and role of antibiotics in the pleural space. Areas covered: PubMed was searched for articles related to adult pleural infection using the terms 'pleural infection', 'empyema' and 'parapneumonic'. The search focused on relevant literature within the last 10 years, with any older citations used only to display context or lack of progress. Tuberculous pleural infection was excluded. We chose to give specific attention to the etiopathogenesis of pleural infection, including recent advances in diagnostics and biomarkers. We discuss our understanding of the pleural microbiome and rationalize the current use of antibiotics in treating this condition. Expert commentary: Understanding of key events in the development of this condition remains limited. The microbiology is unique compared to the lung, and highly variable. Higher culture yields from pleural biopsy may add new insights into the etiopathogenesis. There is little evidence into achievable effective antibiotic concentration within the pleura. Research into issues including the relevance of biofilm formation and significance of pleural thickening is necessary for treatment progress.

Contemporary Approach to the Diagnosis of Malignant Pleural Effusion.

Advanced malignancy is a prevalent cause of exudative pleural effusion. The management of malignant pleural effusion (MPE) has been the subject of several recent randomized controlled trials and excellent reviews. Less attention has been focused on another controversial and challenging aspect of MPE: establishing the diagnosis. Before selecting the optimal management strategy, the presence of an MPE must first be correctly identified with an emphasis on minimizing invasiveness and discomfort in a patient with late-stage cancer. The aim of the present review is to summarize the current knowledge about MPE diagnostics and to propose an algorithm for the diagnosis of MPE in established or suspected malignancy.

A retrospective analysis comparing the use of ProCore® with standard fine needle aspiration in endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA).

Endobronchial ultrasound has become first line in the investigation of mediastinal lesions suspicious for malignancy in keeping with National Institute for Health and Care Excellence (NICE) guidelines; however, needle size and type required to maximise diagnostic sensitivity remains unclear. Previous meta-analyses have compared the use of ProCore with standard fine needle aspiration in the assessment of pancreatic masses with differences noted only in the number of passes required. We aim to assess whether a ProCore needle improves diagnostic sensitivity in EBUS-TBNA. Complete follow-up data regarding all 235 patients undergoing EBUS-TBNA in a district general hospital has been collected since the service's inception in 2012. Results were collated and retrospectively analysed allowing for calculation of test sensitivity and specificity. Comparison was then made between procedures where standard fine needle aspiration was performed and those using a ProCore needle. Overall sensitivity of EBUS-TBNA was shown to be 85% with a specificity of 100% in keeping with quoted figures from other centres. Standard fine needle aspiration produced a sensitivity of 77% (85/110) versus ProCore sensitivity of 92% (115/125) with a p value of 0.0016. Thirty percent (33/110) of patients undergoing standard fine needle aspiration required an appropriate crossover technique such as mediastinoscopy or CT-guided FNA in order to either obtain or confirm the diagnosis compared with 15% (19/125) of the ProCore group with a p value of 0.0064. Our retrospective analysis shows a statistically significant difference in the diagnostic sensitivity of sampling mediastinal lymphadenopathy using a ProCore needle compared with standard fine needle aspiration. It also shows that a significantly fewer number of patients required further procedures in order to obtain or confirm the diagnosis. This could potentially be confounded by the retrospective nature of the study design; however, due to the statistical significance demonstrated, further study is required.

Thoracic ultrasound competence for ultrasound-guided pleural procedures.

Focused thoracic ultrasound has become essential in the guidance and direction of pleural interventions to reduce unwanted complications and as a result now forms a crucial component of physician training. Current training standards along with assessment methods vary widely, and are often not robust enough to ensure adequate competence.This review assesses the current state of training and assessment of thoracic ultrasound competence in various settings, allowing comparison with alternative competency based programmes. Future directions for training and assessment of thoracic ultrasound competence are discussed.

Survival in patients with malignant pleural effusion undergoing talc pleurodesis.

OBJECTIVES: Recent observations indicate a potential survival benefit in patients with malignant pleural effusion (MPE) who achieve successful pleurodesis in comparison to patients who experience effusion recurrence post pleurodesis. This study aimed to explore this observation using two datasets of patients with MPE undergoing talc pleurodesis. MATERIALS AND METHODS: Dataset 1 comprised patients who underwent talc pleurodesis at Oxford Pleural Unit for MPE. Dataset 2 comprised patients enrolled in the TIME1 clinical trial. Pleurodesis success was defined as absence of need for further therapeutic procedures for MPE in the three months following pleurodesis. Data on various clinical, laboratory and radiological parameters were collected and survival was compared according to pleurodesis outcome (success vs. failure) after adjusting for the aforementioned parameters. RESULTS: Dataset 1 comprised 60 patients with mean age 74.1±10.3 years. The most common primary malignancies were mesothelioma, breast and lung cancer. 29 patients (48.3%) achieved pleurodesis. The adjusted odds ratio (aOR) for poor survival with pleurodesis failure was 2.85 (95% CI 1.08-7.50, =p 0.034). Dataset 2 comprised 259 patients from the TIME1 trial. The mean age was 70.8±10.3 and the most common primary malignancies were mesothelioma, lung and breast cancer. Pleurodesis was successful in 205 patients (79%). aOR for poor survival was 1.62 (95% CI 1.09-2.39, p = 0.015). CONCLUSION: Achieving pleurodesis seems to impart a survival benefit in patients with MPE. Further studies are required to explore factors that may contribute to this phenomenon and to address the difference in survival between pleurodesis and indwelling pleural catheter interventions.