DUETS for Light's in separating exudate from transudate.

BACKGROUND: Fifty years since its inception, Light's criteria have aided in classifying pleural effusions (PEs) as exudates if 1 or more criteria are met. Thoracic ultrasound (US) emerges as a non-invasive technique for point of care use especially if pleural procedures are contemplated. OBJECTIVE: We aimed to develop a score based on radiological and US features that could separate exudates from transudates without serum and pleural fluid biochemical tests necessary for Light's criteria. METHODS: A prospective review of consecutive patients with PE who underwent thoracocentesis was performed. CXRs were evaluated for laterality followed by US for echogenicity, pleural nodularity, thickening and septations. PE was classified as exudate or transudate according to Light's criteria and corroborated with albumin gradient. A score combining radiological and US features was developed. RESULTS: We recruited 201 patients with PE requiring thoracocentesis. Mean age was 64 years, 51% were females, 164 (81.6%) were exudates, and 37 (18.4%) were transudates. Assigning 1-point for Diaphragmatic nodularity, Unilateral, Echogenicity, Pleural Thickening and Septations, DUETS ranged from 1 to 5. DUETS ≥2 indicated high likelihood for exudate (PPV 98.8%, NPV 100%) with 1% misclassification versus 6.9% using Light's criteria (p < 0.001). CONCLUSION: DUETS separated exudates from transudates with good accuracy, and could obviate paired serum and pleural fluid tests necessary for Light's criteria computation. Our study reflected real world practice where DUETS performed better than Light's criteria for PE that arose from more than one disease processes, and in the evaluation of patients with PE who have received diuretics.

The third PLeuralEffusion And Symptom Evaluation (PLEASE-3) study: Bendopnoea in patients with pleural effusion.

Background: Pleural effusions often cause disabling breathlessness, however the mechanism is unknown. Patients with pleural effusions are subjected to pleural fluid drainage on a 'trial and error' basis, as symptom relief varies. This population commonly complain of bendopnoea (breathlessness on bending forward) which has not been investigated. Our pilot data found bendopnoea was significantly associated with presence of pleural effusion. The PLEASE-3 study will evaluate bendopnoea as a screening test for effusion-related breathlessness, its predictive value of symptomatic benefits from fluid drainage and explore its underlying physiological mechanism. Methods: PLEASE-3 is a multi-centre prospective study. Eligible patients are assessed at baseline (pre-drainage) and for patients undergoing drainage, up to 72 h post-procedure. Outcome measures include the prevalence of bendopnoea, its correlation with size of effusion and its predictive value of breathlessness relief after drainage. The relationship of bendopnoea with breathlessness, physiological parameters, functional capacity and diaphragmatic characteristics will be assessed. The study will recruit 200 participants. Discussion: This is the first study to investigate bendopnoea in patients with pleural effusion. It has minimal exclusion criteria to ensure that the results are generalisable. The presence and clinical significance of bendopnoea in the context of pleural effusion requires thorough investigation. The post assessment of patients undergoing pleural fluid drainage will provide insight into whether the presence of bendopnoea is able to predict clinical outcomes. Trial Registration: Name of the registry: Australia New Zealand Clinical Trial Registry Trial registration number: ACTRN12622000465752. URL of the trial registry record for this trial: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=383639&isReview=true Date of registration: Registered on 24 March 2022. Funding of the trial: This study has received funding from the Sir Charles Gairdner Research Advisory Council research project grant. The study is sponsored by the Institute for Respiratory Health, a not-for-profit organisation. Name and contact information for the trial sponsor: Mr Bi Lam; Finance manager. Level 2, 6 Verdun Street, Nedlands WA 6009. t‖ + 61 8 6151 0877 e‖ bi.lam@resphealth.uwa.edu.au Role of sponsor : The funder is not involved in the planning of the study, gathering, analysing, and interpreting the data, or in preparing the manuscript.

Leveraging the pleural space for anticancer therapies in pleural mesothelioma.

Most patients with pleural mesothelioma (PM) present with symptomatic pleural effusion. In some patients, PM is only detectable on the pleural surfaces, providing a strong rationale for intrapleural anticancer therapy. In modern prospective studies involving expert radiological staging and specialist multidisciplinary teams, the population incidence of stage I PM (an approximate surrogate of pleura-only PM) is higher than in historical retrospective series. In this Viewpoint, we advocate for the expansion of intrapleural trials to serve these patients, given the paucity of data supporting licensed systemic therapies in this setting and the uncertainties involved in surgical therapy. We begin by reviewing the unique anatomical and physiological features of the PM-bearing pleural space, before critically appraising the evidence for systemic therapies in stage I PM and previous intrapleural PM trials. We conclude with a summary of key challenges and potential solutions, including optimal trial designs, repurposing of indwelling pleural catheters, and new technologies.

Joint ERS/EACTS/ESTS clinical practice guidelines on adults with spontaneous pneumothorax.

BACKGROUND: The optimal management for spontaneous pneumothorax (SP) remains contentious, with various proposed approaches. This joint clinical practice guideline from the ERS, EACTS and ESTS societies provides evidence-based recommendations for the management of SP. METHODS: This multidisciplinary Task Force addressed 12 key clinical questions on the management of pneumothorax, using ERS methodology for guideline development. Systematic searches were performed in MEDLINE and Embase. Evidence was synthesised by conducting meta-analyses, if possible, or narratively. Certainty of evidence was rated with GRADE (Grading of Recommendations, Assessment, Development and Evaluations). The Evidence to Decision framework was used to decide on the direction and strength of the recommendations. RESULTS: The panel makes a conditional recommendation for conservative care of minimally symptomatic patients with primary spontaneous pneumothorax (PSP) who are clinically stable. We make a strong recommendation for needle aspiration over chest tube drain for initial PSP treatment. We make a conditional recommendation for ambulatory management for initial PSP treatment. We make a conditional recommendation for early surgical intervention for the initial treatment of PSP in patients who prioritise recurrence prevention. The panel makes a conditional recommendation for autologous blood patch in secondary SP patients with persistent air leak (PAL). The panel could not make recommendations for other interventions, including bronchial valves, suction, pleurodesis in addition to surgical resection or type of surgical pleurodesis. CONCLUSIONS: With this international guideline, the ERS, EACTS and ESTS societies provide clinical practice recommendations for SP management. We highlight evidence gaps for the management of PAL and recurrence prevention, with research recommendations made.

Joint ERS/EACTS/ESTS clinical practice guidelines on adults with spontaneous pneumothorax.

OBJECTIVES: The optimal management for spontaneous pneumothorax (SP) remains contentious, with various proposed approaches. This joint clinical practice guideline from the ERS, EACTS and ESTS societies provides evidence-based recommendations for the management of SP. METHODS: This multidisciplinary Task Force addressed 12 key clinical questions on the management of pneumothorax, using ERS methodology for guideline development. Systematic searches were performed in MEDLINE and Embase. Evidence was synthesised by conducting meta-analyses, if possible, or narratively. Certainty of evidence was rated with GRADE (Grading, Recommendation, Assessment, Development and Evaluation). The Evidence to Decision framework was used to decide on the direction and strength of the recommendations. RESULTS: The panel makes a conditional recommendation for conservative care of minimally symptomatic patients with primary spontaneous pneumothorax (PSP) who are clinically stable. We make a strong recommendation for needle aspiration over chest tube drain for initial PSP treatment. We make a conditional recommendation for ambulatory management for initial PSP treatment. We make a conditional recommendation for early surgical intervention for the initial treatment of PSP in patients who prioritise recurrence prevention. The panel makes a conditional recommendation for autologous blood patch in secondary SP patients with persistent air leak (PAL). The panel could not make recommendations for other interventions, including bronchial valves, suction, pleurodesis in addition to surgical resection or type of surgical pleurodesis. CONCLUSIONS: With this international guideline, the ERS, EACTS and ESTS societies provide clinical practice recommendations for SP management. We highlight evidence gaps for the management of PAL and recurrence prevention, with research recommendations made. SHAREABLE ABSTRACT: This update of an ERS Task Force statement from 2015 provides a concise comprehensive update of the literature base. 24 evidence-based recommendations were made for management of pneumothorax, balancing clinical priorities and patient views.https://bit.ly/3TKGp9e.

Australasian Malignant PLeural Effusion (AMPLE)-4 trial: study protocol for a multi-centre randomised trial of topical antibiotics prophylaxis for infections of indwelling pleural catheters.

BACKGROUND: Malignant pleural effusion (MPE) is a debilitating condition as it commonly causes disabling breathlessness and impairs quality of life (QoL). Indwelling pleural catheter (IPC) offers an effective alternative for the management of MPE. However, IPC-related infections remain a significant concern and there are currently no long-term strategies for their prevention. The Australasian Malignant PLeural Effusion (AMPLE)-4 trial is a multicentre randomised trial that evaluates the use of topical mupirocin prophylaxis (vs no mupirocin) to reduce catheter-related infections in patients with MPE treated with an IPC. METHODS: A pragmatic, multi-centre, open-labelled, randomised trial. Eligible patients with MPE and an IPC will be randomised 1:1 to either regular topical mupirocin prophylaxis or no mupirocin (standard care). For the interventional arm, topical mupirocin will be applied around the IPC exit-site after each drainage, at least twice weekly. Weekly follow-up via phone calls or in person will be conducted for up to 6 months. The primary outcome is the percentage of patients who develop an IPC-related (pleural, skin, or tract) infection between the time of catheter insertion and end of follow-up period. Secondary outcomes include analyses of infection (types and episodes), hospitalisation days, health economics, adverse events, and survival. Subject to interim analyses, the trial will recruit up to 418 participants. DISCUSSION: Results from this trial will determine the efficacy of mupirocin prophylaxis in patients who require IPC for MPE. It will provide data on infection rates, microbiology, and potentially infection pathways associated with IPC-related infections. ETHICS AND DISSEMINATION: Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee has approved the study (RGS0000005920). Results will be published in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry ACTRN12623000253606. Registered on 9 March 2023.

Topical antibiotics prophylaxis for infections of indwelling pleural/peritoneal catheters (TAP-IPC): A pilot study.

BACKGROUND AND OBJECTIVE: Indwelling pleural catheter (IPC) and indwelling peritoneal catheter (IPeC) have established roles in the management of malignant pleural and peritoneal effusions but catheter-related infections remain a major concern. Topical mupirocin prophylaxis has been shown to reduce peritoneal dialysis catheter infections. This study aimed to assess the (i) compatibility of IPC with mupirocin and (ii) feasibility, tolerability and compliance of topical mupirocin prophylaxis in patients with an IPC or IPeC. METHODS: (i) Three preparations of mupirocin were applied onto segments of IPC thrice weekly and examined with scanning electron microscope (SEM) at different time intervals. (ii) Consecutive patients fitted with IPC or IPeC were given topical mupirocin prophylaxis to apply to the catheter exit-site following every drainage/dressing change (at least twice weekly) and followed up for 6 months. RESULTS: (i) No detectable structural catheter damage was found with mupirocin applied for up to 6 months. (ii) Fifty indwelling catheters were inserted in 48 patients for malignant pleural (n = 41) and peritoneal (n = 9) effusions. Median follow-up was 121 [median, IQR 19-181] days. All patients tolerated mupirocin well; one patient reported short-term local tenderness. Compliance was excellent with 95.8% of the 989 scheduled doses delivered. Six patients developed catheter-related pleural (n = 3), concurrent peritoneal/local (n = 1) and skin/tract (n = 2) infections from Streptococcus mitis (with Bacillus species or anaerobes), Staphylococcus aureus, Klebsiella pneumoniae and Pseudomonas aeruginosa. CONCLUSION: This first study of long-term prevention of IPC- or IPeC-related infections found topical mupirocin prophylaxis feasible and well tolerated. Its efficacy warrants future randomized studies.

The impact of outpatient versus inpatient management on health-related quality of life outcomes for patients with malignant pleural effusion: the OPTIMUM randomised clinical trial.

BACKGROUND: The principal aim of malignant pleural effusion (MPE) management is to improve health-related quality of life (HRQoL) and symptoms. METHODS: In this open-label randomised controlled trial, patients with symptomatic MPE were randomly assigned to either indwelling pleural catheter (IPC) insertion with the option of talc pleurodesis or chest drain and talc pleurodesis. The primary end-point was global health status, measured with the 30-item European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) at 30 days post-intervention. 142 participants were enrolled from July 2015 to December 2019. RESULTS: Of participants randomly assigned to the IPC (n=70) and chest drain (n=72) groups, primary outcome data were available in 58 and 56 patients, respectively. Global health status improved in both groups at day 30 compared with baseline: IPC (mean difference 13.11; p=0.001) and chest drain (mean difference 10.11; p=0.001). However, there was no significant between-group difference at day 30 (mean intergroup difference in baseline-adjusted global health status 2.06, 95% CI -5.86-9.99; p=0.61), day 60 or day 90. No significant differences were identified between groups in breathlessness and chest pain scores. All chest drain arm patients were admitted (median length of stay 4 days); seven patients in the IPC arm required intervention-related hospitalisation. CONCLUSIONS: While HRQoL significantly improved in both groups, there were no differences in patient-reported global health status at 30 days. The outpatient pathway using an IPC was not superior to inpatient treatment with a chest drain.

Intrapleural therapy for pleural infection from bronchopleural fistula in an adult with hyper-IgE syndrome.

We presented the case of an adult patient with hyper-IgE syndrome (HIES) who was admitted acutely with a large hydropneumothorax from lung consolidation, a bronchopleural fistula and pleural infection. He has had recurrent pulmonary and skin infections since childhood and longstanding pneumatoceles. He was treated with systemic antibiotics and chest tube drainage. Administration of two doses of low-dose intrapleural therapy (1 mg tissue plasminogen activator and 5 mg deoxyribonuclease) allowed complete evacuation of his residual loculated pleural fluid, aided resolution of his infection without provoking a significant air leak and avoided the need for surgery.

Indwelling Pleural Catheter: Management of Complications.

Multiple randomized clinical trials have established the advantages of indwelling pleural catheter (IPC) in the management of malignant pleural effusions, resulting in its widespread adoption in clinical practice. Complications can occur with IPC use and must be recognized and managed effectively. This review provides a comprehensive overview of IPC complications and their best care. Pain postinsertion or during drainage of IPC is easily manageable and must be distinguished from tumor-related chest wall pain. IPC-related infections require systemic antibiotics and often intrapleural fibrinolytic/deoxyribonuclease therapy. The removal of IPC for infection is usually unnecessary. Symptomatic loculation usually responds to fibrinolytics but may recur. Catheter tract metastases are common in mesothelioma patients and usually respond to radiotherapy without inducing damages to the IPC. Less common complications include dislodgement, irreversible blockage, and fractures (upon removal) of the catheter. Recommendations on the management of IPC complications by recent consensus statement/guideline are discussed. Expert opinions on management approaches are included in areas where evidence is lacking to guide care.

Geldanamycin treatment does not result in anti-cancer activity in a preclinical model of orthotopic mesothelioma.

Mesothelioma is characterised by its aggressive invasive behaviour, affecting the surrounding tissues of the pleura or peritoneum. We compared an invasive pleural model with a non-invasive subcutaneous model of mesothelioma and performed transcriptomic analyses on the tumour samples. Invasive pleural tumours were characterised by a transcriptomic signature enriched for genes associated with MEF2C and MYOCD signaling, muscle differentiation and myogenesis. Further analysis using the CMap and LINCS databases identified geldanamycin as a potential antagonist of this signature, so we evaluated its potential in vitro and in vivo. Nanomolar concentrations of geldanamycin significantly reduced cell growth, invasion, and migration in vitro. However, administration of geldanamycin in vivo did not result in significant anti-cancer activity. Our findings show that myogenesis and muscle differentiation pathways are upregulated in pleural mesothelioma which may be related to the invasive behaviour. However, geldanamycin as a single agent does not appear to be a viable treatment for mesothelioma.

Oceanic and atmospheric anomalies associated with extreme precipitation events in China 1983-2020.

Observed synoptic anomalies in connection with China's extreme precipitation events/floods in the summers of 1982/83, 1997/98, 2010, 2014, 2015/16, and 2020 are studied. These events mainly occur within the middle and lower Yangtze basins. The dominant moisture source is the Northern Indian Ocean and the Southwestern Pacific Ocean of the Indo-Pacific warm pool (IPWP). Both of these bodies of water have warmed since 1979. In East Asia, the strong land-sea thermal contrast driven by global warming drives the increased East Asian summer monsoon (EASM) circulation, which develops deep convective precipitation. The total precipitable water in the Indo-Pacific region has also been increasing since 1979. The intense southwest Indian monsoon transports moist air to the Yangtze basin in mid-June and forms the Meiyu (plum rain) front. Strengthened Okhotsk/Ural blocking highs in East and West Asia, as well as the Western Pacific subtropical high (WPSH) and the South Asian high (SAH) over south Eurasia, remain stationary for long periods and interact to exacerbate the precipitation. The western edge of the WPSH expands westward towards East Asia to transport moisture. To the north, the WPSH combines with the two blocking highs to trigger more rain. The intensified SAH expands eastward and merges with the extended WPSH to add rain. On the other hand, rainfall is modulated by the El Niño-Southern Oscillation (ENSO), notably in relation to the super El Niño events in 1982-1983, 1997-1998, 2015-2016, and 2020. The research described in this paper highlights changes in the weather systems with warming and, in particular, the enormous and dominating impact of the warming and expanding IPWP on rainfall extremes. Improved seasonal forecasts and planning ahead will protect lives and livelihoods.

A Pt(IV)-conjugated brain penetrant macrocyclic peptide shows pre-clinical efficacy in glioblastoma.

Glioblastoma (GBM) is the most aggressive primary malignant brain tumor, with a median survival of approximately 15 months. Treatment is limited by the blood-brain barrier (BBB) which restricts the passage of most drugs to the brain. We previously reported the design and synthesis of a BBB-penetrant macrocyclic cell-penetrating peptide conjugate (M13) covalently linked at the axial position of a Pt(IV) cisplatin prodrug. Here we show the Pt(IV)-M13 conjugate releases active cisplatin upon intracellular reduction and effects potent in vitro GBM cell killing. Pt(IV)-M13 significantly increased platinum uptake in an in vitro BBB spheroid model and intravenous administration of Pt(IV)-M13 in GBM tumor-bearing mice led to higher platinum levels in brain tissue and intratumorally compared with cisplatin. Pt(IV)-M13 administration was tolerated in naïve nude mice at higher dosage regimes than cisplatin and significantly extended survival above controls in a murine GBM xenograft model (median survival 33 days for Pt(IV)-M13 vs 24 days for Pt(IV) prodrug, 22.5 days for cisplatin and 22 days for control). Increased numbers of γH2AX nuclear foci, biomarkers of DNA damage, were observed in tumors of Pt(IV)-M13-treated mice, consistent with elevated platinum levels. The present work provides the first demonstration that systemic injection of a Pt(IV) complex conjugated to a brain-penetrant macrocyclic peptide can lead to increased platinum levels in the brain and extend survival in mouse GBM models, supporting further development of this approach and the utility of brain-penetrating macrocyclic peptide conjugates for delivering non-BBB penetrant drugs to the central nervous system.

Pharmacokinetics of antibiotics for pleural infection.

INTRODUCTION: Pleural infection causes significant morbidity and mortality. An important aspect in the treatment of pleural infection is the pharmacokinetics of antibiotics, an area often neglected. AREAS COVERED: Pathophysiology of pleural infection and the importance of antibiotic therapy in the treatment of pleural infection are discussed. After reviewing all available literature on pharmacokinetics of antibiotics for pleural infection, the scarcity of data and knowledge gaps are highlighted. EXPERT OPINION: This review aims to heighten awareness of the limited pharmacokinetic data of commonly used antibiotics for pleural infection. It serves to remind clinicians that choice of antibiotics for pleural infection should be based not only on bacterial sensitivity but also adequate delivery of antibiotics to the infected pleural cavity. Antibiotic pharmacokinetics may vary with agents used, pleural thickness and individual characteristics. Consideration must be given to insufficient pleural delivery of systemic antibiotics in patients lacking clinical improvement. Pleural infection research has disproportionately focused on fluid drainage. Optimizing delivery of effective antibiotic therapy to the pleural cavity must be regarded a key priority to progress clinical care. Large comprehensive cohort studies on pharmacokinetic variability are the essential next step. The possibility of intrapleural administration is also an area that warrants additional research.