Specific effects of bortezomib against experimental malignant pleural effusion: a preclinical study

BACKGROUND: We have previously shown that nuclear factor (NF)-κB activation of mouse Lewis lung carcinoma (LLC) specifically promotes the induction of malignant pleural effusions (MPE) by these cells. In the present studies we hypothesized that treatment of immunocompetent mice with bortezomib tailored to inhibit cancer cell NF-κB activation and not proliferation specifically inhibits MPE formation by LLC cells. RESULTS: Treatment of LLC cells with low concentrations of bortezomib (100 ng/ml) inhibited NF-κB activation and NF-κB-dependent transcription, but not cellular proliferation. Bortezomib treatment of immunocompetent C57BL/6 mice bearing LLC-induced subcutaneous tumors and MPEs significantly blocked tumor-specific NF-κB activation. However, bortezomib treatment did not impair subcutaneous LLC tumor growth, but was effective in limiting LLC-induced MPE. This specific effect was evidenced by significant reductions in effusion accumulation and the associated mortality and was observed with both preventive (beginning before MPE formation) and therapeutic (beginning after MPE establishment) bortezomib treatment. The favorable impact of bortezomib on MPE was associated with suppression of cardinal MPE-associated phenomena, such as inflammation, vascular hyperpermeability, and angiogenesis. In this regard, therapeutic bortezomib treatment had identical favorable results on MPE compared with preventive treatment, indicating that the drug specifically counteracts effusion formation. CONCLUSIONS: These studies indicate that proteasome inhibition tailored to block NF-κB activation of lung adenocarcinoma specifically targets the effusion-inducing phenotype of this tumor. Although the drug has limited activity against advanced solid lung cancer, it may prove beneficial for patients with MPE

Cost-effectiveness of intrapleural use of tissue plasminogen activator and DNase in pleural infection:Evidence from the MIST2 randomised controlled trial

The MIST2 trial showed that combined intrapleural use of tissue plasminogen activator (t-PA) and DNase was effective when compared to single agents or placebo. However, the treatment costs are significant and overall cost-effectiveness of combined therapy remains unclear.An economic evaluation of the MIST2 trial was performed to assess the cost-effectiveness of combined therapy. Costs included were those related to study medications, initial hospital stay, and subsequent hospitalisations. Outcomes were measured in terms of life-years gained. All costs were reported in Euros (€) and in 2016 prices.Mean annual costs were lowest in the tPA-DNase group (€10 605 for t-PA, €17 856 for DNase; €13 483 for placebo, €7248 for t-PA-DNase (p=0.209)). Mean 1-year life expectancy was: 0.988 for t-PA; 0.923 for DNase; and 0.969 for both placebo and t-PA-DNase (p=0.296). Both DNase and placebo were less effective, in terms of life-years gained, and more costly than t-PA. When t-PA-DNase was compared to placebo, the incremental cost per life-year gained of t-PA-DNase was €1.6 billion, with a probability of 0.85 of t-PA-DNase being cost-effective.This study demonstrates that combined t-PA-DNase is likely to be highly cost-effective. In light of this evidence, a definitive trial designed to facilitate a thorough economic evaluation is warranted to provide further evidence on cost-effectiveness of this promising combined intervention

Assessment of patient-reported outcome measures in pleural interventions

Introduction: There is a lack of data evaluating the clinical effect on symptoms of pleural intervention procedures. This has led to the development of patient-reported outcome measures (PROMs) to define what constitutes patient benefit. The primary aim of this paper was to prospectively assess the effect of pleural procedures on PROMs and investigate the relationship between symptom change and clinical factors. Methods: We prospectively collected data as part of routine clinical care from 158 patients with pleural effusion requiring interventions. Specific questionnaires included two patient-reported scores (a seven-point Likert scale and a 100 mm visual analogue scale (VAS) to assess symptoms). Results: Excluding diagnostic aspiration, the majority of patients (108/126, 85.7%) experienced symptomatic benefit from fluid drainage (mean VAS improvement 42.6 mm, SD 24.7, 95% CI 37.9 to 47.3). There was a correlation between symptomatic benefit and volume of fluid removed post aspiration. A negative association was identified between the number of septations seen on ultrasound and improvement in dyspnoea VAS score in patients treated with intercostal chest drain. Conclusion: The results of our study highlight the effect of pleural interventions from a patient’s perspective. The outcomes defined have the potential to form the basis of a clinical useful tool to appraise the effect, compare the efficiency and identify the importance of pleural interventions to the patients

Malignant pleural mesothelioma:An update on investigation, diagnosis and treatment

Malignant pleural mesothelioma is an aggressive malignancy of the pleural surface, predominantly caused by prior asbestos exposure. There is a global epidemic of malignant pleural mesothelioma underway, and incidence rates are predicted to peak in the next few years.This article summarises the epidemiology and pathogenesis of malignant pleural mesothelioma, before describing some key factors in the patient experience and outlining common symptoms. Diagnostic approaches are reviewed, including imaging techniques and the role of various biomarkers. Treatment options are summarised, including the importance of palliative care and methods of controlling pleural effusions. The evidence for chemotherapy, radiotherapy and surgery is reviewed, both in the palliative setting and in the context of trimodality treatment. An algorithm for managing malignant pleural effusion in malignant pleural mesothelioma patients is presented. Finally new treatment developments and novel therapeutic approaches are summarised

Mutant KRAS promotes malignant pleural effusion formation

Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition

Providing safe and effective pleural medicine services in the UK:an aspirational statement from UK pleural physicians

Physicians face considerable challenges in ensuring safe and effective care for patients admitted to hospital with pleural disease. While subspecialty development has driven up standards of care, this has been tempered by the resulting loss of procedural experience in general medical teams tasked with managing acute pleural disease. This review aims to define a framework though which a minimum standard of care might be implemented. This review has been written by pleural clinicians from across the UK representing all types of secondary care hospital. Its content has been formed on the basis of literature review, national guidelines, National Health Service England policy and consensus opinion following a round table discussion. Recommendations have been provided in the broad themes of procedural training, out-of-hours management and pleural service specification. Procedural competences have been defined into descriptive categories: emergency, basic, intermediate and advanced. Provision of emergency level operators at all times in all trusts is the cornerstone of out-of-hours recommendations, alongside readily available escalation pathways. A proposal for minimum standards to ensure the safe delivery of pleural medicine have been described with the aim of driving local conversations and providing a framework for service development, review and risk assessment

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

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

Static and dynamic mechanics of the murine lung after intratracheal bleomycin

<p>Abstract</p> <p>Background</p> <p>Despite its widespread use in pulmonary fibrosis research, the bleomycin mouse model has not been thoroughly validated from a pulmonary functional standpoint using new technologies. Purpose of this study was to systematically assess the functional alterations induced in murine lungs by fibrogenic agent bleomycin and to compare the forced oscillation technique with quasi-static pressure-volume curves in mice following bleomycin exposure.</p> <p>Methods</p> <p>Single intratracheal injections of saline (50 μL) or bleomycin (2 mg/Kg in 50 μL saline) were administered to C57BL/6 (<it>n </it>= 40) and Balb/c (<it>n </it>= 32) mice. Injury/fibrosis score, tissue volume density (TVD), collagen content, airway resistance (<it>R_N</it>), tissue damping (<it>G</it>) and elastance coefficient (<it>H</it>), hysteresivity (<it>η</it>), and area of pressure-volume curve (PV-A) were determined after 7 and 21 days (inflammation and fibrosis stage, respectively). Statistical hypothesis testing was performed using one-way ANOVA with LSD <it>post hoc </it>tests.</p> <p>Results</p> <p>Both C57BL/6 and Balb/c mice developed weight loss and lung inflammation after bleomycin. However, only C57BL/6 mice displayed cachexia and fibrosis, evidenced by increased fibrosis score, TVD, and collagen. At day 7, PV-A increased significantly and <it>G </it>and <it>H </it>non-significantly in bleomycin-exposed C57BL/6 mice compared to saline controls and further increase in all parameters was documented at day 21. <it>G </it>and <it>H</it>, but not PV-A, correlated well with the presence of fibrosis based on histology, TVD and collagen. In Balb/c mice, no change in collagen content, histology score, TVD, <it>H </it>and <it>G </it>was noted following bleomycin exposure, yet PV-A increased significantly compared to saline controls.</p> <p>Conclusions</p> <p>Lung dysfunction in the bleomycin model is more pronounced during the fibrosis stage rather than the inflammation stage. Forced oscillation mechanics are accurate indicators of experimental bleomycin-induced lung fibrosis. Quasi-static PV-curves may be more sensitive than forced oscillations at detecting inflammation and fibrosis.</p

Randomized controlled trial of urokinase versus placebo for nondraining malignant pleural effusion

Rationale: Patients with malignant pleural effusion experience breathlessness, which is treated by drainage and pleurodesis. Incomplete drainage results in residual dyspnea and pleurodesis failure. Intrapleural fibrinolytics lyse septations within pleural fluid, improving drainage. Objectives: To assess the effects of intrapleural urokinase on dyspnea and pleurodesis success in patients with nondraining malignant effusion. Methods: We conducted a prospective, double-blind, randomized trial. Patients with nondraining effusion were randomly allocated in a 1:1 ratio to intrapleural urokinase (100,000 IU, three doses, 12-hourly) or matched placebo. Measurements and Main Results: Co–primary outcome measures were dyspnea (average daily 100-mm visual analog scale scores over 28 d) and time to pleurodesis failure to 12 months. Secondary outcomes were survival, hospital length of stay, and radiographic change. A total of 71 subjects were randomized (36 received urokinase, 35 placebo) from 12 U.K. centers. The baseline characteristics were similar between the groups. There was no difference in mean dyspnea between groups (mean difference, 3.8 mm; 95% confidence interval [CI], −12 to 4.4 mm; P = 0.36). Pleurodesis failure rates were similar (urokinase, 13 of 35 [37%]; placebo, 11 of 34 [32%]; adjusted hazard ratio, 1.2; P = 0.65). Urokinase was associated with decreased effusion size visualized by chest radiography (adjusted relative improvement, −19%; 95% CI, −28 to −11%; P < 0.001), reduced hospital stay (1.6 d; 95% CI, 1.0 to 2.6; P = 0.049), and improved survival (69 vs. 48 d; P = 0.026). Conclusions: Use of intrapleural urokinase does not reduce dyspnea or improve pleurodesis success compared with placebo and cannot be recommended as an adjunct to pleurodesis. Other palliative treatments should be used. Improvements in hospital stay, radiographic appearance, and survival associated with urokinase require further evaluation. Clinical trial registered with ISRCTN (12852177) and EudraCT (2008-000586-26)