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.

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.

[Chinese expert consensus on treatment of malignant pleural effusion (2023 Edition)].

Malignant pleural effusion (MPE) is a pleural effusion that is caused by a malignant tumor originating in the pleura or by a metastatic malignant tumor from another site that has invaded the pleura. MPE is associated with poor prognosis. Members of the Pleural and Mediastinal Diseases Working Group (preparatory) of Chinese Thoracic Society and some external experts selected clinical issues related to the management of MPE and conducted rigorous evidence retrieval and evaluation. After several meetings and revisions of the manuscript, recommendations were made. This consensus applies to patients aged≥18 years old with MPE caused by various malignancies except for pleural mesothelioma. It included four chapters: pathogenesis of MPE, prognostic evaluation of MPE, local thoracic treatment, and systemic anticancer therapy for MPE.The main recommendations of this consensus are as follows:1. Prognosis evaluation of MPE was valuable in formulating treatment options. It is suggested to comprehensively evaluate the patient's prognosis by combining the patient's performance status, tumor type, and laboratory examination.2. It is recommended that in patients with symptomatic MPE, therapeutic thoracentesis could be used as the initial therapeutic option. Evaluate whether the lung is expandable after thoracentesis and drainage, and then develop a therapeutic regimen.3. In patients with MPE and known expandable or nonexpandable lung, an indwelling pleural catheter (IPC) is recommended as a first-line pleural management. Daily IPC drainages are recommended. In patients with MPE and expandable lung, talc pleurodesis by talc poudrage or talc slurry is recommended if the drug is accessible. Other pleurodesis agents include povidone iodine, bleomycin, and doxycycline.4. After drainage, it is suggested to consider the option of intrapleural use of recombinant human endostatin or bevacizumab alone or in combination with intrapleural chemotherapy. Intrapleural intervention including electrocautery, argon knife, cryotherapy, laser and radiofrequency ablation, is recommended for use in patients who have undergone rigorous evaluation in eligible hospitals. The use of intrapleural urokinase or streptokinase via pleural catheter is recommended for patients with symptomatic MPE and loculated effusion.5. For patients with good performance status and metastatic malignancies, systemic anti-cancer treatment is recommended as standard of care.

The randomised thoracoscopic talc poudrage+indwelling pleural catheters versus thoracoscopic talc poudrage only in malignant pleural effusion trial (TACTIC): study protocol for a randomised controlled trial.

INTRODUCTION: Malignant pleural effusion (MPE) is common, with 50 000 new cases per year in the UK. MPE causes disabling breathlessness and indicates advanced disease with a poor prognosis. Treatment approaches focus on symptom relief and optimising quality of life (QoL). Patients who newly present with MPE commonly require procedural intervention for both diagnosis and therapeutic benefit.Thoracoscopic pleural biopsies are highly sensitive in diagnosing pleural malignancy. Talc poudrage may be delivered at thoracoscopy (TTP) to prevent effusion recurrence by effecting pleurodesis. Indwelling pleural catheters (IPCs) offer an alternative strategy for fluid control, enabling outpatient management and are often used as 'rescue' therapy following pleurodesis failure or in cases of 'trapped lung'. It is unknown whether combining a TTP with IPC insertion will improve patient symptoms or reduce time spent in the hospital.The randomised thoracoscopic talc poudrage + indwelling pleural catheters versus thoracoscopic talc poudrage only in malignant pleural effusion trial (TACTIC) is the first randomised controlled trial (RCT) to examine the benefit of a combined TTP and IPC procedure, evaluating cost-effectiveness and patient-centred outcomes such as symptoms and QoL. The study remains in active recruitment and has the potential to radically transform the pathway for all patients presenting with MPE. METHODS AND ANALYSIS: TACTIC is an unblinded, multicentre, RCT comparing the combination of TTP with an IPC to TTP alone. Co-primary outcomes are time spent in the hospital and mean breathlessness score over 4 weeks postprocedure. The study will recruit 124 patients and aims to define the optimal pathway for patients presenting with symptomatic MPE. ETHICS AND DISSEMINATION: TACTIC is sponsored by North Bristol NHS Trust and has been granted ethical approval by the London-Brent Research Ethics Committee (REC ref: 21/LO/0495). Publication of results in a peer-reviewed journal and conference presentations are anticipated. TRIAL REGISTRATION: ISRCTN 11058680.

NHLBI ASTHMA NETWORKS: IMPROVING PATIENT CARE, MOVING TOWARD PERSONALIZED MEDICINE.

The first NHLBI Clinical Trials Research Network was the Asthma Clinical Research Network (ACRN 1), which was born in 1993 to perform multiple controlled clinical trials for asthma: "… dispassionately examine new & existing therapies for asthma" and "… rapidly communicate findings to medical community," and therefore, to perform clinical trials drug companies could not or would not do. Among the many areas studied by the ACRN and its successor networks, through 2019, was how to effectively and safely use long-acting beta-agonists and to find novel alternatives for them. In its Tiotropium Add-On Trial (TALC) trial, the ACRN demonstrated that tiotropium as add on-therapy to inhaled corticosteroids (ICS) was effective and non-inferior to long-acting beta-agonist add on-therapy. During the lifetime of the clinical trial networks (1993-2020), 71 manuscripts including 25 major clinical trials were published, many which have laid the groundwork for precision approaches for asthma therapy and the now ongoing PrecISE Asthma Network.

Recommendations of the Spanish Society of Thoracic Surgery for the management of malignant pleural effusion.

This article summarizes the clinical guidelines for the diagnosis and treatment of malignant pleural effusion (MPE) sponsored by the Spanish Society of Thoracic Surgery (SECT). Ten clinical controversies were elaborated under the methodology of PICO (Patient, Intervention, Comparison, Outcome) questions and the quality of the evidence and grading of the strength of the recommendations was based on the GRADE system. Immunocytochemical and molecular analyses of pleural fluid may avoid further invasive diagnostic procedures. Currently, the definitive control of MPE can be achieved either by pleurodesis (talc poudrage or slurry) or the insertion of a indwelling pleural catheter (IPC). It is likely that the combination of both techniques (i.e., thoracoscopy with talc poudrage and insertion of a IPC, or instillation of talc slurry through a IPC) will have a predominant role in the future therapeutic management.

Postoperative outcome after palliative treatment of malignant pleural effusion.

BACKGROUND: The objective of this nationwide, registry-based study was to compare the two most frequently used procedures for the palliative treatment of a malignant pleural effusion (MPE) and to evaluate differentiated indications for these two procedures. METHODS: This was a retrospective observational study based on data of the "PLEURATUMOR" registry of the German Society for Thoracic Surgery. Patients who were documented in the period from January 2015 to November 2021 and had video-assisted thoracic surgery (VATS) talc pleurodesis or implantation of an indwelling pleural catheter (IPC) were included. RESULTS: A total of 543 patients were evaluated. The majority suffered from secondary pleural carcinomatosis (n = 402; 74%). VATS talc pleurodesis (n = 361; 66.5%) was performed about twice as often as IPC implantation (n = 182; 33.5%). The duration of surgery was significantly shorter in IPC-patients with 30 min compared to VATS talc pleurodesis (38 min; p = 0.000). Postoperative complication rate was 11.8% overall and slightly higher after VATS talc pleurodesis (n = 49; 13.6%) than after IPC implantation (n = 15; 8.2%). After VATS talc pleurodesis patients were hospitalized significantly longer compared to the IPC group (6 vs. 3.5 days; p = 0.000). There was no significant difference in postoperative wound infections between the groups (p = 0.10). The 30-day mortality was 7.9% (n = 41). CONCLUSION: The implantation of an IPC can significantly shorten the duration of surgery and the hospital stay. For this reason, the procedure should be matched with the patient's expectations preoperatively and the use of an IPC should be considered not only in the case of a trapped lung.

Silver Nitrate-coated versus Standard Indwelling Pleural Catheter for Malignant Effusions: The SWIFT Randomized Trial.

Rationale: Tunneled, indwelling pleural catheters (IPCs) have been demonstrated to be an effective method of managing malignant pleural effusions. However, they allow pleurodesis and can therefore be removed in only a subset of patients. A novel, silver nitrate-coated IPC was developed with the intention of creating a rapid, effective chemical pleurodesis to allow more frequent and earlier catheter removal. This study represents the pivotal clinical trial evaluating that catheter versus the standard IPC. Objectives: To compare the efficacy of a novel silver nitrate-eluting indwelling pleural catheter (SNCIPC) with that of a standard, uncoated catheter. Methods: The SWIFT [A Pivotal Multi-Center, Randomized, Controlled, Single-Blinded Study Comparing the Silver Nitrate-Coated Indwelling Pleural Catheter (SNCIPC) to the Uncoated PleurX® Pleural Catheter for the Management of Symptomatic, Recurrent, Malignant Pleural Effusions] trial was a multicenter, parallel-group, randomized, controlled, patient-blind trial. Central randomization occurred according to a computer-generated schedule, stratified by site. Recruitment was from 17 secondary or tertiary care hospitals in the United States and 3 in the United Kingdom and included adult patients with malignant pleural effusion needing drainage, without evidence of lung entrapment or significant loculation. The intervention group underwent insertion of an SNCIPC with maximal fluid drainage, followed by a tapering drainage schedule. The control group received a standard, uncoated catheter. Follow-up was conducted until 90 days. The primary outcome measure was pleurodesis efficacy, measured by fluid drainage, at 30 days. Results: A total of 119 patients were randomized. Five withdrew before receiving treatment, leaving 114 (77 SNCIPC, 37 standard IPC) for analysis. The mean age was 66 years (standard deviation, 11). More patients in the SNCIPC group were inpatients (39% vs. 14%; P = 0.009). For the primary outcome, pleurodesis rates were 12 (32%) of 37 in the control group and 17 (22%) of 77 in the SNCIPC group (rate difference, -0.10; 95% confidence interval, -0.30 to 0.09). Median time to pleurodesis was 11 days (interquartile range, 9 to 23) in the control group and 4 days (interquartile range, 2 to 15) in the SNCIPC group. No significant difference in treatment-related adverse event rates was noted between groups. Conclusions: The SNCIPC did not improve pleurodesis efficacy compared with a standard IPC. This study does not support the wider use of the SNCIPC device. Clinical trial registered with www.clinicaltrials.gov (NCT02649894).

Histology of the pleural rind at [18F]FDG PET/CT hot and cold spots in mesothelioma patients after talc pleurodesis and neoadjuvant chemotherapy.

The role of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography ([18F]FDG PET/CT) in evaluating induction chemotherapy in pleural mesothelioma (PM) patients is debated. We compared histology at tumor sites with high versus low [18F]FDG uptake in order to define a morphologic correlate for persistent metabolic activity. Twenty PM patients with talc pleurodesis and induction chemotherapy followed by extrapleural pleuro-pneumonectomy (EPP, n = 17) or tumor debulking (n = 3) were included. All patients received a PET/CT scan prior to surgery. Orthogonal tissue sections of pleural rind (n total=86) were taken at areas of maximum standardized uptake value (SUVmax, n = 53) and of low [18F]FDG uptake (n = 33) and scored on hematoxylin-eosin and immunohistochemical stainings. Total metabolic activity was scored semiquantitatively. Mean SUVmax of hot and cold spots correlated with total metabolic activity per patient, but no correlation was found with ypT and tumor cells were present in both hot and cold areas. SUVmax of only hot spots and cold versus hot spots as well as cold versus hot patients correlated with increased thickness of total pleural rind and fibrosis reaction, but not thickness of vital tumor cells or giant cell reaction. They further correlated with increased expression of glucose transporter 1 (GLUT1) in giant cells but not mesothelioma amount, density, vitality or vascularization. Biphasic histology was associated with SUVmax in only hot spots and higher total metabolic activity (all p-values <0.05). Interpretation of [18F]FDG PET/CT in PM patients is difficult after talc pleurodesis and induction chemotherapy. High glucose turnover is mostly related to fibro-inflammatory remodeling of the pleural rind and GLUT1 transporter expression in giant cells. Response assessment using this technology should only be done to assess extra-thoracic lesions.

Investigation on factors associated with ovarian cancer: an umbrella review of systematic review and meta-analyses.

Following cervical and uterine cancer, ovarian cancer (OC) has the third rank in gynecologic cancers. It often remains non-diagnosed until it spreads throughout the pelvis and abdomen. Identification of the most effective risk factors can help take prevention measures concerning OC. Therefore, the presented review aims to summarize the available studies on OC risk factors. A comprehensive systematic literature search was performed to identify all published systematic reviews and meta-analysis on associated factors with ovarian cancer. Web of Science, Cochrane Library databases, and Google Scholar were searched up to 17th January 2020. This study was performed according to Smith et al. methodology for conducting a systematic review of systematic reviews. Twenty-eight thousand sixty-two papers were initially retrieved from the electronic databases, among which 20,104 studies were screened. Two hundred seventy-seven articles met our inclusion criteria, 226 of which included in the meta-analysis. Most commonly reported genetic factors were MTHFR C677T (OR=1.077; 95 % CI (1.032, 1.124); P-value<0.001), BSML rs1544410 (OR=1.078; 95 %CI (1.024, 1.153); P-value=0.004), and Fokl rs2228570 (OR=1.123; 95 % CI (1.089, 1.157); P-value<0.001), which were significantly associated with increasing risk of ovarian cancer. Among the other factors, coffee intake (OR=1.106; 95 % CI (1.009, 1.211); P-value=0.030), hormone therapy (RR=1.057; 95 % CI (1.030, 1.400); P-value<0.001), hysterectomy (OR=0.863; 95 % CI (0.745, 0.999); P-value=0.049), and breast feeding (OR=0.719, 95 % CI (0.679, 0.762) and P-value<0.001) were mostly reported in studies. Among nutritional factors, coffee, egg, and fat intake significantly increase the risk of ovarian cancer. Estrogen, estrogen-progesterone, and overall hormone therapies also are related to the higher incidence of ovarian cancer. Some diseases, such as diabetes, endometriosis, and polycystic ovarian syndrome, as well as several genetic polymorphisms, cause a significant increase in ovarian cancer occurrence. Moreover, other factors, for instance, obesity, overweight, smoking, and perineal talc use, significantly increase the risk of ovarian cancer.

A mechanism for improved talc pleurodesis via foam delivery.

Talcum powder is recognized as the leading drug for pleurodesis, a treatment of choice for malignant pleural effusions. Recently, it was shown that hydrogel foam delivery systems significantly enhanced the number of adhesions between the chest wall and the lung in a New Zealand rabbit model due to the sol-gel transition. However, many questions still remain regarding the cause of improved efficacy, such as: (1) Would only hydrogel foams improve the efficacy of talc pleurodesis? (2) Is it possible to achieve the same efficacy of hydrogels using non-hydrogel foams? 3) What are the physicochemical properties that can be correlated to the efficacy of talc pleurodesis? In this study, we use non-hydrogel foam formulations to determine the efficacy of pleurodesis. Foam stability and rheology of the formulations were correlated to adhesion formation. The results clearly suggest a correlation of pleurodesis efficacy to the viscosity and modulus of the foam delivery system.

Comparison of Hydroxyethyl starch 130/0.4 (6%) with commonly used agents in an experimental Pleurodesis model.

BACKGROUND: Hydroxyethyl Starch (HES) 130/0.4 (6%) is a commonly used intravascular volume expander with anti-inflammatory and antioxidant properties. In this study, we aimed to compare the histopathologic activity of HES 130/0.4 (6%) with various widely-used agents in pleurodesis. METHODS: Forty male Wistar-Albino rats were divided into five groups: controls, povidone-iodine recipients (PI group), sterile talcum recipients (Talcum group), autologous blood recipients (AB group) and HES 130/0.4 (6%) recipients (HES group). Thirty days after application of agents, pleural and lung tissues were resected. Evaluation was performed via macroscopic scoring (adhesion) and specimens were stained with H&E for microscopic examination (inflammation and fibrosis). RESULTS: HES recipients had significantly higher adhesion compared to controls (lower grade 0, higher grade 1 frequency vs. controls), they were found to have significantly lower frequency of grade 2 adhesion (vs. PI, Talc and AB) and grade 3 adhesion (vs. AB), indicating that the adhesion-generating properties of HES were only superior to the control group. HES recipients had significantly higher inflammatory grades compared to controls (lower grade 0, higher grade 1 frequency), while they had lower grades compared to the PI, Talc and AB groups. Although the PI, Talc and AB groups were statistically similar in most comparisons, we observed a trend towards higher success with the use of Talc and especially AB. CONCLUSION: Our results do not support a role for HES in pleurodesis. We believe that the autologous blood method remains as an effective and successful procedure without side effects.

Indwelling pleural catheter versus talc pleurodesis for malignant pleural effusion: a meta-analysis.

Malignant pleural effusion (MPE) results from primary mesothelioma or the spreading of metastatic cancer. Both talc pleurodesis (TP) and indwelling pleural catheter (IPC) improve MPE symptoms. We performed a meta-analysis of randomized controlled trials to compare the efficacy of TP with that of IPC in patients with MPE. PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov databases were searched for studies published before February 2020. Individual effect sizes were standardized, and a meta-analysis was conducted to calculate a pooled effect size by using random effects models. In total, 4 trials with 500 patients were reviewed. Difference in pleurodesis success rate and change in dyspnea scores at 4 and 6 weeks between MPE patients treated with IPC and those treated with TP for pleurodesis were nonsignificant. The number of hospital inpatient days was significantly lower among patients who were treated with IPC (weight mean difference: 2.19; 95% confidence interval 0.70-3.67) than among those who were treated with TP. No significant difference was shown in adverse event profile between patients treated with IPC and those treated with TP for pleurodesis. In conclusion, both TP and IPC are equally effective in treating patients with MPE. The number of hospitalization days was significantly lower for patients who were treated with IPC, but the magnitude of the difference is of uncertain clinical importance.

Estudio de los niveles basales de survivina y otros marcadores para la predicción de los resultados de la pleurodesis con talco en derrames pleurales malignos / Study on the baseline levels of survivin and other markers to predict the results of pleurodesis with talc in malignant pleural effusions

La survivina se encuentra sobre-expresada en tumores, y podría ser un buen biomarcador diagnóstico y pronóstico en derrames pleurales malignos. OBJETIVO: estudiar la concentración de survivina en pacientes con derrame pleural maligno sometidos a pleurodesis con talco, relacionarla con el resultado de ésta y comparar sus resultados con otros marcadores como pH, glucosa y LDH en líquido pleural. MÉTODOS: se han incluido 84 pacientes con derrame pleural maligno (32 con cáncer de mama, 25 de pulmón y 27 mesoteliomas) sometidos a toracoscopia y pleurodesis con talco. Se recogieron muestras de líquido pleural antes (basal) y 24 horas después de la pleurodesis, y en ellas se midieron los niveles de survivina, pH, glucosa y LDH. También se estudió la carga tumoral en la pleura y la re-expansión del pulmón tras la toracoscopia y pleurodesis.R RESULTADOS: la presencia de niveles basales de survivina > 30 pg/mL se asoció a alto índice de fracaso de la pleurodesis (p = 0,002), y superó en poder predictivo a pH (p = 0,004), glucosa (p = 0,005) y LDH (p = 0,013) CONCLUSIÓN: la survivina juega un poderoso papel como marcador pronóstico en derrames pleurales malignos, y se suma a otros marcadores clásicos como pH, glucosa y LDH, que están asociados a la agresividad tumoral

Survivin is found to be overexpressed in tumors and could be a good diagnostic and prognostic biomarker in malignant pleural effusions. OBJECTIVE: To study the concentration of survivin in patients with a malignant pleural effusion who undergo pleurodesis with talc, associate it with the result of the procedure and compare the results with other markers like pH, glucose and LDH in pleural liquid. METHODS: 84 patients with malignant pleural effusion (32 with breast cancer, 25 lung cancer and 27 mesotheliomas) who underwent thoracoscopy and pleurodesis with talc were included in the study. Pleural liquid samples were taken before (baseline) and 24 hours after the pleurodesis, measuring the levels of survivin, pH, glucose and LDH. The tumor burden in the pleura and the re-expansion of the lung after thoracoscopy and pleurodesis were also studied. RESULTS: The presence of baseline levels of survivin >30 pg/mL was associated with a high rate of pleurodesis failure (p = 0.002) and surpassed the predictive power of pH (p = 0.004), glucose (p = 0.005) and LDH (p = 0.013). CONCLUSION: Survivin plays a powerful role as a prognostic marker in malignant pleural effusions and joins other classic markers like pH, glucose and LDH, which are associated with tumor aggression

The efficacy of hydrogel foams in talc Pleurodesis.

BACKGROUND: Malignant pleural effusions are a serious complication of many late stage cancers that adversely affect quality of life. Pleurodesis with talc slurry is a standard treatment option, but clinical failures occur, possible due to poor talc delivery. A novel drug-delivery system was developed that fills the entire thoracic cavity with a liquid foam containing talc. The foam is designed to gel and adhere to the tissue walls at body temperature, to improve talc deposition and efficacy. METHODS: Rheology, foam stability, and ex-vivo coating and bio-adhesion studies were performed on three concentrations of a novel hydrogel talc foam system that was developed to improve delivery of talc to the pleural surfaces. A New Zealand rabbit model of pleurodesis was used to evaluate effectiveness of the foams at inducing adhesion formation and compared to talc slurry. The rabbits were recovered after they had one of the test agents instilled into their pleura, and then sacrificed after 28 days. Pleurodesis was assessed by a blinded pathologist using a standardized pathological scoring system. RESULTS: All talc foam formulations produced foams that gelled at physiological temperatures and were relatively stable for at least two hours. As the concentration of the formulation increased the gelation temperature decreased and the foam adhesiveness increased. Rabbits that received talc foam had significantly greater adhesion formation than talc slurry (mean score of 2.21 vs. 1.18 (p < 0.05)). Rabbits that received the 20% foam developed the most adhesions. CONCLUSIONS: This study demonstrates that our triblock copolymer hydrogel foam delivery system enhances adhesion formation in an experimental model. This novel approach can have important clinical impact, potentially improving efficacy of existing therapies and reducing the need for more invasive treatments.

Interventions for the management of malignant pleural effusions: a network meta-analysis.

BACKGROUND: Malignant pleural effusion (MPE) is a common problem for people with cancer and usually associated with considerable breathlessness. A number of treatment options are available to manage the uncontrolled accumulation of pleural fluid, including administration of a pleurodesis agent (via a chest tube or thoracoscopy) or placement of an indwelling pleural catheter (IPC). This is an update of a review published in Issue 5, 2016, which replaced the original, published in 2004. OBJECTIVES: To ascertain the optimal management strategy for adults with malignant pleural effusion in terms of pleurodesis success and to quantify differences in patient-reported outcomes and adverse effects between interventions. SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid) and three other databases to June 2019. We screened reference lists from other relevant publications and searched trial registries. SELECTION CRITERIA: We included randomised controlled trials of intrapleural interventions for adults with symptomatic MPE, comparing types of sclerosant, mode of administration and IPC use. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data on study design, characteristics, outcome measures, potential effect modifiers and risk of bias. The primary outcome was pleurodesis failure rate. Secondary outcomes were adverse events, patient-reported breathlessness control, quality of life, cost, mortality, survival, duration of inpatient stay and patient acceptability. We performed network meta-analyses of primary outcome data and secondary outcomes with enough data. We also performed pair-wise meta-analyses of direct comparison data. If we deemed interventions not jointly randomisable, or we found insufficient available data, we reported results by narrative synthesis. For the primary outcome, we performed sensitivity analyses to explore potential causes of heterogeneity and to evaluate pleurodesis agents administered via a chest tube only. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We identified 80 randomised trials (18 new), including 5507 participants. We found all except three studies at high or unclear risk of bias for at least one domain. Due to the nature of the interventions, most studies were unblinded. Pleurodesis failure rate We included 55 studies of 21 interventions in the primary network meta-analysis. We estimated the rank of each intervention's effectiveness. Talc slurry (ranked 6, 95% credible interval (Cr-I) 3 to 10)  is an effective pleurodesis agent (moderate certainty for comparison with placebo) and may result in fewer pleurodesis failures than bleomycin and doxycycline (bleomycin versus talc slurry: odds ratio (OR) 2.24, 95% Cr-I 1.10 to 4.68; low certainty; ranked 11, 95% Cr-I 7 to 15; doxycycline versus talc slurry: OR 2.51, 95% Cr-I 0.81 to 8.40; low certainty; ranked 12, 95% Cr-I 5 to 18). There is little evidence of a difference between the pleurodesis failure rate of talc poudrage and talc slurry (OR 0.50, 95% Cr-I 0.21 to 1.02; moderate certainty). Evidence for any difference was further reduced when restricting analysis to studies at low risk of bias (defined as maximum one high risk domain in the risk of bias assessment) (pleurodesis failure talc poudrage versus talc slurry: OR 0.78, 95% Cr-I 0.16 to 2.08). IPCs without daily drainage are probably less effective at obtaining a definitive pleurodesis (cessation of pleural fluid drainage facilitating IPC removal) than talc slurry (OR 7.60, 95% Cr-I 2.96 to 20.47; rank = 18/21, 95% Cr-I 13 to 21; moderate certainty). Daily IPC drainage or instillation of talc slurry via IPC are likely to reduce pleurodesis failure rates. Adverse effects Adverse effects were inconsistently reported. We performed network meta-analyses for the risk of procedure-related fever and pain. The evidence for risk of developing fever was of low certainty, but suggested there may be little difference between interventions relative to talc slurry (talc poudrage: OR 0.89, 95% Cr-I 0.11 to 6.67; bleomycin: OR 2.33, 95% Cr-I 0.45 to 12.50; IPCs: OR 0.41, 95% Cr-I 0.00 to 50.00; doxycycline: OR 0.85, 95% Cr-I 0.05 to 14.29). Evidence also suggested there may be little difference between interventions in the risk of developing procedure-related pain, relative to talc slurry (talc poudrage: OR 1.26, 95% Cr-I 0.45 to 6.04; very-low certainty; bleomycin: OR 2.85, 95% Cr-I 0.78 to 11.53; low certainty; IPCs: OR 1.30, 95% Cr-I 0.29 to 5.87; low certainty; doxycycline: OR 3.35, 95% Cr-I 0.64 to 19.72; low certainty). Patient-reported control of breathlessness Pair-wise meta-analysis suggests there is likely no difference in breathlessness control, relative to talc slurry, of talc poudrage ((mean difference (MD) 4.00 mm, 95% CI -6.26 to 14.26) on a 100 mm visual analogue scale for breathlessness; studies = 1; participants = 184; moderate certainty) and IPCs without daily drainage (MD -6.12 mm, 95% CI -16.32 to 4.08; studies = 2; participants = 160; low certainty). Overall mortality There may be little difference between interventions when compared to talc slurry (bleomycin and IPC without daily drainage; low certainty) but evidence is uncertain for talc poudrage and doxycycline. Patient acceptability Pair-wise meta-analysis demonstrated that IPCs probably result in a reduced risk of requiring a repeat invasive pleural intervention (OR 0.25, 95% Cr-I 0.13 to 0.48; moderate certainty) relative to talc slurry. There is likely little difference in the risk of repeat invasive pleural intervention with talc poudrage relative to talc slurry (OR 0.96, 95% CI 0.59 to 1.56; moderate certainty). AUTHORS' CONCLUSIONS: Based on the available evidence, talc poudrage and talc slurry are effective methods for achieving a pleurodesis, with lower failure rates than a number of other commonly used interventions. IPCs provide an alternative approach; whilst associated with inferior definitive pleurodesis rates, comparable control of breathlessness can probably be achieved, with a lower risk of requiring repeat invasive pleural intervention.  Local availability, global experience of agents and adverse events (which may not be identified in randomised trials) and patient preference must be considered when selecting an intervention. Further research is required to delineate the roles of different treatments according to patient characteristics, such as presence of trapped lung. Greater attention to patient-centred outcomes, including breathlessness, quality of life and patient preference is essential to inform clinical decision-making. Careful consideration to minimise the risk of bias and standardise outcome measures is essential for future trial design.

Quality of life after interventions for malignant pleural effusions: a systematic review.

BACKGROUND: Malignant pleural effusion (MPE) results in breathlessness and impairment of health-related quality of life (HRQOL). This study reviews the existing literature on HRQOL following invasive interventions in MPE. METHODS: Five electronic databases were systematically searched and assessed three times during the review process and last completed on 15 June 2018. We included all studies evaluating HRQOL outcomes for the following interventions: therapeutic thoracocentesis, talc slurry (TS) pleurodesis, indwelling pleural catheter (IPC) insertion and thoracoscopic talc poudrage (TTP) pleurodesis. Meta-analysis was not performed due to substantial heterogeneity in the published data. RESULTS: 17 studies were included in the review reporting HRQOL outcomes in 2515 patients. TTP, TS and IPC were associated with modest but inconsistent improvements in HRQOL up to 12 weeks. No intervention was significantly different from another in HRQOL outcomes at any time point. The attrition to follow-up was 48.3% (664/1374) at 3 months. The overall quality of studies was inadequate. CONCLUSION: TTP, TS and IPC seem to improve HRQOL in MPE over 4-12 weeks, but there are insufficient longer term data due to high attrition rates. Evidence on the most effective treatment strategy is limited by the small number of randomised or comparative studies. TRIAL REGISTRATION NUMBER: CRD42016051003.

Mechanical versus Chemical Pleurodesis after Bullectomy for Primary Spontaneous Pneumothorax: A Systemic Review and Meta-Analysis.

INTRODUCTION: Primary spontaneous pneumothorax (PSP) and its high recurrence rate pose a therapeutic challenge to both patients and their managing surgeons. Mechanical or chemical pleurodesis can be used to prevent recurrence, but the optimal treatment often remains a matter of debate. This meta-analysis aims to compare the outcomes between mechanical and chemical pleurodesis following bullectomy for PSP. MATERIALS AND METHODS: Studies published up to 2019 were searched from Medline, Embase, Google Scholar, and Cochrane databases. A meta-analysis of randomized controlled trials (RCTs) and observational cohort studies (OCSs) comparing outcomes between mechanical and chemical pleurodesis for PSP was performed. RESULTS: Seven studies (one RCT and six OCSs) were included, comprising 1,032 cases of mechanical (799 abrasions, 202 pleurectomies, and 31 unspecified abrasions/pleurectomies/both), and 901 cases of chemical (643 talc, 69 minocycline, and 189 unspecified talc/kaolin) pleurodesis. The recurrence rate of pneumothorax after chemical pleurodesis (1.2%) was significantly lower than mechanical pleurodesis (4.0%) (pooled odds ratio [OR] = 3.00; 95% confidence interval [CI] = 1.59-5.67; p = 0.0007; I 2 = 19%). Hospital stay was also slightly shorter in the chemical pleurodesis group (pooled mean difference [MD] = 0.42 days; 95% CI = 0.12-0.72; p = 0.005; I 2 = 0%). There was no statistically significant difference in postoperative complications (pooled OR = 1.18; 95%CI = 0.40-3.48; p = 0.76; I 2 = 71%) and operative time (pooled MD = 3.50; 95%CI = -7.28 to 14.28; p = 0.52; I 2 = 99%) between these two groups. CONCLUSION: Chemical pleurodesis is superior to mechanical pleurodesis following bullectomy for PSP in reducing hospital stay and recurrence rate. However, more RCTs with longer follow-up are necessary to demonstrate the benefit of chemical pleurodesis for PSP.

Pre-EDIT: A Randomized Feasibility Trial of Elastance-Directed Intrapleural Catheter or Talc Pleurodesis in Malignant Pleural Effusion.

BACKGROUND: Talc slurry pleurodesis (TSP) prevents recurrence of symptomatic malignant pleural effusion (MPE) in 71% to 78% patients. Nonexpansile lung (NEL) frequently accounts for TSP failure but is often occult predrainage, impairing selection of patients. NEL is associated with high pleural elastance (PEL), but technical limitations have hampered the development of PEL as a predictive NEL marker. We performed a single-center, randomized, controlled, open-label feasibility trial of EDIT (elastance-directed indwelling pleural catheter or TSP) management, using a novel digital manometer and a new definition of high PEL. METHODS: Patients with symptomatic MPE were randomized 1:1 between EDIT and standard care (TSP). EDIT involved PEL assessment during large-volume thoracentesis; patients with high PEL (maximum PEL sustained over 250 mL [MaxPEL250] ≥ 14.5 cm H2O/L) were allocated to immediately receive an indwelling pleural catheter; the remainder underwent immediate drain placement for TSP. The primary outcome measure was recruitment feasibility, defined a priori as 30 patients over 12 months. Secondary outcomes included safety, technical reliability, and the aspiration volume required to detect high PEL. The accuracy of the PEL definition for NEL was analyzed post hoc. RESULTS: Thirty-one patients were randomized (one allocation failure) over 12 months. PEL assessment (mean duration, 33 minutes) was successful in 13 of 15 patients (87%). No directly attributable serious adverse events occurred. High PEL was detected in seven of 13 patients (54%), associated with 100% sensitivity and 67% specificity for NEL, and was first detected at a median volume of 325 mL (range, 250-800 mL). CONCLUSIONS: A phase 3 trial testing the effect of EDIT management on symptomatic MPE recurrence following TSP is feasible. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03319186; URL: www.clinicaltrials.gov.