Alteplase Dose Assessment for Pleural infection Therapy (ADAPT) Study-2: Use of 2.5 mg alteplase as a starting intrapleural dose.

BACKGROUND AND OBJECTIVE: Intrapleural tissue plasminogen activator/deoxyribonuclease (tPA/DNase) therapy is increasingly used in pleural infection. Bleeding risks and costs associated with tPA remain the clinical concerns. Our dose de-escalation series aims to establish the lowest effective dosing regimen for tPA/DNase. This study assesses the intrapleural use of 2.5 mg tPA/5 mg DNase for pleural infection. METHODS: Consecutive patients with pleural infection treated with a starting regime of 2.5 mg tPA/5 mg DNase were included from two centres in Australia and UK. Escalation of tPA dose was permitted if clinical response was inadequate. RESULTS: Sixty-nine patients (mean age 61.0 years) received intrapleural 2.5 mg tPA/5 mg DNase. Most (88.4%) were treated successfully and discharged from hospital without surgery by 90 days. Patients received a median of 5 [interquartile range [IQR] = 3-6] doses of tPA/DNase. Total amount of tPA used per patient was 12.5 mg [median, IQR = 7.5-15.0]. Seventeen patients required dose escalation of tPA; most (n = 12) for attempted drainage of distant non-communicating locule(s). Treatment success was corroborated by clearance of pleural opacities on radiographs (from median 27.0% [IQR = 17.1-44.5] to 11.0% [IQR = 6.4-23.3] of hemithorax, p < 0.0001), increased pleural fluid drainage (1.98 L [median, IQR = 1.38-2.68] over 72 h following commencement of tPA/DNase) and reduction of serum C-reactive protein level (by 45.0% [IQR = 39.3-77.0] from baseline at day 5, p < 0.0001). Two patients required surgery. Six patients with significant comorbidities (e.g., advanced cancer) had ongoing infection when palliated and died. Two patients experienced self-limiting pleural bleeding and received blood transfusion. CONCLUSION: A starting intrapleural regime of 2.5 mg tPA/5 mg DNase, with up-titration if needed, can be effective and deserves further exploration.

Assessment of Anti-tumor Efficacy of Osimertinib in Non-Small Cell Lung Cancer Patients by Liquid Biopsy Using Bronchoalveolar Lavage Fluid, Plasma, or Pleural Effusion.

PURPOSE: This study was to evaluate anti-tumor efficacy of osimertinib in patients positive for acquired epidermal growth factor receptor (EGFR) T790M mutation in liquid biopsy using plasma, bronchoalveolar lavage fluid (BALF) or bronchial washing fluid (BWF), and pleural effusion. MATERIALS AND METHODS: Among patients benefited from previous EGFR‒tyrosine kinase inhibitor treatment followed by treatment failure, patients in whom T790M mutations are detected in at least one of the samples including tumor tissues, BALF/BWF, plasma, and pleural effusion were enrolled. T790M mutation was detected by extracting cell free DNA from liquid biopsy samples, using PANA Mutyper. Objective response rate (ORR) and progression-free survival (PFS) with osimertinib treatment were evaluated. RESULTS: Between January 2018 and December 2019, 63 patients were enrolled and received osimertinib. Mean age was 63 years, and 38 (60.3%) were female. Twenty-six patients had T790M mutation in both liquid and tissue samples (group A), 19 patients had only in tissue biopsy samples (group B), and 18 patients had T790M mutation only in liquid biopsy samples (group C). ORR in overall population was 63.5%, and was 61.5% in group A, 68.4% in group B, and 61.1% in group C, respectively. Median PFS in overall patients was 15.6 months (95% confidence interval, 10.7 to 24.2). There was no significant difference in ORR or PFS between groups. CONCLUSION: Osimertinib showed favorable efficacy in lung cancer patients with acquired resistance to prior EGFR-TKI therapies, who screened positive for harboring T790M mutation detected from cell free DNA extracted from plasma, BALF/BWF, and pleural effusion.

Survey of hospital procedures for parapneumonic effusion in children highlights need for standardised management.

AIM: This study sought to evaluate the initial management of children with parapneumonic effusion admitted to all French university hospitals. METHODS: A nationwide survey of all 35 university hospitals took place in 2011 to assess practices for children with parapneumonic effusion, using a hypothetical clinical vignette and a standardised questionnaire. Two to four paediatricians per hospital were interviewed and asked about their initial management, probabilistic antibiotic therapy and its adaptation to microbiological results and subsequent course. Answers from paediatricians working in emergency departments, intensive care units and conventional paediatric units were compared. RESULTS: Of the 100 paediatricians contacted, 95 responded. Of these, 98% would order an initial blood test, 70% would order diagnostic thoracentesis, and all would start immediate antibiotic therapy: 31% with a single drug, 67% with two drugs and 2% with three drugs. The most frequent initial choices were third-generation cephalosporin alone (17%) or combined with rifampicin (34%) or vancomycin (24%). Adaptation varied according to drug used, dose and duration, especially when the microorganism was not Streptococcus pneumoniae. Practices did not differ significantly among the different groups of paediatricians. CONCLUSION: Standardised management of parapneumonic effusion, including routine thoracentesis and more consistent prescription of antibiotics, is needed.

Intrapleural urokinase treatment in children with complicated parapneumonic effusion.

Intrapleural instillation of fibrinolytic agent such as urokinase has been shown to be effective as an adjunctive therapy for children with complicated parapneumonic effusion and empyema. In this study, we described our experience with the use of intrapleural urokinase in the management of complicated parapneumonic effusion in children. We collected 13 patients with a mean age of 50.8 months with parapneumonic pleural effusion or empyema; all were treated with intrapleural urokinase after poor response to appropriate antibiotics and simple tube drainage. We also reviewed another 13 patients with a mean age of 45.8 months from the clinical records of children hospitalized with the same conditions prior to urokinase introduction as a control group. The mean fluid drained during the first 24 hours and the first 72 hours after urokinase instillation were significantly greater than those during 24 hours before instillation, p=0.002 and p<0.001, respectively. The total volume of fluid drained was also greater in the urokinase group than that in the control group (p<0.001). The mean duration of chest tube drainage was significantly shorter in the urokinase group (8.7 +/- 2.8 days vs. 14.7 +/- 6.1 days, p<0.02). The mean length of hospitalization was also significantly shorter in the urokinase group (15.5 +/- 5.3 days vs. 24.4 +/- 6.9 days, p=0.002). All 13 patients were managed successfully with urokinase treatment without further surgical procedures. None of the patients experienced any side effect or adverse event after urokinase instillation. Two patients of the control group finally underwent surgical debridement. In conclusion, the use of intrapleural urokinase treatment in children with complicated parapneumonic effusion is an effective and safe therapy.

Tissue plasminogen activator as an adjuvant therapy for pleural empyema in pediatric patients.

The authors retrospectively review the clinical course and outcome of 6 pediatric patients, ranging in age from 2 to 13 years, who were treated with TPA for complex empyema. Efficacy was assessed by evaluating pleural fluid drainage for 6 hours prior to and subsequent to each dose of TPA, as well as by resolution of fever and length of hospital stay. The average volume drained for 6 hours before infusion of TPA was 22.5 mL +/- 18.4 mL, and the average volume 6 hours after TPA therapy was 141.7 mL +/- 28.3 mL, P <.0001. After initiation of TPA therapy, 5 out of 6 patients became afebrile within 48 hours. The median length of stay after initiation of TPA therapy was 6 days, with a range from 4 days to 12 days. A discussion of other current therapies for empyema, along with a comparison of these therapies to TPA regarding the costs of therapies and risk-benefit ratios, is also included.

Intrapleural fibrinolytic therapy for complicated pleural effusions.

Intrapleural administration of fibrinolytic agents can be used to degrade the fibrin present in complicated pleural effusions, thus decreasing viscosity of the fluid and enhancing evacuation of the pleural space via chest tube drainage. Patients who may otherwise need surgical intervention could benefit from this treatment. As more knowledge is gained through clinical experience and research studies, patients' outcomes may show major improvement.

Intrapleural streptokinase versus urokinase in the treatment of complicated parapneumonic effusions: a prospective, double-blind study.

Intrapleural administration of fibrinolytics has been shown in small numbers of patients with complicated parapneumonic effusions (CPE) and pleural empyema to be effective and relatively safe. Although streptokinase (SK) is recommended as the fibrinolytic of choice, there are no comparative studies among fibrinolytics. We therefore compared the efficacy, safety, and the cost of treatment two of the most used thrombolytics, SK and urokinase (UK). Fifty consecutive patients with CPE or empyema were randomly allocated to receive either SK (25 patients) or UK, in a double-blind fashion. All patients had inadequate drainage through chest tube (< 70 ml/24 h). Both drugs were diluted in 100 ml normal saline and were infused intrapleurally through the chest tube in a daily dose of 250,000 IU of SK or 100,000 IU of UK. The chest tube was clamped for 3 h after instillation. Response was assessed by clinical outcome, fluid drainage, chest radiography, pleural ultrasound, and/or computed tomography. Clinical and radiologic improvement was noted in all but two patients in each group, who required surgical intervention. The mean volume drained during the first 24 h after instillation was significantly increased; 380 +/- 99 ml for the SK group (p < 0.001) and 420.8 +/- 110 ml for the UK group (p < 0.001). The total volume (mean +/- SD) of fluid drained after treatment was 1,596 +/- 68 ml for the SK group, and 1,510 +/- 55 ml for the UK group (p > 0.05). The SK instillations (mean +/- SD) were 6 +/- 2.16 (range, 3 to 10) and those of UK 5.92 +/- 2.05 (range, 3 to 8). High fever as adverse reaction to SK was observed in two patients. The total cost of the drug in the UK group was two times higher than that of SK ($180 +/- 47 for SK and $320 +/- 123 for UK). The mean total hospital stay after beginning fibrinolytic therapy was 11.28 +/- 2.44 d (range, 7 to 15) for the SK group and 10.48 +/- 2.53 d (range, 6 to 18) for the UK group (p = 0.32). We conclude that intrapleural SK or UK is an effective adjunct in the management of parapneumonic effusions and may reduce the need for surgery. UK could be the thrombolytic of choice given the potentially dangerous allergic reactions to SK and relatively little higher cost of UK.