Use of lipoteichoic acid-T for pleurodesis in malignant pleural effusion: a phase I toxicity and dose-escalation study

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Use of lipoteichoic acid-T for pleurodesis in malignant pleural effusion: a phase I toxicity and dose-escalation study Najib M Rahman*, Helen E Davies*, Marc Salzberg, Peter Truog, Rachel Midgely, David Kerr, Colin Clelland, Emma L Hedley, Y C Gary Lee, Robert J O Davies

Summary Lancet Oncol 2008; 9: 946–52 Published Online September 4, 2008 DOI:10.1016/S14702045(08)70205-5 See Reflection and Reaction page 912 *NMR and HED had equal roles in the design, delivery, and publication of this study Oxford Pleural Unit, Oxford Centre for Respiratory Medicine, University of Oxford and Oxford Radcliffe Hospital, Oxford, UK (N M Rahman MRCP, H E Davies MRCP, E L Hedley, Y C G Lee PhD, Prof R J O Davies DM); Pharma Brains Ltd, Basel, Switzerland (M Salzberg); Lunamed, Chur, Switzerland (P Truog MD); Cancer Research UK, Churchill Hospital, Headington, Oxford, UK (R Midgely FRCP); Department of Clinical Pharmacology, University of Oxford, Oxford, UK (Prof D Kerr DSc); Department of Pathology, John Radcliffe Hospital, Oxford, UK (C Clelland FRCPath); and Centre for Respiratory Research, University College London, London, UK (Y C G Lee) Correspondence to: Prof Robert J O Davies, Oxford Centre for Respiratory Medicine, Churchill Hospital Site, Oxford Radcliffe Hospital, Headington, Oxford OX3 7LJ, UK [email protected]

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Background Bacterial infection of the pleural space often causes adherence of the pleural membranes by fibrous tissue, probably mediated by inflammation initiated by bacterial cell-wall motifs, including lipoteichoic acid-T (LTA-T). We postulated that therapeutically administered LTA-T might produce a similar effect, achieving control of malignant pleural effusion (pleurodesis). Methods Patients with histocytologically proven symptomatic malignant pleural effusions were included in this phase I toxicity and dose-escalation study, An indwelling pleural catheter was placed in the pleural effusion to drain the fluid fully. A control dose of intrapleural saline was administered after complete drainage (day 1) and pleural-fluid production was recorded for 7 days. On day 7 a single dose of intrapleural LTA-T (increasing in each patient) was administered and pleural-fluid production was monitored for a further 7 days. Long-term fluid control was recorded. This study is registered as an International Standard Randomised Controlled Trial, ISRCTN44367564. Findings Between November, 2004, and November, 2005, 14 patients were enrolled on the trial at the Oxford Centre for Respiratory Medicine (Oxford, UK). 13 of 14 patients received escalated doses of LTA-T. A dose-limiting toxic effect (ie, systemic inflammation) occurred at 3000 μg, and a therapeutic dose of 750–1500 µg was established. Toxic effects were mild and had no consistent pattern at the therapeutic dose. Pleural-fluid production decreased significantly after a dose of at least 750 µg LTA-T, compared with saline control (mean fluid production after saline control 1244 mL [SD 933], mean fluid production after LTA-T 394 mL [SD 375], mean difference –850 mL [SD 699], p=0·028), and six of seven (86%) patients achieved pleural-fluid control at 1 month with no further intervention. Interpretation The toxic effects of intrapleural LTA-T seem to be mild and favourable when compared with the toxicity profiles of standard pleurodesis agents. There is early evidence of LTA-T-induced pleurodesis efficacy, suggesting that this might be a viable therapeutic strategy for the control of malignant pleural effusion. Funding Lunamed, Chur, Switzerland.

Introduction There are about 300 000 new cases of malignant pleural effusions each year in the UK and USA.1,2 Therapeutic drainage is effective in treating breathlessness caused by pleural fluid, but most effusions recur after single drainage,3 and need repeated drainage or adherence of the lung to the chest wall by pleurodesis, which requires inpatient care and has associated health costs.4 Intrapleural talc is the most widely used agent to induce such pleurodesis,1,3 but has never been assessed by the usual drug-development methods, and causes substantial adverse events. Most patients have pain after talc pleurodesis.5–7 Some talc preparations (especially those used in the USA and UK) cause clinically significant hypoxaemia,8 and between 1% and 9% of patients receiving some preparations have potentially life-threatening respiratory failure.9–12 This toxic effect can be decreased by the use of large-particle talc,8 but in a recent prospective cohort study in which large-particle talc was used, seven of 558 patients (1·3%) developed new pulmonary infiltrates after thoracoscopic talc poudrage,13 even though no patients developed frank respiratory failure. Thus, there is a need for agents with

good efficacy for pleurodesis and better adverse-event profiles. Pleural infection is characterised by fibrotic obliteration of the pleural cavity (pleurodesis) during an indolent illness, and therapeutic replication of this response could produce a clinically effective pleurodesis for malignant pleural effusion. Gram-positive pathogens are immunologically recognised by the binding of their cell-wall motifs to toll-like receptors (TLRs) on the cell surface. One such motif is lipoteichoic acid-T (LTA-T),14 which mediates its effects by TLRs, in particular TLR-2.15 We postulated that LTA-T might be capable of inducing a therapeutically effective pleurodesis for the control of malignant pleural effusion. We did a dose-escalation study to assess the toxic effects and tolerability of LTA-T administered into the pleural space, and to produce preliminary data assessing potential pleurodesis efficacy.

Methods Patients This study was designed as a phase I toxicity and doseescalation study. Inclusion criteria were: age 18 years or greater; histocytologically proven malignant pleural www.thelancet.com/oncology Vol 9 October 2008

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effusion; Karnofsky performance status of 60% or greater; life expectancy of more than 3 months; and at least 4 weeks since last chemotherapy cycle. Exclusion criteria included serious uncontrolled intercurrent infection; proven infection during the current episode of pleural effusion; any bleeding diathesis such that chest-tube insertion would be hazardous; previous surgical pleurodesis for the current pleural effusion; or any of the following abnormal laboratory findings: haemoglobin concentration less than 80 g/L (correction by transfusion allowed), neutrophil count less than 2·0×10⁹/L, platelet count less than 100×10⁹/L, serum creatinine concentration more than three-times the upper normal limit (ie, 150 μmol/L), serum bilirubin concentration more than five-times the upper normal limit (ie, 17 μmol/L), and alanine transaminase or aspartate aminotransferase concentrations more than five-times the upper normal limits (ie, 30 IU/L and 45 IU/L, respectively). Patients were also excluded if they had a known sensitivity to LTA-T. Women who were pregnant or lactating were excluded, as were all women of childbearing potential unless a reliable and appropriate contraceptive method was used and a negative pregnancy test confirmed. Any patients with organ allografts, substantial cardiac disease, uncontrolled seizures, CNS disorders, or psychiatric disability were also excluded, as were those who had participated in any other investigational drug study within 4 weeks of enrolment or who lived too far from the study centre to attend for follow-up. Written informed consent was obtained from all patients before treatment, and the study was approved by the Oxford Research Ethics Committee (OXREC, REC Reference No: 04/Q1606/53).

Procedures Eligible patients had an indwelling pleural catheter (PleurX, Denver, CO, USA) placed in the pleural effusion and the pleural space was fully drained. Markers of toxicity (ie, clinical symptoms, blood parameters, and performance status) were recorded daily during the first 14 days of the study and at intervals thereafter (figure 1). After initial complete fluid drainage, 30 mL of intrapleural saline was administered as a control (day 1; NMR). Daily pleural-fluid drainage was then recorded for 7 days to quantify the rate of production of pleural fluid (week 1). On day 7, patients received a single intrapleural injection of LTA-T, according to the escalating-dose schedule (table 1). The starting dose was 250 µg. Patients remained in hospital for one night after LTA-T administration in a respiratory unit equipped for the care of acute respiratory failure to allow immediate adverseevent monitoring. From day 7 to day 14, daily pleural-fluid drainage and pleural-fluid cytology for malignant cells (CC) was done unless pleural-fluid flow ceased (week 2). On day 14, the intrapleural catheter was flushed and closed, but left in www.thelancet.com/oncology Vol 9 October 2008

Histocytologically proven malignant pleural effusion requiring pleurodesis

Baseline data obtained Indwelling pleural catheter placed Pleural space fully drained

Day 1 Intrapleural saline control

Days 1 to 6 Adverse-event monitoring and daily pleural-fluid drainage

Day 7 Administration of intrapleural dose of LTA-T

Days 7 to 13 Adverse-event monitoring and daily pleural-fluid drainage

Day 14 Catheter flushed and closed Not drained again unless symptomatic breathlessness thought to be secondary to pleural effusion re-accumulation

Follow-up days 22, 43, 64, 85 Monitoring of adverse events and performance status, clinical assessment, and assessment of need for pleural drainage

Figure 1: Chronological scheme of trial LTA-T=lipoteichoic acid-T.

situ, and not used again for the duration of the study unless recurrent pleural fluid caused dyspnoea. Concentrations of arterial blood gases taken with the patient breathing air were recorded in the first week on days 1 and 3 (ie, before and after saline control) and in the second week on days 7 and 9 (ie, before and after LTA-T) to identify any impaired gas exchange (a recognised problem with talc pleurodesis).8 The efficiency of lung oxygen exchange was quantified from the change in the alveolar to arterial gradient for the partial pressure of oxygen, calculated from these blood-gas samples by use of standard methods.16 Clinical symptoms, performance status, pleural-fluid recurrence (identified by chest radiography), adverse events, and the clinical need for further pleural-fluid drainage, were assessed on days 22, 43, 64, and 85. Where further fluid drainage was needed, the time from administration of LTA-T to first additional drainage was recorded. Patients with recurrent pleural fluid were offered sterile talc pleurodesis (as standard care). All patients were followed up to death. The primary endpoint was adverse events.

Pleural-fluid cytokine quantification Pleural-fluid samples were collected on ice and centrifuged at 1400 g for 10 min. The supernatants were stored at –80°C until assayed. Cytokine concentrations 947

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N=14 Median age (SD), years

analysis was used on the blood-parameter indices to identify any potential adverse events.

57 (13)

Sex, n

Role of the funding source

Men

6

Women

8

10 (77)

The study was funded by an unrestricted grant provided by Lunamed, Chur, Switzerland. RJOD is funded by a grant from the UK National Insitute for Health Research Biomedical Research Centre programme. The funding sources had no role or influence on the study design, analysis, or execution of the study. The study was sponsored by the University of Oxford (Oxford, UK), which had no role in the collection, analysis, or interpretation of data, nor any contribution to the writing of the report. NMR, HED, ELH, YCGL, and RJOD had access to the raw data, and NMR, HED, and RJOD had final responsibility to submit for publication.

Haemoglobin (g/dL)

13·1 (1·9)

Results

White-blood-cell count (x109)

10·9 (8·4)

Between November, 2004, and November, 2005, 14 patients (six men, eight women; mean age 57 years [SD 13]) with histocytologically proven malignant pleural effusion were enrolled in the trial at the Oxford Centre for Respiratory Medicine (Oxford, UK). The patients’ characteristics are shown in table 1. The initial dose of LTA-T, based on previous human and animal experience, was 250 µg intrapleurally. No adverse events were noted after administration of the intrapleural saline control. Full descriptions of toxic effects in all patients are listed in table 2. In terms of dose escalation, the second patient to receive LTA-T had a mild fever (subsequently shown to be a concomitant urinary-tract infection; table 2). The next dose escalation was therefore halved to 375 μg for patients 4, 5, and 6. Patient 8 deteriorated rapidly from progressive malignancy without receiving LTA-T and was withdrawn from the study. This patient’s data are excluded from the analysis. The study was terminated when patient 14 (3000 µg), developed a systemic inflammatory reaction likely to be attributable to the trial drug, and needed hospital readmission. Therefore, the therapeutic dose was identified to be 750–1500 µg based on the presence of detectable systemic inflammation at this dose. Overall, there was a significant increase in peripheral white-blood-cell count (WBC) after administration of LTA-T compared with saline control (mean change after LTA-T 4·10 [SD 6·34] vs mean change in WBC after saline control –0·42 [SD 1·17]; mean difference 4·96 [SD 7·37; 95% CI 0·27–9·64], p=0·053; figure 2). In the seven patients who received 750 µg of LTA-T or more (ie, the therapeutic dose), the mean change in WBC after LTA-T was 4·49 (SD 3·65; mean change after saline control 0·21 [SD 0·38]; mean difference 4·70 [SD 3·77; 95% CI 1·21–8·18], p=0·016; figure 2). With the exception of peripheral WBC, there were no clinically significant changes in any other blood parameter. Small, transient, and marginally significant,

Median Karnofsky performance index on recruitment (IRQ), %

80 (60–90)

Primary tumour, n Epithelioid mesothelioma

4

Breast adenocarcinoma

7

Ovarian adenocarcinoma

1

Adenocarcinoma (unknown primary)

1

Non-small-cell lung cancer Median survival (IQR), days Patients alive at 3 months, n (%)

1 186 (88–424)

Blood parameters, mean (SD)

Platelet count (x109)

394·0 (116)

Prothrombin time (s)

12·6 (2·0)

Activated partial thromboplastin time (s)

26·6 (5·7)

Sodium concentration (mmol/L)

138·0 (2·4)

Potassium concentration (mmol/L)

4·1 (0·4)

Urea concentration (mmol/L)

6·2 (2·3)

Creatinine concentration (mmol/L) Gamma glutamyl transferase concentration (mmol/L)

86·0 (17·0) 131·6 (261·0)

Dose escalation Patients 1 to 3

250 μg

Patients 4 to 6

375 μg

Patients 7, 9, and 10*

750 μg

Patients 11–13

1500 μg

Patient 14

3000 μg

*Patient 8 was withdrawn from the trial due to rapidly progressive malignant disease before administration of lipoteichoic acid-T. This patient’s findings are excluded from the analysis.

Table 1: Baseline patient characteristics and dosing schedule for intrapleural lipoteichoic acid-T

were measured by use of commercially available ELISA kits for interleukin 8 (IL-8), vascular endothelial growth factor (VEGF), monocyte chemotactic protein 1, transforming growth factor (TGF)-β1, and TGF-β2 (Peprotech and R&D Systems, London, UK) according to manufacturer’s instructions. To activate latent TGF-β1 and TGF-β2, samples were treated with 1N HCl, followed by 1·2N NaOH/0·5M HEPES (Sigma, Poole, UK), as per instructions from the manufacturer. This study is registered as an International Standard Randomised Controlled Trial, ISRCTN44367564.

Statistical analyses Changes in continuous variables were compared with baseline values by use of a paired t test and Wilcoxon Signed Rank test (SPSS version v12.0.1), as appropriate. p<0·05 was considered statistically significant. This 948

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Patient

LTA-T dose (μg)

Dose per kg body weight (μg/kg)

Temperature Change in white-blood-cell after LTA-T count after LTA-T (×109 cells)

Side-effect profile

1

250

4·53

No

–5·30

None

2

250

4·76

Yes (37·6°C)

20·62

Mild chest pain 2 h after administration of LTA-T, lasting 3 h. 12 h after administration, tachycardia and fever—both settled with no specific treatment within 12 h. Shown to have a urinary tract infection (E coli in urine culture), retrospectively

3

250

4·66

No

1·43

None

4

375

5·17

No

4·64

None

5

375

5·23

No

–1·15

None

6

375

6·13

No

1·61

Mild headache and light-headedness 4 h after LTA-T administration—resolved spontaneously within 8 h. Observations and examination normal

9·95

No

2·20

None

7 8

750 Withdrawn before LTA-T administration

NA

9

750

9·87

10

750

12·10

11

1500

12

1500

13 14

NA

NA

NA

No

4·88

Mild back pain on inspiration after LTA-T—resolved within 24 h with no treatment

Yes (39·2°C)

8·48

Nausea, vomiting, and pyrexia for 3 days after LTA-T administration. Raised inflammatory markers. Resolved spontaneously with no specific treatment. Patient known to have previous similar reactions to chemotherapy agents

29·07

No

0·08

None

20·33

No

0·28

None

1500

22·42

No

7·65

None

3000

45·18

No

7·87

High fevers, breathlessness, and vomiting associated with systemic inflammatory response and pain on side of LTA-T administration within 24 h. Needed re-admission to hospital—symptoms resolved over a 2-week period

LTA-T=lipoteichoic acid-T. NA=not available.

Table 2: Individual patient LTA-T doses and toxicity descriptions

changes were seen in some blood-parameter indices at isolated time points compared with baseline. However, none of these changes were associated with detectable clinical consequences and are likely to have been the result of the highly sensitive statistical approach used for adverse-event detection. To assess the potential pulmonary toxic effects noted with other pleurodesis agents, the alveolar to arterial gradient in the partial pressure of oxygen was assessed before and after saline control and LTA-T administration. Mean changes in the alveolar to arterial gradient for the partial pressure of oxygen were similar after LTA-T and saline control (LTA-T: baseline 4·24 kPa [SD 2·92], after LTA-T 4·88 kPa [1·80], mean difference –0·64 kPa [1·98; 95% CI –2·29 to 1·02], p=0·39; saline control: baseline 4·86 kPa [2·00], after saline 4·69 kPa [1·92], mean difference 0·17 kPa [0·92; –0·45 to 0·79], p=0·55). Pleural-fluid production was compared between measurements taken after the saline control and measurements taken after LTA-T administration. In one patient, advanced deposition of tumour cells on the visceral pleura entirely prevented lung expansion, and so fluid control by pleurodesis was not achievable. In the remaining 12 patients who received intrapleural LTA-T, the rate of pleural-fluid production was significantly decreased after LTA-T compared with the saline control (mean total drainage after LTA-T 993 mL [1577] vs mean total pleuralfluid drainage after saline control 1597 mL [SD 1541], www.thelancet.com/oncology Vol 9 October 2008

p=0·023 Wilcoxon Signed Rank test, figure 2). In the seven patients who received sufficient LTA-T to produce an increase in systemic WBC (≥750 µg), the volume of pleural-fluid drainage decreased significantly after administration of LTA-T compared with after the saline control (mean total fluid drainage after LTA-T 394 mL [375] vs mean total fluid production after saline control 1244 mL [933], p=0·028 Wilcoxon Signed Rank test, figure 2). Long-term pleural-fluid control was assessed by recording which patients needed late therapeutic pleuralfluid drainage from their indwelling catheter in association with clinical symptoms (excluding a patient who could not achieve pleurodesis due to a trapped lung caused by advanced visceral pleural tumour). 12 of 13 (92%) patients did not need further therapeutic pleural drainage after 1 month from trial entry. Between day 14 (when the indwelling catheter was first locked closed) and 1 month, three patients received one therapeutic fluid drainage (pleurodesis was successful from day 14 in 9 of 12 patients [75%]). In patients who received the therapeutic dose (≥750 µg) of intrapleural LTA-T, six of seven needed no therapeutic drainage at 1 month (86% pleurodesis success rate). Performance status did not significantly change throughout the study. To assess the potential anti-tumour activity of LTA-T, pleural-fluid cytology was assessed in eight patients before and after LTA-T administration. Fluid from the 949

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6000 3000 5000

4000

Pleural-fluid volume (mL)

Pleural-fluid volume (mL)

2500

3000

2000

2000

1500

1000

1000

500 p=0·028 0

25

10

Change in peripheral white-blood-cell count (×10⁹ cells)

Change in peripheral white-blood-cell count (×10⁹ cells)

p=0·023 0

20 15 10 5 0 –5 p=0·053 –10 Saline control (week 1)

8

6

4

2

2 p=0·016 –2 Saline control (week 1)

LTA-T (week 2)

LTA-T (week 2)

Figure 2: Pleural-fluid production and peripheral white-blood-cell count Graphs show pleural-fluid production by week of study in 12 patients who received intrapleural LTA-T (A) and in seven patients receiving ≥750 μg LTA-T (B), and peripheral white-blood-cell count 24 h after administration of intrapleural saline control or LTA-T in 12 patients who received intrapleural LTA-T (C) and in seven patients receiving ≥750 μg LTA-T (D). Individual patient results are shown in addition to means and error bars for each group. p values derived from Wilcoxon Signed Rank test.

Cytokine (units)

Pre-LTA-T, mean (SD)

Post-LTA-T, mean (SD)

Total TGF-β1 (arbitrary units)

5064 (1646)

5658 (1752)

Total TGF-β2 (arbitrary units) IL-8 (pg/mL) MCP-1 (pM) VEGF (pg/mL)

511 (500)

321 (202)

3124 (2993)

4787 (6646)

Mean difference (SD) 595 (1267) –190 (373) 1663 (3950)

95% CI for difference –379 to 1568 –477 to 97

p value 0·197 0·165

–1374 to 4699

0·242

835 (1293)

948 (1400)

114 (341)

–149 to 375

0·348

4259 (4402)

4464 (4146)

204 (1619)

–1040 to 1449

0·715

Mean cytokine concentration before LTA-T administration (days 1—7) was compared with mean cytokine concentration after LTA-T administration (days 9–11) by a paired t test. LTA-T=lipoteichoic acid-T. TGF=transforming growth factor. IL=interleukin. MCP=monocyte chemotactic protein. VEGF=vascular endothelial growth factor.

Table 3: Changes in pleural-fluid cytokine concentrations before and after LTA-T administration in patients in whom pleural fluid was available

remaining five patients was unavailable due to complete cessation of pleural-fluid production immediately after LTA-T administration. Three patients had no malignant cells in their pleural fluid either before or after LTA-T administration, four patients showed malignant cells both before and after LTA-T administration, and one patient showed malignant cells before, but not after, LTA-T administration. Levels of TGF-β, IL-8, MCP-1, and VEG-F showed small increases after LTA-T administration 950

compared with those after saline control, but these did not reach statistical significance (table 3).

Discussion We assessed a new pleurodesis agent on the basis of a bacterial cell-wall motif known to produce inflammation in human beings. Dose-limiting toxic effects consisted of systemic inflammation and occurred at a dose of 3000 µg; the therapeutic dose range was 750–1500 µg (equating to www.thelancet.com/oncology Vol 9 October 2008

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10–30 µg/kg). Toxic effects at the therapeutic dose were mild, with no consistent side-effect profile, and there were substantially less toxic effects than expected with the clinical standard of talc pleurodesis.5,9–12 At doses of 1500 µg or less, no toxic effects were noted from monitoring of blood parameters, respiratory status, or performance. Intrapleural LTA-T administration was followed by a decrease in pleural-fluid production compared with that seen after the saline control, and permanent pleurodesis was achieved after 1 month in 75% of patients in whom pleurodesis was technically possible. This level of efficacy seems similar to that expected from talc pleurodesis.17–24 Although the toxicity profile of LTA-T cannot be fully defined by this study, it does seem to compare favourably with the toxicity profile of intrapleural talc reported in previous studies. LTA-T caused minor chest pain in only two patients, and no hypoxaemia. By contrast, a talc often causes severe pain, which is the most commonly reported side-effect,5 and some preparations cause clinically significant hypoxaemia in about 20% of patients,8 infiltrates,13 and sometimes respiratory failure.9,12,18,25–27 In the USA, between 1% and 9% of patients have been reported to develop respiratory failure after talc pleurodesis.9–12 Describing pleurodesis efficacy was not the primary aim of this study. However, the data from those receiving a therapeutic dose of intrapleural LTA-T are encouraging in this regard. There was a clinically significant decrease in the amount of pleural fluid produced after intrapleural LTA-T administration in those receiving at least 750 μg compared with saline control, and six of seven (86%) of these patients showed pleural-fluid control at 1 month. If this efficacy is replicated in larger studies, it will be comparable to the 71–96% efficacy of talc pleurodesis quoted in published work.17–24 Large studies to accurately assess this outcome, and to fully document the toxicity profile of LTA-T, are now warranted. Data on changes in pleural-fluid cytokine concentrations after LTA-T were only available for patients in whom pleural-fluid production did not cease entirely after LTA-T administration, and therefore, are probably conservative assessments of the actual pleural changes induced in the whole study group. In the sample available, we noted that there was no significant increase in the proportions of pleural-fluid cytokines that have been previously associated with the administration of pleurodesis agents. This finding is most likely to be due to the paucity of available pleuralfluid samples from patients with the most effective pleuralfluid control, but might also suggest that LTA-T induces pleurodesis via different mechanisms than previously investigated agents.28–34 We did not note any anti-tumour activity after administration of LTA-T in this study. This study expands the current knowledge on the use of immune molecules and bacterial moieties for pleurodesis with apparent safety. Other agents that have www.thelancet.com/oncology Vol 9 October 2008

been explored in this setting include recombinant IL-2,35,36 Staphylococcal superantigen,37 and OK-432 (derived from Streptococcus pyogenes type A3).38–41 We have established the preliminary safety profile and therapeutic dose (750–1500 μg) of intrapleural LTA-T for pleurodesis. Randomised trials are now needed to assess the efficacy of intrapleural LTA-T as a pleurodesis agent in malignant pleural effusion, and to further address the mechanism of action of this molecule. Contributors NMR, HED, MS, DK, and RJOD conceived and designed the trial. PT and RM commented on the trial conception. NMR and ELH enrolled patients and collected and compiled data. CC (cytology) and YCGL (cytokines) did the central pathological review. NMR, HED, and RJOD analysed and interpreted the data. NMR and RJOD wrote the report. HED, MS, PT, RM, DK, CC, ELH, and YCGL commented on and revised the report. All authors approved the final version. Conflicts of interest RJOD holds patent rights to the use of LTA-T for pleurodesis. All other authors declared no conflicts of interest. References 1 American Thoracic Society. Management of malignant pleural effusions. Am J Respir Crit Care Med 2000; 162: 1987–2001. 2 Dresler CM. Systemic distribution of talc. Chest 1999; 116: 266. 3 Antunes G, Neville E, Duffy J, Ali N. BTS guidelines for the management of malignant pleural effusions. Thorax 2003; 58 (suppl 2): ii29–ii38. 4 Erickson KV, Yost M, Bynoe R, Almond C, Nottingham J. Primary treatment of malignant pleural effusions: video-assisted thoracoscopic surgery poudrage versus tube thoracostomy. Am Surg 2002; 68: 955–59. 5 Lee YC, Baumann MH, Maskell NA, et al. Pleurodesis practice for malignant pleural effusions in five English-speaking countries: survey of pulmonologists. Chest 2003; 124: 2229–38. 6 Tschopp JM, Boutin C, Astoul P, et al. Talcage by medical thoracoscopy for primary spontaneous pneumothorax is more cost-effective than drainage: a randomised study. Eur Respir J 2002; 20: 1003–09. 7 Stefani A, Natali P, Casali C, Morandi U. Talc poudrage versus talc slurry in the treatment of malignant pleural effusion. A prospective comparative study. Eur J Cardiothorac Surg 2006; 30: 827–32. 8 Maskell NA, Lee YC, Gleeson FV, Hedley EL, Pengelly G, Davies RJ. Randomized trials describing lung inflammation after pleurodesis with talc of varying particle size. Am J Respir Crit Care Med 2004; 170: 377–82. 9 Brant A, Eaton T. Serious complications with talc slurry pleurodesis. Respirology 2001; 6: 181–85. 10 Kuzniar TJ, Blum MG, Kasibowska-Kuzniar K, Mutlu GM. Predictors of acute lung injury and severe hypoxemia in patients undergoing operative talc pleurodesis. Ann Thorac Surg 2006; 82: 1976–81. 11 de Campos JR, Vargas FS, de Campos WE, et al. Thoracoscopy talc poudrage: a 15-year experience. Chest 2001; 119: 801–06. 12 Rehse DH, Aye RW, Florence MG. Respiratory failure following talc pleurodesis. Am J Surg 1999; 177: 437–40. 13 Janssen JP, Collier G, Astoul P, et al. Safety of pleurodesis with talc poudrage in malignant pleural effusion: a prospective cohort study. Lancet 2007; 369: 1535–39. 14 Weber JR, Moreillon P, Tuomanen EI. Innate sensors for Grampositive bacteria. Curr Opin Immunol 2003; 15: 408–15. 15 Takeuchi O, Hoshino K, Kawai T, et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 1999; 11: 443–51. 16 Guenter CA. Respiratory function of the lungs and blood. In: Guenter CA, Welch MH, eds. Pulmonary medicine, 2nd edn. Philadelphia: JP Lippincott, 1982: 168. 17 Fentiman IS, Rubens RD, Hayward JL. A comparison of intracavitary talc and tetracycline for the control of pleural effusions secondary to breast cancer. Eur J Cancer Clin Oncol 1986; 22: 1079–81.

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