Advanced Powder Technol., Vol. 18, No. 6, pp. 739– 750 (2007) © VSP and Society of Powder Technology, Japan 2007. Also available online - www.brill.nl/apt
Invited paper Talc pleuradesis: a particulate analysis SCOTT C. BROWN 1 , MOHAMMED KAMAL 2 , NAJMUNNISA NASREEN 2 , AIDOS BAUMURATOV 2 , PARVESH SHARMA 1 , VEENA B. ANTONY 2 and BRIJ M. MOUDGIL 1,∗ 1 Department
of Materials Science & Engineering and Particle Engineering Research Center, PO Box 116135, University of Florida, Gainesville, FL 32611, USA 2 Division of Pulmonary and Critical Care Medicine, Department of Medicine, PO Box 100225, University of Florida, Gainesville, FL 32610, USA Received 17 May 2007; accepted 23 July 2007 Abstract—The administration of talc particles to the pleural space for the production of symphysis has been practiced for over 70 years with little understanding of the key particle parameters that lead to desired or undesired clinical outcomes. Nevertheless, talc has become the sclerosant of choice for pleuradesis. In addition to its ability to obliterate the pleural space, talc has also been indicated to slow the progression of cancer leading to improved quality of life and longer lifespans for patients suffering from malignant pleural effusions. However, the occurrence of fatal side effects — particularly acute respiratory distress syndrome (ARDS) — has recently raised concerns. The potential influence of the physical properties and chemical state (impurity levels and type) of clinically administered talc on the frequency of ARDS in clinical outcomes is investigated in this study. The outcomes indicate a need for cross-disciplinary collaborations between physicians and particle scientists to yield an improved understanding of the fundamental talc particle properties that instigate therapy and those that induce adverse effects. These developments are expected to lead to further insights into the interactions that occur between particles and tissues, in addition to strategies for engineering multifunctional nextgeneration pleuradesis agents. Keywords: Talc; particle characterization; pleuradesis; acute respiratory distress syndrome; cancer; mesothelial cell.
1. INTRODUCTION
The pleural space is an area of the body spanning from the membrane lining the inner chest wall to an opposing membrane on the outer portion of the lungs. In normal individuals a small amount of intervening liquid is present between the pleura membranes totaling only approximately 2–3 ml in volume. In the case ∗ To
whom correspondence should be addressed. E-mail:
[email protected]fl.edu
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of pleural effusions and pneumothoracies abnormal accumulations of fluid (liquid and air, respectively) occur in the pleural space, resulting in restricted or lost lung function. Both ailments are commonly treated via the instillation of a sclerosant agent into the pleural space intended to obliterate the pleural space. Sclerosants induce the formation of scar tissue, which in the case of pleuradesis binds the outer lungs to the chest wall physically maintaining lung expansion and essentially replacing the pleural space with scar tissue. By doing so, the risk of reoccurrence for both pleural effusions and pneumothoracies is dramatically reduced — principally because the reservoir for fluid accumulation is removed. Over the years, a variety of sclerotic agents have been tested for the purpose of pleuradesis with a distribution of success rates and drawbacks. These include talc, iodopovidone, radioactive colloidal gold, autologous blood, fibrin glue, biological agents (suspension of killed Corynebacterium parvum or bacille Calmette-Guerin), nitrates (silver nitrate), antibiotics (tetracyclines, minocycline and doxycycline), antimalarials (quinacrine and mepacrine), antineoplastic drugs (bleomycin, mitomicin, thiotepa, nitrogen mustard) and immunomodulating agents (interferon-α and -γ ) [1 –10]. In the literature there is some disagreement, and many ongoing investigations, as to which material produces the best results. Although the existing data is inconclusive, which may be a result of the variability in the design and interpretation of the studies, talc, either delivered as powder or in slurry form (talc powder dispersed in saline solution), is generally considered to be the most effective sclerosing agent for pleuradesis [2, 5]. The use of talc for the production of pleural symphysis was first described by Bethune in 1935 [11]. Since then it has been actively researched in both animal models and in a clinical setting. As early as the 1940s, talc began to be clinically administered for the treatment of pneumothorax and a decade later for the treatment of pleural effusions [2]. Today, there are more than 4000 reported cases where talc has been used as a pleurodesis agent to treat malignant and non-malignant pleural effusions and pneumothorax. The amount of clinical research accumulated for talc exceeds that reported for all other agents combined and the average success rate with talc is nearly 90% (around 87% for slurry, around 93% for poundrage) [5, 7, 10, 12]. There is also an increasing amount of evidence in the literature that talc has some anticancer properties, and when used as a pleuradesis agent for patients with malignant effusions an enhancement in both quality of life and life expectancy occurs [13]. Approximately half of all patients with metastatic cancer develop a pleural effusion; therefore a pleuradesis agent with both sclerotic and antitumorgenic properties is highly desirable. This has been a driving force for testing and application of many chemotherapeutic agents as sclerosants for pleuradesis; however, few could produce results comparable to those induced by talc. In vitro, the internalization of talc has been shown to induce selective apoptosis in malignanant cells, but not in normal pleural mesothelial cells (the cells that line the pleural space membranes) [14]. More recently, we have also shown, in vitro and in vivo, that talc also induces
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the induction of endostatin — an inhibitor of angiogenesis — which may modulate the malignant growth on the pleura by tilting the pro-angiogenic environment of the pleural space to an anti-angiogenic milieu [15]. However, scattered reports of respiratory complications, including acute respiratory distress syndrome (ARDS), and even deaths subsequent to talc administration have brought scrutiny to the safety of using talc for pleuradesis. There are at least 32 cases in the literature where ARDS is identified to occur after the intrapleural administration of talc, 17 after the use of talc slurry and the remaining 15 after talc insufflation (dry powder aerosolization) [16 –22]. In eight instances the patient died [17, 19 –21]. However, the incidence of ARDS occurring after talc administration has varied markedly from series to series. Most of the reported cases have been from the US and the highest incidence was that reported by Rehse et al. [20], who reviewed 89 talc pleurodesis procedures in 78 patients. They reported that the incidence of respiratory complications or death was 33%; eight patients were diagnosed with ARDS, one patient died, six patients developed dyspnea and three patients developed re-expansion pulmonary edema [20]. Although it has been suggested that respiratory failure might be more common after larger doses of talc or talc slurry [23], Campos Milanez et al. reported that acute respiratory failure developed in four of 338 patients (1.2%) who received 2 g of insufflated talc for either recurrent pleural effusion or pneumothorax [17]. On the other hand, it should be noted that the reported incidence of respiratory complications is zero in some large series. Weissberg reported no incidences of acute respiratory distress in 360 patients who received talc pleurodesis [23], whereas Rodriguez-Panadero and Antony reported no cases of acute respiratory distress in 299 patients [24]. Although some gains have been made in deconvoluting the mechanism by which talc induces pleuradesis [25, 26], very little is known about the mechanism or mechanisms by which talc produces acute lung injury. Conventional wisdom suggests that these complications may be potentially avoided by appropriately selecting the powder, dose and administration technique; however this cannot be achieved without reliable mechanistic insights. Since talc is a naturally mined, pulverized, foliated, hydrated magnesium silicate, the composition and properties of talc from different deposits and processing protocols are likely to be unique with regard to both chemistry and morphology. Material parameters such as particle size distribution, prevalent impurities, effective wettability, surface area, solvation properties, exfoliation propensity and modulus need to be addressed with respect to efficacy, translocation and toxicity. However, because talc particles used in clinical studies are rarely characterized, efforts to draw conclusions with regard to principle talc properties involved in therapy or acute lung injury have had limited success. To date, the principle hypothesis for the mechanism of the observed adverse side effects is the translocation of talc particles outside of the pleura. Supporting evidence for this mechanism has been presented by Rinaldo et al. [21] and by Campos Milanez et al. [17]. In one provocative human autopsy, Milanez Campos
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and collegues reported the presence of talc crystals in almost every organ, including the lung, brain, liver, kidney, heart and skeletal muscle. Similar results illustrating talc translocation from the pleura has been shown in rabbits [27] and rats [28]. As many of the identified particles found outside of the pleural space appeared to be of smaller micron-scale sizes it has been hypothesized that the smaller talc particles lead to the adverse side effects. Indeed, the instillation of talc samples of different mean sizes from the same source appeared to indicate that larger talc samples appeared less frequently in lungs [29] and randomized clinical trials suggested greater systemic inflammation with talc particles containing smaller particle populations. However, it is important to note that in both of these studies the talc was dosed by mass and not by surface area or number. This would lead to a greater number of particles being instilled when using the smaller mean sized talc samples and could be an alternative explanation for the presented results. Biological interactions with insoluble particles have been shown to scale with surface area or particle number and not by particle mass [30]. Hence the doses provided in the comparisons may not be equivalent. Moreover, incidence of ARDS were not observed in either study and the smaller talc principally used in Ferrer et al.’s research, which is frequently applied in Europe for pleuradesis, has not been reported to be linked to the occurrence of ARDS, in contrast to the talc commonly administered in the US. It is still debatable whether or not particle size is the true culprit leading to adverse side effects in talc pleuradesis. In the current study, clinically administered talc powders obtained from different sources are characterized in an attempt to aid in the identification of particle properties that could potentially correlate to the onset of ARDS. Specific attention is placed on the role of particle size, bulk and surface properties.
2. MATERIALS AND METHODS
Talc powder samples were received from Humco (Texakana, TX, USA), Bryan (Sclerosol® ; Woburn, MA, USA) and Novatech (Steritalc® ; La Ciotat, France). A fourth powder was kindly donated by Dr Rodriguez-Panadero (Seville, Spain). For convenience in data representation, these talc samples will be aliased as represented in Table 1. All other chemical reagents were at least ACS grade. Table 1. Talc sample alias designation Alias
Talc sample
SM1a
Humco talc Sclerosol talc from Spain Steritalc
SM2a SM3 SM4 a Sample
associated with ARDS risk.
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2.1. Particle size analysis The particle size distributions for the four samples were measured by a combination of laser diffraction and polarization intensity differential scattering (PIDS) via a Coulter LS13220 particle sizing apparatus (Beckman Coulter, Fullerton, CA, USA). To ensure proper dispersion a series of tests were preformed in which talc particles were either vortexed or sonicated for extended periods of time in deionized water. After 10 min of vortexing or sonication the volume distribution stabilized for all powders, suggesting adequate dispersion. Extended tests for 24 h also showed insignificant changes in particle size distributions. The particle size distributions presented in this study were measured after 15 min of vortexing. The particle sized distribution obtained via the above method were comparable to values estimated from field emission scanning electron microscopy (JSM 6330F; JEOL, Tokyo, Japan). 2.2. Surface area analysis The specific surface area of the talc powders was measured by the physisorption of krypton gas (Quantachrome Autosorb 1C-MS; Quantochrome, Boyton Beach, FL, USA) using the Brunauer–Emmet–Teller (BET) method. Krypton was chosen over nitrogen due to limited talc sample mass. All samples were out-gassed on the gas adsorption analyzer for 24 h at 110◦ C under vacuum prior to measurement. 2.3. ζ potential analysis A Zeta-Reader Mark 21 (Zetapotential Instruments, Bedminster, NJ, USA) electrophoresis apparatus was used to measure particle mobility as a function of applied voltage. The talc powders were dispersed by vortexing in deionized water containing 1 mM NaCl background electrolyte. The solutions were titrated with the use of sodium hydroxide and hydrochloric acid. Prior to experimentation, focus on the stationary plane was verified. 2.4. Bulk composition The bulk elemental composition of the talc samples was determined through energy dispersive X-ray spectroscopy (EDS) using a JEOL JSM6330F cold field emission scanning electron microscope (SEM). For each sample, a 0.5-mm thick bed of talc powder was fixed on a piece of carbon tape attached to a graphite stub. To minimize surface charging 20 nm of carbon was evaporated onto the prepared surface. All reported values are the average of 20 measurements of different areas. 2.5. Crystalline impurities The presence of crystalline impurities was evaluated using X-ray diffraction in a Phillips APD 3700 powder X-ray diffractometer (PANalytical, Almelo, The
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Netherlands). Briefly, a paste from talc and a 7:1 mixture of amyl acetate and colloidan was prepared and then applied to a glass slide. Diffraction patterns were obtained from with cobalt/nickel-filtered copper-Kα radiation (40 kV, 20 mA). Peak identification from the resulting diffraction pattern was used to determine the presence of crystalline impurites. 2.6. Surface composition The surface elemental composition of the talc samples was determined by X-ray photoelectron spectroscopy (XPS) using an Kratos Analytical Surface Analyzer XSAM 800 (Kratos Analytical, Manchester, UK). 2.7. Surface wettability The advancing and receding contact angles of the talc powders were determined using a Rame-hart Advanced Goniometer Model 500 with an Automated Drop Dispenser and Tilting Base (Rame-Hart Instrument, Netcong, NJ, USA). The talc powders were applied to an inert adhesive on a planar glass slide. Measures were taken to ensure an even and thorough coating of the adhesive surface. To approximate the advancing and receding angles a talc sample with a fresh 10-μl drop (pH 7.4 deionized water) was tilted until just before the drop began slide. All reported values are the average of 10 different experiments.
3. RESULTS AND DISCUSSION
To date, there are very few examples where clinical evaluations of particulate materials are accompanied by an appropriate amount of characterization. Much of the existing data on talc-associated ARDS onset provides little or no information on the characteristics of the administered talc, impeding our ability to draw correlations between fundamental particle properties and the onset of ARDS. In an attempt to determine whether or not a clear correlation could exist between inherent talc properties and ARDS risk, we have examined four talc samples that have been used for pleuradesis. Two of these samples, i.e. Humco (SM1) and Sclerosol (SM2), have been linked to ARDS by clinical observations, whereas the other samples are believed to have essentially no risk. In the past, ARDS has been associated with the administered particle size; however convincing particle size data is rarely present. Nonetheless, it has been hypothesized that smaller talc particles are able to translocate throughout the body, initiating a sequence of events leading to the onset of ARDS. Indeed, a few authors have experimentally shown the translocation of small talc particles outside the pleural space [17, 27, 28, 31]. However, the direct link between ARDS and particle size has not been made. It is plausible that talc particles less than about 5 μm could be ingested and translocated via cells, and smaller particles of approximately 50 nm
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or less could diffuse across intact pleura. Particles up to the tens of microns have the potential to locally transit across a damaged pleura, e.g. across the lung rupture site during treatment for pneumothorax. In the current investigation primary particle size does not appear to be associated with ARDS occurrence, as indicated in Fig. 1. It is evident that the mean particle sizes for the number distributions are essentially the same, whereas the volume distributions vary with sample, but not ARDS propensity. It is stressed that these measures are approximate since talc is a platy and birefringent material. To confirm the trends, SEM micrographs were used for confirmation (Fig. 2) and powder surface areas were analyzed. A comparison of specific surface area as estimated from spherical surface approximations from the particles sizing data and that directly measured by BET analysis is given in Table 2. The same progression in surface area is found by both methods, confirming the relative validity of the results. A clear trend in prevalent particle number distribution and surface area data indicates that for the current samples dosimetric issues cannot be justified as the sole reason for ARDS outcome. Clinical practitioners are known to vary talc dosage by a factor of 2; the surface areas measured in the current research fell within this window except for sample SM1. To determine if a variation in impurity composition is linked to ARDS occurrence, the bulk composition of the talc particles was also investigated. As with the sizing data and surface area data, a clear trend was not found, as indicated in Table 3. Calcium and iron impurities were identified in all samples; aluminum was present in SM2, SM3 and SM4, but not SM1. X-ray diffraction data given in Table 4 also does not show a trend in crystalline impurities with ARDS occurrence. Since the processing of the different talc powders may vary, it is likely that the surface of the talc particles may also be different. The relative surface composition and surface charge of the four talc samples were investigated through XPS and ζ potential analysis, respectively. These factors have the potential to modify disper-
Figure 1. Light scattering particle size measurements. (a) Number percent size distribution for dispersed talc powders and corresponding (b) volume percent size distributions. Note that samples SM1 and SM2 are associated with ARDS risk, whereas samples SM3 and SM4 are not.
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Figure 2. SEM micrographs of the four talc samples. All images are of the same magnification (×400). Table 2. Specific surface area of talc samples
Approximated surface area BET surface area (m2 /g) a Sample
(m2 /g)b
SM1a
SM2a
SM3
SM4
2.38 9.32
1.12 2.16
1.62 3.29
0.85 1.56
associated with ARDS risk. from light scattering data assuming a spherical particle volume.
b Estimated
sion, biomolecule adsorption and the resulting cell surface interactions, all of which may be important factors defining talc efficacy. However, the results indicated in Tables 4 and 5 also show no significant clear trends. It should be noted, however, that sample SM2 exhibited the presence of surface fluorine atoms. Sample SM2 is provided by the manufacturer in a sterile aerosol canister containing a fluorocarbon propellant that appears to remain on the talc surface post-administration. It is not clear whether the presence of this contaminant is significant enough to have a biological impact and requires additional study. An analysis of the wettability of the four particle samples revealed that the two samples associated with ARDS risk had a greater contact angle hysterisis than the
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Table 3. EDS elemental composition of talc samples
Magnesium Oxygen Silicon Aluminum Calcium Iron a Sample
SM1a
SM2a
SM3
SM4
Pure talcb
14.8 61.8 22.5 – 0.4 0.5
15.1 62.0 22.2 0.2 0.4 0.2
15.2 61.5 22.6 0.3 0.2 0.2
14.8 63.5 21.1 0.2 0.4 0.2
15.8 63.2 21.1 – – –
associated with ARDS risk. composition of impurity free talc.
b Theoretical
Table 4. Elemental surface composition of talc powders
Magnesium Oxygen Silicon Flourine Carbon a Sample
SM1a
SM2b
SM3
SM4
4.2 74.1 8.0 – 13.8
3.8 70.4 7.1 4.4 14.3
4.4 71.7 7.8 – 16.1
4.8 74.9 8.5 – 11.8
associated with ARDS risk.
Table 5. Zeta potential analysis of talc powders
Isoelectric point (pH) Smoluchowski ζ potential (mV)b a Sample
SM1a
SM2a
SM3
SM4
1.7 ± 0.4 −60 ± 6
1.3 ± 0.4 −72 ± 10
1.3 ± 0.3 −58 ± 4
1.3 ± 0.3 −56 ± 4
associated with ARDS risk. water adjusted to pH 7.4, 1 mM NaCl background electrolyte.
b Deionized
Table 6. Talc powder contact angle measurements
Advancing contact angle (deg) Receding contact angle (deg) a Sample
SM1a
SM2a
SM3
SM4
62 ± 3 47 ± 3
82 ± 3 62 ± 3
59 ± 2 49 ± 2
83 ± 2 71 ± 2
associated with ARDS risk.
samples that were not indicative of ARDS. This result indicates the presence of a larger surface heterogeneity in samples SM1 and SM2 as compared to samples SM3 and SM4. It is interesting to note that samples SM2 and SM4 are derived from the same source (a Luzenac talc source in France) with the principle difference
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being packaging. Sample SM4 is supplied as a sterile dry powder in a bottle under atmospheric pressure, whereas sample SM2 is provided as an aerosol as indicated above. The smaller particle size and greater surface area associated with SM2 is partially believed to be attributed to the milling phenomena that occurs upon talc administration from the manufacturer-provided aerosol nozzle. The rapid ejection process through the orifice results in particle fracture, providing freshly cleaved high-energy talc edge surfaces. The presence of these surfaces is believed to lead to the lower receding contact angles observed in SM2. The hysterisis in SM1, however, is believed to be due to its microstructure. Unlike the other samples which are platy in nature, SM1 has a microcrystalline structure. As such, the principle crystal features are less aligned and the much more hydrophilic edge surfaces are more randomly oriented, resulting in a higher probability that they are likely to be oriented upwards during wetability analysis. This is believed to lead to the greater hysterisis in the contact angles measured in SM1. In all cases, the maximum and minimum contact angles from the samples associated and not associated with ARDS risk are comparable, and no trends in the overall hydrophobic or hydropillic nature of the materials are observed. The later has more impact on the differential adsorption and denaturing of biomolecules, which could lead to an alternative biological response and potentially ARDS. In addition to the contact angle hysterisis results, in some recent unpublished experiments a correlation appears to have been found between the ratio of siloxane and silanol groups in the talc samples. Via Fourier transform infrared spectroscopy it has been observed that the talcs with ARDS propensity have considerable less hydroxyl groups compared to siloxanes as determined from their Si–O bending and OH stretching peaks. This was particularly surprising since sample SM1 was microcrystalline in nature, and samples SM2 and SM4 were obtained from the same talc source. Although this data is encouraging, the number of talc samples acquired for analysis that have been linked to ARDS is too small to draw conclusions. Hence, it is apparent that cooperative research between particle scientists and physicians will be necessary in order to gain a larger sample population to identify meaningful relationships. Yet, because of the infrequency of ARDS, a clear link between particle properties and risk may be difficult to come by. Contrary to popular belief, it is largely possible that the occurrences could be linked to patient specific interactions or practitioner differences. For instance, the ejection rate and force from the SM2 aerosol canister is much greater than that applied using a traditional insuffulator, and could possibly cause pleural damage when applied by a less experienced physician, particularly when administered to patients having thinned pleural membranes. Despite the need to identify the principle factors associated with ARDS risk, the relatively small clinical data sets and associated large patient variablities suggest that this venture will take decades to resolve. A more promising venture with potentially immediate results is to refocus efforts to identify the material properties of talc that leads to its therapeutic effects. A basic understanding of mesothelial cell–talc interactions is expected to lead to the development of
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synthetic particle-based pleuradesis agents and new inorganic anticancer agents. Open and active cross-disciplinary collaborations between physicians and particle scientists will be a necessary step to achieve these goals. 4. CONCLUDING REMARKS
Although the occurrence of ARDS has been suggested to be linked to remnant impurities and particles size, the current study does not indicate such a correlation. Instead, the degree of hydroxylation, sample variability, and patient and practitioner differences may provide the greatest contributions to ARDS risk. Du to the limited data sets and samples attributed to ARDS, more recent efforts have been focused on delineating the mechanisms imbibed by talc that lead to its therapeutic effects. The isolation of these attributes and the synthesis of synthetic therapeutic particles may indirectly serve to mitigate ARDS occurrence in the future. The alleviation of the variability associated with talc source and poorly disseminated processing techniques may provide a solution to ARDS concerns, and could result in potentially more effective broad-based particulate therapeutics. Acknowledgments The authors acknowledge the financial support of the Particle Engineering Research Center (PERC) at the University of Florida and the Industrial Partners of the PERC for support of this research. Partial financial support by the National Institutes of Health (grant no. 1-P20-RR020654-01) is also acknowledged. REFERENCES 1. V. B. Antony, Pleurodesis — testing the waters, Amer. Rev. Respir. Dis. 135, 775–779 (1987). 2. L. Kennedyand and S. A. Sahn, Talc pleurodesis for the treatment of pneumothorax and pleural effusion, Chest 106, 1215–1222 (1994). 3. E. M. Marom, E. F. Patz, Jr, J. J. Erasmus, H. P. McAdams, P. C. Goodman and J. E. Herndon, Malignant pleural effusions: treatment with small-bore-catheter thoracostomy and talc pleurodesis, Radiology 210, 277–281 (1999). 4. E. Martinez-Moragon, J. Aparicio, M. C. Rogado, J. Sanchis, F. Sanchis and V. Gil-Suay, Pleurodesis in malignant pleural effusions: a randomized study of tetracycline versus bleomycin, Eur. Respir. J. 10, 2380–2383 (1997). 5. F. Rodriguez Panadero and V. B. Antony, Pleurodesis: state of the art, Eur. Respir. J. 10, 1648– 1654 (1997). 6. F. S. Vargas, L. R. Teixeira, L. M. M. F. Silva, A. O. Carmo and R. W. Light, Comparison of silver-nitrate and tetracycline as pleural sclerosing agents in rabbits, Chest 108, 1080–1083 (1995). 7. F. S. Vargas, N. S. Wang, L. R. Teixeira, A. O. Carmo, L. M. Silva and R. W. Light, Corynebacterium parvum versus tetracycline as pleural sclerosing agents in rabbits, Eur. Respir. J. 8, 2174–2177 (1995). 8. P. B. Walkerrenard, L. M. Vaughan and S. A. Sahn, Chemical pleurodesis for malignant pleural effusions, Ann. Intern. Med. 120, 56–64 (1994). 9. U. Wied, E. Halkier, K. Hoeiermadsen, B. Plucnar, E. Rasmussen and J. Sparup, Tetracycline versus silver-nitrate pleurodesis in spontaneous pneumothorax, J. Thorac. Cardiovasc. Surg. 86, 591–593 (1983).
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