Ioannis Kalomenidis

Malignant Pleural Effusion

Malignant pleural effusion (MPE) poses a significant clinical problem. Current nonetiologic management is suboptimal in terms of efficacy and safety. In light of recent research progress, we propose herein a new view of MPE development, which may rapidly translate into meaningful changes in therapeutics. In addition to tumor-induced impairment of pleural fluid drainage, pertinent findings point toward another pathway to MPE formation: a vicious loop of interactions between pleural-based tumor cells and the host vasculature and immune system that results in increased net fluid production via enhanced plasma extravasation into the pleural space. The ability of tumor cells to trigger this cascade likely rests on a specific and distinct transcriptional repertoire, which results in important vasoactive events in the pleural space. Although the characterization of tumor-derived factors responsible for MPE development is in the making, an additional, indirect path to MPE was recently demonstrated: tumor cells recruit and co-opt host cells and mediators, which, in turn, amplify tumor cell-primed fluid leakage and impact tumor cell functions. Importantly, recent evidence suggests that the biologic events that culminate in clinical MPE are likely amenable to therapeutic inhibition and even prevention. In this perspective, the scientific basis for an update of current concepts of MPE formation is highlighted. Key questions for future research are posed. Finally, a vision for novel, effective, safe, and convenient treatment modalities that can be offered to outpatients with MPE is set forth.

Octreotide and chylothorax.

Purpose of review This article reviews the current literature concerning the role of somatostatin and its synthetic analogue, octreotide, in the treatment of chylothorax. Recent findings Management of chylothorax includes evacuation of the pleural cavity through a chest tube to alleviate dyspnoea, and dietary fat restriction aimed at reducing lymph flow. When these measures fail to control lymph flow, surgical interventions are employed to achieve definite closure of the thoracic duct leak. Several case reports and series have shown that octreotide is safe and probably effective in both children and adults with chylothorax of different origins. The property of somatostatin and octreotide to induce leak closure is attributed to a decelerating effect on lymph flow, although their exact mechanism of action is not well defined. In successful cases, a substantial reduction of lymph drainage through the chest tube is evident within the first few days of commencing the drug, and treatment lasts for 1–2 weeks. Treatment failure has been also reported, however. Summary Accumulating evidence suggests that octreotide is a putative novel therapeutic intervention for chylothorax. It is imperative that randomized controlled studies are conducted in order to fully elucidate the efficacy and safety of this treatment.

Eosinophilic pleural effusions.

Eosinophilic pleural effusions, defined as a pleural effusion that contains at least 10% eosinophils, may be caused by almost every condition that can cause pleural disease. Eosinophilic pleural effusion occurs most commonly during conditions associated with the presence of blood or air in the pleural space, infections, and malignancy. Drug-induced pleural effusions, pleural effusions accompanying pulmonary embolism, and benign asbestos pleural effusions are also among the common causes of eosinophilic pleural effusion. No etiology is found in as many as one third of patients. Because studies evaluating different diagnostic approaches with eosinophilic pleural effusions are lacking, the authors suggest that certain noninvasive and invasive diagnostic tools must be used based on the patients clinical characteristics.

A Central Role for Tumor-derived Monocyte Chemoattractant Protein-1 in Malignant Pleural Effusion

BACKGROUND Tumor cells in malignant pleural effusions (MPEs) are an important source of monocyte chemoattractant protein (MCP)-1. However, the role of tumor-derived MCP-1 in the pathogenesis and progression of MPE has not been determined. METHODS B16 mouse skin melanoma cells, which are deficient in MCP-1 expression, and mouse Lewis lung cancer (LLC) cells, which express high levels of MCP-1, were engineered to stably express MCP-1 and short hairpin RNAs (shRNAs) targeting the MCP-1 transcript, respectively. Cells were injected into the pleural cavities of syngeneic immunocompetent mice, and MPE volume and pleural tumors were quantified at necropsy (day 14). MCP-1 and other mediators were determined by cytometric bead array and enzyme-linked immunosorbent assay, and mononuclear and endothelial cells were identified by immunolabeling of F4/80 and factor VIII-related antigen respectively. Mouse survival was assessed using Kaplan-Meier analysis. Vascular permeability in mice with MPE was assessed using albumin-binding Evans blue. Statistical tests were two-sided. RESULTS LLC cells expressing shRNA against MCP-1 elaborated less than 5% of the MCP-1 level in cells expressing nonspecific shRNA (control cells), and intrapleural delivery of these cells resulted in less MPE (mean MPE volume = 86 and 585 muL, respectively; difference = 499 muL; 95% confidence interval [CI] = 331 to 669 muL; P < .001), reduced MCP-1 levels in the pleural fluid, and lower mortality than when control cells were delivered. Overexpression of MCP-1 in intrapleurally injected B16 melanoma cells led to increased MPE and reduced survival. In mice with MPE, MCP-1 was a potent inducer of vascular permeability, mononuclear recruitment, and, in pleural tumors, of angiogenesis. CONCLUSION MCP-1 produced by tumor cells is an important determinant of their capacity to induce the formation of MPE and may be a useful target for the treatment of malignant pleural disease.

Tumor Necrosis Factor-α Promotes Malignant Pleural Effusion

Tumor necrosis factor (TNF)-α is present in the microenvironment of human tumors, including malignant pleural effusion (MPE). Although the cytokine is produced in the pleural cavity by both tumor and host cells, its effects on MPE formation are unknown. In these studies, we sought to determine the role of TNF-α in the pathogenesis of MPE and to assess the therapeutic effects of its neutralization in a preclinical model. For this, MPEs were generated in immunocompetent mice using intrapleural injection of mouse lung adenocarcinoma cells. The roles of tumor- and host-derived TNF-α were assessed using combined experimentation with TNF-α gene–deficient mice and in vivo TNF-α neutralization. To expand the scope of preclinical data, TNF-α and vascular endothelial growth factor (VEGF) expression were determined in human cancer cell lines and human MPE. In the MPE model, TNF-α of host and tumor origin was present. TNF-α neutralization significantly limited tumor dissemination, effusion formation, vascular hyperpermeability, TNF-α and VEGF expression, and angiogenesis, thereby improving survival. In contrast, these variables were not different between TNF-α gene–sufficient and TNF-α gene–deficient mice. In mouse cancer cells, TNF-α functioned via nuclear factor-κB– and neutral sphingomyelinase–dependent pathways to induce TNF-α and VEGF, respectively. These results were recapitulated in human cancer cells, and a correlation was detected between TNF-α and VEGF content of human MPE. We conclude that tumor-derived TNF-α is important in the development of MPE in mice, and provide preclinical evidence supporting the efficacy of TNF-α blockade against malignant pleural disease. [Cancer Res 2007;67(20):9825–34]

Bench-to-bedside review: Pulmonary–renal syndromes – an update for the intensivist

The term Pulmonary–renal syndrome refers to the combination of diffuse alveolar haemorrhage and rapidly progressive glomerulonephritis. A variety of mechanisms such as those involving antiglomerular basement membrane antibodies, antineutrophil cytoplasm antibodies or immunocomplexes and thrombotic microangiopathy are implicated in the pathogenesis of this syndrome. The underlying pulmonary pathology is small-vessel vasculitis involving arterioles, venules and, frequently, alveolar capillaries. The underlying renal pathology is a form of focal proliferative glomerulonephritis. Immunofluorescence helps to distinguish between antiglomerular basement membrane disease (linear deposition of IgG), lupus and postinfectious glomerulonephritis (granular deposition of immunoglobulin and complement) and necrotizing vasculitis (pauci-immune glomerulonephritis). Patients may present with severe respiratory and/or renal failure and require admission to the intensive care unit. Since the syndrome is characterized by a fulminant course if left untreated, early diagnosis, exclusion of infection, close monitoring of the patient and timely initiation of treatment are crucial for the patients outcome. Treatment consists of corticosteroids in high doses, and cytotoxic agents coupled with plasma exchange in certain cases. Renal transplantation is the only alternative in end-stage renal disease. Newer immunomodulatory agents such as those causing TNF blockade, B-cell depletion and mycophenolate mofetil could be used in patients with refractory disease.

Zoledronic Acid Is Effective against Experimental Malignant Pleural Effusion

RATIONALE Aminobiphosphonates, such as zoledronic acid (ZA), exert potent indirect antitumor effects and are currently being tested against human solid tumors. The antitumor actions of aminobiphosphonates, including angiostasis, are relevant to the pathogenesis of malignant pleural effusion (MPE), but no study has addressed the efficacy of these compounds against malignant pleural disease. OBJECTIVES Here we hypothesized that treatment of immunocompetent mice with ZA would halt tumor progression in a mouse model of adenocarcinoma-induced MPE. METHODS To induce MPE in mice, Lewis lung carcinoma cells were delivered directly into the pleural space. Subsequently, animals were treated with ZA in both a prevention and a regression protocol. MEASUREMENTS AND MAIN RESULTS ZA treatment resulted in significant reductions in pleural fluid accumulation and tumor dissemination, while it significantly prolonged survival. These effects of ZA were linked to enhanced apoptosis of pleural tumor cells, decreased formation of new vessels in pleural tumors, and reduced pleural vascular permeability. In addition, ZA was able to inhibit the recruitment of mononuclear cells to pleural tumors, with concomitant reductions in matrix metalloproteinase-9 release into the pleural space. Finally, ZA limited the expression of proinflammatory and angiogenic mediators, as well as the activity of small GTP proteins Ras and RhoA, in tumor cells in vivo and in vitro. CONCLUSIONS ZA is effective against experimental MPE, suggesting that this intervention should be considered for testing in clinical trials.

Chylothorax: diagnostic approach

Purpose of review This review evaluates recent research findings and proposes an up-to-date diagnostic approach for patients with suspected chylothorax. Recent findings Typically, chylothorax is a milky exudate with high triglyceride content (>110 mg/dl). However, milky appearance is not always the case and triglyceride levels can be less than 110 mg/dl, especially in fasting or malnourished patients. Transudative chylothoraces have been reported when cirrhosis, nephrosis or heart failure co-exist. In addition, although the vast majority of the white blood cells in chyle are lymphocytes, chylothoraces can be neutrophilic, especially the postsurgical ones. Summary Chylothorax is the accumulation of chyle into the pleural cavity usually due to thoracic duct leak and should be suspected not only in patients with milky effusions but also in the presence of certain co-morbidities or history of chest/neck trauma. Fluid triglycerides more than 110 mg/dl or less than 50 mg/dl virtually establish or exclude the diagnosis, respectively; ambiguous cases with values 50–110 mg/dl require lipoprotein analysis for the demonstration of chylomicrons. In fasting or malnourished patients lipoprotein analysis is suggested even with triglycerides less than 50 mg/dl. Typical pleural fluid in chylothorax is a lymphocytic exudate with low lactate dehydrogenase; atypical fluid characteristics (i.e. transudative nature, neutrophil-predominance or high lactate dehydrogenase) may be a sign of additional causes of pleural fluid accumulation.

Host-derived Interleukin-5 Promotes Adenocarcinoma-induced Malignant Pleural Effusion

RATIONALE IL-5 is a T helper 2 cytokine important in the trafficking and survival of eosinophils. Because eosinophils can be found in malignant pleural effusions (MPE) from mice and humans, we asked whether IL-5 is involved in the pathogenesis of MPE. OBJECTIVES To determine the role of IL-5 in MPE formation. METHODS The effects of IL-5 on experimental MPE induced in C57BL/6 mice by intrapleural injection of syngeneic lung (Lewis lung cancer [LLC]) or colon (MC38) adenocarcinoma cells were determined using wild-type (il5(+/+)) and IL-5-deficient (il5⁻(/)⁻) mice, exogenous administration of recombinant mouse (rm) IL-5, and in vivo antibody-mediated neutralization of endogenous IL-5. The direct effects of rmIL-5 on LLC cell proliferation and gene expression in vitro were determined by substrate reduction and microarray. MEASUREMENTS AND MAIN RESULTS Eosinophils and IL-5 were present in human and mouse MPE, but the cytokine was not detected in mouse (LLC) or human (A549) lung and mouse colon (MC38) adenocarcinoma-conditioned medium, suggesting production by host cells in MPE. Compared with il5(+/+) mice, il5⁻(/)⁻ mice showed markedly diminished MPE formation in response to both LLC and MC38 cells. Exogenous IL-5 promoted MPE formation in il5(+/+) and il5⁻(/)⁻ mice, whereas anti-IL-5 antibody treatment limited experimental MPE in il5(+/+) mice. Exogenous IL-5 had no effects on LLC cell proliferation and gene expression; however, IL-5 was found to be responsible for recruitment of eosinophils and tumor-promoting myeloid suppressor cells to MPE in vivo. CONCLUSIONS Host-derived IL-5 promotes experimental MPE and may be involved in the pathogenesis of human MPE.

Pathogenesis of the eosinophilic pleural effusions.

Purpose of review Eosinophilic pleural effusions (EPE) are defined as those that contain at least 10% eosinophils. EPEs account for 5 to 16% of exudative pleural effusions. However, their pathogenesis is poorly understood. The purpose of this review is to discuss the mechanisms that lead to eosinophilic pleural inflammation. Recent findings Eosinophilic pleural effusions are caused by the presence of air or blood or both in the pleural space, infectious or other inflammatory diseases, malignancy, pulmonary emboli, asbestos exposure, and drug reactions. Differences in the clinical features suggest that a variety of mechanisms operate to induce eosinophilic pleural inflammation and pleural fluid accumulation. Human and animal studies indicate that interleukin (IL)-5 is an important common contributor of different pathogenetic pathways. The possible role of other cytokines, chemokines, and adhesion molecules in the development of EPE is under investigation. Summary Understanding the pathogenesis of EPE will permit the development of novel therapies for the persistent, symptomatic, posttraumatic and idiopathic EPE. Anti-IL-5 treatment is an interesting option that requires further research.