A. Scherpereel

Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare tumour but with increasing incidence and a poor prognosis. In 2008, the European Respiratory Society/European Society of Thoracic Surgeons Task Force brought together experts to propose practical and up-to-dated guidelines on the management of MPM. To obtain an earlier and reliable diagnosis of MPM, the experts recommend performing thoracoscopy, except in cases of pre-operative contraindication or pleural symphysis. The standard staining procedures are insufficient in ∼10% of cases. Therefore, we propose using specific immunohistochemistry markers on pleural biopsies. In the absence of a uniform, robust and validated staging system, we advice use of the most recent TNM based classification, and propose a three step pre-treatment assessment. Patients performance status and histological subtype are currently the only prognostic factors of clinical importance in the management of MPM. Other potential parameters should be recorded at baseline and reported in clinical trials. MPM exhibits a high resistance to chemotherapy and only a few patients are candidates for radical surgery. New therapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasise that patients who are considered candidates for a multimodal approach should be included in a prospective trial at a specialised centre.

Endocan is a novel chondroitin sulfate/dermatan sulfate proteoglycan that promotes hepatocyte growth factor/scatter factor mitogenic activity.

Proteoglycans that modulate the activities of growth factors, chemokines, and coagulation factors regulate in turn the vascular endothelium with respect to processes such as inflammation, hemostasis, and angiogenesis. Endothelial cell-specific molecule-1 is mainly expressed by endothelial cells and regulated by pro-inflammatory cytokines (Lassalle, P., Molet, S., Janin, A., Heyden, J. V., Tavernier, J., Fiers, W., Devos, R., and Tonnel, A. B. (1996) J. Biol. Chem. 271, 20458–20464). We demonstrate that this molecule is secreted as a soluble dermatan sulfate (DS) proteoglycan. This proteoglycan represents the major form either secreted by cell lines or circulating in the human bloodstream. Because this proteoglycan is specifically secreted by endothelial cells, we propose to name it endocan. The glycosaminoglycan component of endocan consists of a single DS chain covalently attached to serine 137. Endocan dose-dependently increased the hepatocyte growth factor/scatter factor (HGF/SF)-mediated proliferation of human embryonic kidney cells, whereas the nonglycanated form of endocan did not. Moreover, DS chains purified from endocan mimicked the endocan-mediated increase of cell proliferation in the presence of HGF/SF. Overall, our results demonstrate that endocan is a novel soluble dermatan sulfate proteoglycan produced by endothelial cells. Endocan regulates HGF/SF-mediated mitogenic activity and may support the function of HGF/SF not only in embryogenesis and tissue repair after injury but also in tumor progression.

Electromagnetic navigation diagnostic bronchoscopy for small peripheral lung lesions

The present study prospectively evaluated the diagnostic yield and safety of electromagnetic navigation-guided bronchoscopy biopsy, for small peripheral lung lesions in patients where standard techniques were nondiagnostic. The study was conducted in a tertiary medical centre on 40 consecutive patients considered unsuitable for straightforward surgery or computed tomography (CT)-guided transthoracic needle aspiration biopsy, due to comorbidities. The lung lesion diameter was mean±sem 23.5±1.5u2005mm and the depth from the visceral-costal pleura was 14.9±2u2005mm. Navigation was facilitated by an electromagnetic tracking system which could detect a position sensor incorporated into a flexible catheter advanced through a bronchoscope. Information obtained during bronchoscopy was superimposed on previously acquired CT data. Divergence between CT data and data obtained during bronchoscopy was calculated by the systems software as a measure of navigational accuracy. All but one of the target lesions was reached and the overall diagnostic yield was 62.5% (25–40). Diagnostic yield was significantly affected by CT-to-body divergence; yield was 77.2% when estimated divergence was ≤4u2005mm. Three pneumothoraces occurred and chest drainage was required in one case. Electromagnetic navigation-guided bronchoscopy has the potential to improve the diagnostic yield of transbronchial biopsies without additional fluoroscopic guidance, and may be useful in the early diagnosis of lung cancer, particularly in nonoperable patients.

Characterization of the Secreted Form of Endothelial-Cell-Specific Molecule 1 by Specific Monoclonal Antibodies

Endothelial-cell-specific molecule 1 (ESM-1) is a recently identified endothelial cell molecule. As ESM-1 mRNA is preferentially expressed in human lung and kidney tissues, and as ESM-1 mRNA expression is regulated by inflammatory cytokines, ESM-1 is thought to play a role in the vascular contribution to organ-specific inflammation. In order to define its behavior, mouse anti-ESM-1 monoclonal antibodies were developed, and three distinct epitopes were mapped, which allowed development of a specific ELISA assay, immunohistological staining and immunoblot analysis. Here, we demonstrate that ESM-1 is present in cell lysates of human endothelial cells (human umbilical vein endothelial cells) with an apparent molecular weight of 20 kD. In contrast, the secreted form of ESM-1 is shifted to an apparent molecular weight of 50 kD, indicating that the secreted form of ESM-1 is posttranslationally modified. By ELISA, we show that the secretion of ESM-1 is significantly enhanced in the presence of TNFα. In contrast, the spontaneous as well as TNFα-induced secretion of ESM-1 is strongly inhibited by IFNγ. Moreover, ESM-1 was detected in the serum of healthy subjects at an average concentration of 1.08 ng/ml, and we demonstrated that the serum level of ESM-1 is dramatically increased in patients presenting a septic shock. Analysis of ESM-1 expression in normal human tissues by immunohistochemistry showed that ESM-1 is localized in the vascular network, but also in the bronchial and renal epithelia. Our results demonstrate that ESM-1 is mainly expressed in the vascular endothelium both in vitro and in vivo, but also by different epithelia. ESM-1 may represent a new marker of endothelial cell activation, and may have a functional role in endothelium-dependent pathological disorders.

Fatal interstitial lung disease associated with oral erlotinib therapy for lung cancer

BackgroundErlotinib is a Human Epidermal Growth Factor Receptor Type 1/tyrosine kinase (EGFR) inhibitor which is used for non-small-cell lung cancer treatment. Despite that erlotinib is considered to have a favorable safety profile, adverse events such as interstitial lung disease (ILD) were reported in pivotal studies. The authors report the first histologically confirmed case of fatal ILD associated with erlotinib therapy.Case PresentationThe medical record of a patient who developed fatal ILD after receiving erlotinib treatment was reviewed to identify the cause of death and other factors potentially contributive to this adverse outcome. A 55-year-old smoker with no evidence of pre-existing interstitial disease developed bilateral ILD and respiratory failure which could be explained only as a toxicity of erlotinib. He had a history of stage IV left upper lobe squamous-cell carcinoma for which he had received three successive regimens of chemotherapy (ifosfamide plus gemcitabine, docetaxel, mitomycin plus navelbine), followed five months later by erlotinib. At initiation of erlotinib treatment there were no radiological signs suggestive of ILD disease or apparent clinical signs of respiratory distress. While the patient completed two months with erlotinib therapy he developed bilateral interstitial infiltrates; despite discontinuation of erlotinib he was admitted with respiratory failure two weeks later. Diagnostic work up for other causes of pneumonitis including infectious diseases, congestive cardiac failure and pulmonary infraction was negative. Empiric treatment with oxygene, corticosteroids and later with cyclophosphamide was ineffective and the patient progressively deteriorated and died. The clinical and post-mortem examination findings are presented and the possible association relationship between erlotinib induced ILD and previous chemotherapy is discussed.ConclusionPhysicians should be alert to the fact that erlotinib related ILD, although infrequent, is potential fatal. The association between selective EGFR-inhibitors and ILD should be further investigated.

Serum mesothelin has a higher diagnostic utility than hyaluronic acid in malignant mesothelioma

UNLABELLEDnWe assessed comparatively the diagnostic value of two potential malignant pleural mesothelioma (MPM) markers: hyaluronic acid (HA) and soluble mesothelin.nnnMATERIALS AND METHODnWe measured serum and pleural fluid values of mesothelin and hyaluronic acid in 76 patients with MPM, 33 patients with pleural metastases of carcinomas (Mets group) and 27 patients with benign pleural effusion related to asbestos exposure (BPLAE).nnnRESULTSnUsing a serum HA cut-off of 100 microg/L, 8 patients/33 (24.2%) were positive in the Mets group versus 20/76 (26.3%) in the MPM group and only 1/27 BPLAE patients. The area under ROC curve for serum HA in MPM versus Mets or BPLAE groups was only 0.617 while it was 0.755 for mesothelin. In pleural fluid, both markers had similar diagnostic values.nnnCONCLUSIONSnSerum mesothelin is more sensitive than hyaluronic acid in diagnosing MPM and there is no benefit in combining both markers.

Outpatient management of primary spontaneous pneumothorax: a prospective study

We prospectively assessed the safety and cost saving of a small-bore drain based procedure for outpatient management of first episodes of primary spontaneous pneumothorax. Patients were managed by observation alone or insertion of an 8.5-F “pig-tail” drain connected to a one-way valve, according to size and clinical tolerance of the pneumothorax. All patients were reassessed after 4 h, on the first working day after discharge and on day 7. Patients still exhibiting air leak on day 4 underwent thoracoscopy. The primary end-point was complete lung re-expansion at day 7. 60 consecutive patients entered the study. 48 (80%) met the definition of large pneumothorax. The success rate was 83%. The 1-year recurrence rate was 17%. 36 (60%) patients were discharged after 4 h and 50% had full outpatient management. No severe complication was observed. The mean±sd length of hospitalisation was 2.3±3.1 days. This policy resulted in about a 40% reduction in hospital stay-related costs. The present study supports the use of a single system combined with a well-defined management algorithm including safe discharge criteria, as an alternative to manual aspiration or chest tube drainage. This approach participates in healthcare cost-savings. Primary spontaneous pneumothorax can be managed outside the hospital, subject to strict pre-discharge safety criteria http://ow.ly/qVxcd

Surrogate markers predicting overall survival for lung cancer: ELCWP recommendations

The present systematic review was performed under the auspices of the European Lung Cancer Working Party (ELCWP) in order to determine the role of early intermediate criteria (surrogate markers), instead of survival, in determining treatment efficacy in patients with lung cancer. Initially, the level of evidence for the use of overall survival to evaluate treatment efficacy was reviewed. Nine questions were then formulated by the ELCWP. After reviewing the literature with experts on these questions, it can be concluded that overall survival is still the best criterion for predicting treatment efficacy in lung cancer. Some intermediate criteria can be early predictors, if not surrogates, for survival, despite limitations in their potential application: these include time to progression, progression-free survival, objective response, local control after radiotherapy, downstaging in locally advanced nonsmall cell lung cancer (NSCLC), complete resection and pathological TNM in resected NSCLC, and a few circulating markers. Other criteria assessed in these recommendations are not currently adequate surrogates of survival in lung cancer.

Defect in recruiting effector memory CD8+T-cells in malignant pleural effusions compared to normal pleural fluid

BackgroundMalignant pleural effusions (MPE) are a common and fatal complication in cancers including lung or breast cancers, or malignant pleural mesothelioma (MPM). MPE animal models and immunotherapy trials in MPM patients previously suggested defects of the cellular immunity in MPE. However only few observational studies of the immune response were done in MPM patients, using questionable control groups (transudate…).MethodsWe compared T cell populations evaluated by flow cytometry from blood and pleural effusion of untreated patients with MPM (nu2009=u200958), pleural metastasis of adenocarcinoma (nu2009=u200930) or with benign pleural lesions associated with asbestos exposure (nu2009=u200923). Blood and pleural fluid were also obtained from healthy subjects, providing normal values for T cell populations.ResultsBlood CD4+ or CD8+ T cells percentages were similar in all groups of patients or healthy subjects. Whereas pleural fluid from healthy controls contained mainly CD8+ T cells, benign or malignant pleural effusions included mainly CD4+ T cells. Effector memory T cells were the main T cell subpopulation in pleural fluid from healthy subjects. In contrast, there was a striking and selective recruitment of central memory CD4+ T cells in MPE, but not of effector cells CD8+ T cells or NK cells in the pleural fluid as one would expect in order to obtain an efficient immune response.ConclusionsComparing for the first time MPE to pleural fluid from healthy subjects, we found a local defect in recruiting effector CD8+ T cells, which may be involved in the escape of tumor cells from immune response. Further studies are needed to characterize which subtypes of effector CD8+ T cells are involved, opening prospects for cell therapy in MPE and MPM.

Loss of Endocan tumorigenic properties after alternative splicing of exon 2.

BackgroundEndocan was originally described as a dermatan sulfate proteoglycan found freely circulating in the blood. Endocan expression confers tumorigenic properties to epithelial cell lines or accelerate the growth of already tumorigenic cells. This molecule is the product of a single gene composed of 3 exons. Previous data showed that endocan mRNA is subject to alternative splicing with possible generation of two protein products. In the present study we identified, and functionally characterized, the alternative spliced product of the endocan gene: the exon 2-deleted endocan, called endocanΔ2.MethodsStable, endocanΔ2-overexpressing cell lines were generated to investigate the biological activities of this new alternatively spliced product of endocan gene. Tumorigenesis was studied by inoculating endocan and endocanΔ2 expressing cell lines subcutaneously in SCID mice. Biochemical properties of endocan and endocanΔ2 were studied after production of recombinant proteins in various cell lines of human and murine origin.ResultsOur results showed that the exon 2 deletion impairs synthesis of the glycan chain, known to be involved in the pro-tumoral effect of endocan. EndocanΔ2 did not promote tumor formation by 293 cells implanted in the skin of severe combined immunodeficient (SCID) mice.ConclusionOur results emphasize the key role of the polypeptide sequence encoded by the exon 2 of endocan gene in tumorigenesis, and suggest that this sequence could be a target for future therapies against cancer.