Frank Reichenberger

Proinflammatory Cytokine Levels in Patients with Lung Cancer and Carcinomatous Pleurisy

Increased levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) have been reported in various diseases, including lung cancer. The role of the soluble form of the IL-6 receptor (sIL-6R) remains to be explored. We therefore measured IL-6, IL-8 and sIL-6R in effusion fluid and blood serum of 10 lung cancer patients with carcinomatous pleurisy (5 men, 5 women, age 64.3 ± 4.4 years) by enzyme-linked immunosorbent assays. Serum levels of healthy individuals served as control. Concentrations of sIL-6R were much higher in serum compared to pleural effusion fluids of tumor patients (25,698 ± 1,993 vs. 9,438 ± 1,407 pg/ml; p < 0.0001). In contrast, IL-6 and IL-8 were found at high concentrations in carcinomatous pleural effusions in comparison to serum (IL-6: 964 ± 176 vs. 10.2 ± 1.3 pg/ml, p < 0.0001; IL-8: 319 ± 85 vs. 9.6 ± 9.6 pg/ml, p < 0.0001). The serum concentrations of IL-6 were not significantly increased in lung cancer patients (10.2 ± 1.3 pg/ml) in comparison to controls (7.3 ± 1.0 pg/ml). IL-8 was detected in the serum of only 1 patient and in low levels in the serum of controls (8.0 ± 1.5 pg/ml; all values are mean ± SEM). We conclude from this study that decreased levels of sIL-6R, but increased levels of IL-6 and IL-8, are found in pleural effusion fluid of patients with lung cancer and carcinomatous pleurisy. The low sIL-6R levels in the presence of high IL-6 levels in pleural effusions and the high sIL-6R levels in the presence of low IL-6 levels in serum may suggest a downregulation of sIL-6R expression or sIL-6R shedding in the presence of excessive amounts of IL-6.

Compartmentalization of pro-inflammatory cytokines in tuberculous pleurisy

Increased levels of interleukin-6 (IL-6) and IL-8 are found in various immunologically mediated inflammatory disorders. Concentrations of IL-6, IL-8 and the soluble form of the IL-6 receptor (sIL-6R) were determined in serum and effusion fluid of 25 patients with tuberculous pleurisy utilizing enzyme linked immunosorbent assays (EIA). Serum IL-6 levels were only slightly increased in patients with tuberculous pleurisy in comparison to controls (11.1 +/- 2.1 vs 7.3 +/- 1.0 pg ml-1). IL-8 could not be detected in the serum of tuberculosis patients, but it was detected in the serum of healthy controls (8.0 +/- 1.5 pg ml-1). In comparison to serum, IL-6 and IL-8 were found in high concentrations in pleural effusions (IL-6: 932 +/- 70 vs 11.1 +/- 2.1 pg ml-1, P < 0.0001; IL-8: 450 +/- 85 vs 0 +/- 0 pg ml-1). In contrast, sIL-6R concentrations were much higher in serum compared to pleural effusion levels [30,477 +/- 1905 vs 9881 +/- 1177 pg ml-1, P < 0.0001 (mean +/- SEM)]. The authors conclude that elevated levels of IL-6 and IL-8 in pleural effusions are compartmentalized at the site of active disease. The low levels of sIL-6R in the presence of high levels of IL-6 in pleural effusions, and the high levels of sIL-6R in the presence of low levels of IL-6 in serum suggest that the expression or shedding of sIL-6R may be downregulated in the presence of excessive amounts of IL-6.

Pulmonary Mucosa-Associated Lymphoid Tissue Lymphoma in a Patient with Common Variable Immunodeficiency Syndrome

Common variable immunodeficiency syndrome (CVID) is a primary immunodeficiency typically presenting with recurrent sinopulmonary infections. Non-Hodgkin’s lymphoma and other secondary cancers are typical late complications of CVID. We report on a patient suffering from CVID with a history of recurrent sinopulmonary infections, interstitial pulmonary changes and hepatic granulomas. Despite treatment with intravenous immunoglobulin followed by a reduction in the number of pulmonary infections, reticular and nodular lung changes progressed. Video-assisted thoracoscopic lung biopsy showed a low-grade B cell lymphoma of the mucosa-associated lymphoid tissue (MALT) of the bronchus without evidence of pulmonary infection. In conclusion, MALT lymphoma of the lung should be considered in the differential diagnosis of progressive lung disease in CVID.

Recurrent Pleural Effusion and a Mediastinal Mass

Accessible online at: www.karger.com/journals/res A 59-year-old male barkeeper was hospitalized because of voluminous pleural effusion. He complained of progressive dyspnea, cough, backpain and moderate weight loss over 3 weeks, and no improvement with antibiotic treatment. He had no history of previous diseases. On physical examination the patient suffered from severe dyspnea and moderate tachycardia. Dullness to percussion and diminished breath sounds were found over the left hemithorax. Besides mild hepatomegaly no further abnormalities were found. Laboratory studies revealed elevated levels of CRP 78.6 mg/l (normal ! 5 mg/l), serum lipase 13.3 Ìmol/l Ws (normal !3.1 Ìmol/l Ws), and serum amylase 9.1 Ìmol/l Ws (normal !3.7 Ìmol/l Ws). Differential blood cell count, liver and renal function tests were normal. The chest X-ray showed nearly complete opacification of the left lung with a mediastinal shift towards the right side (fig. 1). An abdominal ultrasound confirmed the hepatomegaly and revealed two gallbladder polyps and a cyst in the left kidney. Initially, thoracocentesis was performed and 1.5 liters of hemorrhagic pleural fluid was drained showing an exudate (pH 8.0, protein 43.4 g/l, LDL 18 Ìmol/l Ws, lipase 1,689 Ìmol/l Ws, amylase 553 Ìmol/l Ws) with a few neutrophils and lymphocytes, but without signs of malignancy or bacterial infection. Despite repeated thoracocentesis the pleural effusion recurred after a short time. A thoracic CT scan revealed a liquid-filled structure situated in the posterior mediastinum ventral to the distal esophagus (fig. 2). What is your suspected diagnosis? Which additional diagnostic procedures should be performed? Fig. 1. Chest X-ray showing a massive left-sided pleural effusion with a concomitant mediastinal shift. Fig. 2. Thoracic CT scan with a cyst in the posterior mediastinum ventral to the esophagus (white arrow). 1

Pulmonary Hypertension for Clinicians: Time to Call on Genetics?

tery pressure response to exercise and hypoxia, an early indicator of altered pulmonary vascular function [2] . The pathogenesis of PAH is complex and involves a variety of cellular and molecular mechanisms, including the serotoninand nitric oxide system. Therefore, genetic modifiers have been suggested to be involved in the development of PAH [3] . Are genetic changes relevant in our current clinical management of pulmonary hypertension? In the current issue of Respiration , Ulrich et al. [4] describe genetic changes in patients with idiopathic PAH and chronic thromboembolic pulmonary hypertension (CTEPH) who were referred to the pulmonary hypertension centre in Zurich (Switzerland). They performed extensive genetic studies including the analysis of the BMPR2 gene, and polymorphisms in a variety of genes involved in the serotonin and nitric oxide pathway. Additionally, they investigated patients with distinct left heart disease but without pulmonary hypertension. The authors did not find any difference in the genetic analysis between patients with CTEPH, idiopathic PAH or left heart disease. However, they detected a BMPR2 mutation in a patient with coronary artery disease without PAH or a family history of PAH. Furthermore, different polymorphisms of the BMPR2 gene were either present in PAH, or in CTEPH or in both. PAH patients carrying a Over the last decade, pulmonary hypertension has developed from a largely unknown disease to a very well recognised disorder. During this period, three world conferences have been held addressing pathobiology, diagnosis, and treatment of the disease. Currently, we classify approximately 30 different forms of pulmonary hypertension. The early recognition of a hereditary type of pulmonary arterial hypertension (PAH) was suggestive of a genetic cause of the disease. Basic research has revealed genetic alterations in the TGFsystem to be involved in the pathogenesis of PAH. Among the TGFsuperfamily, a mutation in the bone morphogenetic protein receptor 2 (BMPR2) has been linked to PAH, leading to an altered intracellular signalling with subsequent proliferation of smooth muscle cells and increased endothelial cell apoptosis in the pulmonary vasculature. Epidemiological studies have shown a high frequency of BMPR2 mutation in hereditary PAH (70%) and idiopathic PAH (20%), rarely in PAH associated with congenital heart disease and ingestion of appetite suppressants, but so far not in other forms of pulmonary hypertension. Patients carrying a BMPR2 mutation are known to have an earlier onset of the disease and are less likely to show an acute vasodilator response [1] . Furthermore, healthy relatives of PAH patients, who carry the identical BMPR2 mutation, exhibit a higher proportion of hypertensive pulmonary arPublished online: December 7, 2009

Successful resection of a re-occurred pulmonary myosarcoma in a patient with turner syndrome mosaic.

We describe a patient who underwent thoracic radiation therapy for biopsy-proven pulmonary spindle cell sarcoma in the left lower lobe, 15 months after birth. At the age of 37 she developed shoulder pain, fatigue, and progressive exertion dyspnoea. Chest X-ray revealed a pulmonary mass in the left lower lobe due to a cytology-proven malignant tumour.The patient underwent left pneumonectomy. Histology revealed a myosarcoma of the lung, similar to the previous sarcoma. Furthermore, the patient was diagnosed to have Turner syndrome mosaic and chromosomal analysis revealed a translocation t(1;13) in 3/50 metaphases. However a germline mutation of the p53 tumour suppressor gene was excluded. After 2 years of follow-up the patient is stable and there are no signs of recurrence of the tumour.We conclude a re-occurrence of this very rare malignant disorder of the lung after a 36-year interval in a patient with Turner syndrome mosaic. Following initial curative radiation therapy, with a remission over 36 years, lung resection was now successfully performed.