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In the histopathology of malignant mesotheliomas three different types (epithelial, connective tissue and mixed type) are distinguished. Some authors believe all tumours to be of mixed type, but consider that due to inadequate sampling or small biopsies this may be missed frequently. In this study the relationship between the histopathological diagnosis and the amount of tissue examined was investigated. In a series of 124 cases of malignant pleural mesothelioma a high percentage of mixed type tumours was found (55%). In cases where the decisive diagnostic procedure had been an Abrams biopsy (the "small-specimen" technique) mixed-type histology was found in 36%. If thoracoscopy, thoracotomy or autopsy (the "large-specimen" techniques) had delivered a definite diagnosis, mixed-type histology was found in 63%. Apparently diagnosing the mixed-type variety depends on the amount of tumour tissue obtained. However, the assumption that all mesotheliomas are of mixed type cannot be confirmed.

Cytogenetic analyses of 40 confirmed malignant mesotheliomas (MMs) are reported. Pleural effusion cells were studied in 90% of the cases by direct method or after culture or both. Biopsy and ascites fluid were also analyzed in some patients. A normal karyotype was found in nine cases, and complex karyotypic abnormalities were observed in 30 cases. In one case, analyzable metaphases were not obtained. The chromosomal changes were all complex and heterogeneous; no consistent presumably specific abnormality was detected. Nevertheless, two main patterns of nonrandom abnormalities were observed: 1) loss of chromosomes 4 and 22, 9p, and 3p in the most of the abnormal cases and corresponding to a hypodiploid and/or hypotetraploid modal chromosome number; and 2) gain of chromosomes 7, 5, and 20 with deletion or rearrangement of 3p as well in the hyperdiploid cases, which were a minority in our series. These findings are discussed in view of other reported cytogenetic studies of MM, asbestos exposure, and possible mechanisms of malignant transformation.

The identification of malignant mesothelial cells in cytological smears prepared from serous effusions is still hampered by the lack of features specific for mesothelial differentiation. We examined the diagnostic value of collagen cores within clusters of tumour cells in cytological smears prepared from effusions from 43 patients with malignant mesothelioma and of 62 cases of metastatic adenocarcinoma. In Giemsa-stained smears collagen cores were detected in 51% of the cases of malignant mesothelioma and in none of the smears with metastatic adenocarcinoma. Using the Azan stain, collagen cores were detected in 64% of the malignant mesotheliomas and 4% of the adenocarcinomas. Immunoelectron microscopy demonstrated that the collagen cores are largely composed of collagen type III fibrils and some elastin embedded in a homogenous extracellular matrix. It can be concluded that the presence of collagen cores within clusters of tumour cells is highly suggestive of mesothelial differentiation and a common finding in malignant mesothelioma.

The inflammatory mediators PGE2, DC-PGI2 and histamine as well as the beta-adrenergic drugs isoprenaline and salbutamol increase intracellular cyclic AMP-concentrations whereas Platelet Activating Factor does not induce any change in adenyl cyclase activity of normal human alveolar macrophages. Functional H2-histaminergic and beta 2-adrenergic receptor-subtypes are coupled to macrophage adenyl cyclase.

Three human malignant mesothelioma cell lines, designated Mero-14, Mero-25, and Mero-41, have been isolated from effusions and from autopsy material of confirmed cases of malignant mesothelioma. Light and electron microscopy, cytogenetics, growth requirements, and intermediate filament expression of these cell lines were studied and, where possible, compared with the original tumor material of the patient. Cytologic and ultrastructural morphology was consistent with the mesothelial nature of the cells. All cell lines displayed a hyperdiploid karyotype similar to that of the tumor cells obtained directly from the patient. All three malignant mesothelioma cell lines had marker chromosomes 1, 3, 9, and 22, as well as other markers that were occasionally present in these cell lines and in other malignant mesotheliomas studied. Growth kinetic studies in medium supplemented with epidermal growth factor (EGF) showed increased proliferation and a decreased proliferation in medium supplemented with hydrocortisone (HC) or EGF plus HC. The three malignant mesothelioma cell lines were positive for the cytokeratins 7, 8, 18, and 19 based on immunofluorescence and immunoblotting tests with chain-specific monoclonal antibodies. The characteristics of these cell lines support the assumption that Mero-14, Mero-25 and Mero-41 are derived from malignant mesotheliomas and have retained their original character.

The clinical data, diagnostic procedures and survival are reported in 19 cases diagnosed as malignant peritoneal mesothelioma. All patients were men and 74% had an occupational exposure to asbestos, whereas in 26% no information about asbestos exposure was available. The median interval between asbestos exposure and the diagnosis appeared to be 44.7 years (range 18-49 years). The most common presenting symptoms were abdominal pain, weight loss and dysphagia. Most patients presented with a large amount of ascites. In the majority of patients no therapy except pain relief was given and the median survival from the time of diagnosis was 6 months (range: 0-29 months). Some patients received surgery or chemotherapy, which however did not prolong survival. Only in 2 patients survival exceeded 1 year, although these patients did not receive therapy. The autopsy findings of some patients showed that there were positive abdominal lymph nodes in 2 of them, while in no case positive thoracic lymph nodes were found. The relative short survival period from the time of the first diagnosis in contrast to malignant pleural mesotheliomas is probably the reason for the absence of distant metastases. In this series only in a minority of patients cytology of the ascites was positive and often a laparotomy had to be done. Since cytologic specimens are often negative, we suggest that in patients suspected of a malignant peritoneal mesothelioma, laparoscopy with directed biopsies is the diagnostic procedure of first choice.

Twenty-one patients presenting with extrapulmonary sarcoidosis, 20 patients with pulmonary sarcoidosis, and 12 healthy volunteers were investigated. They were evaluated for roentgenographic findings, as well as for immunologic marker expression of cells in bronchoalveolar lavage (BAL) fluid. The patients presenting with extrapulmonary sarcoidosis could be divided in two groups: nine of 21 (43 percent) presented with a stage 1 or stage 2 chest x-ray film, while 12 of 21 (57 percent) had no chest x-ray film abnormalities (stage 0). In all three groups of sarcoidosis patients, a significant increase of CD3+ T lymphocytes in the BAL fluid was found as compared to the healthy volunteers. However, the percentages of T lymphocytes in BAL fluid of patients with extrapulmonary sarcoid lesions and a normal (stage 0) chest x-ray film was significantly lower as compared to patients with extrapulmonary sarcoidosis and an abnormal (stage 1, 2) chest x-ray film, while the latter patient group did not differ from the patients with pulmonary sarcoidosis. This suggests that in patients with extrapulmonary sarcoidosis, a gradual progression of the T cell alveolitis may occur. Furthermore, these data indicate that a marked discrepancy between chest x-ray film abnormalities and the presence of an alveolitis as determined by immunologic marker analysis exists in more than 50 percent of the patients with extrapulmonary sarcoidosis.

The immunologic phenotype of the monocyte-macrophage cell populations in bronchoalveolar lavage (BAL) fluid and monocytes in peripheral blood (PB) were studied in 20 patients with sarcoidosis, 18 with idiopathic pulmonary fibrosis (IPF), seven with extrinsic allergic alveolitis (EAA), and 12 healthy volunteers. There were no significant differences in expression of the immunologic markers CD13(My7), CD14(My4), and Monocyte-2 on blood monocytes between the patient groups and healthy volunteers, but there were marked differences between groups in the expression of the three markers on BAL macrophages. The percentage of Monocyte-2+ macrophages was increased in BAL in subjects with sarcoidosis, EAA, and IPF compared with healthy volunteers, greatest in EAA. This increase is probably due to increased recruitment of blood monocytes into alveoli, since the cells had a monocytic morphology on phase contrast microscopy (in normal subjects the majority of blood monocytes, but few alveolar macrophages, express the Monocyte-2 antigen). Patients with IPF had a significantly lower percentage of CD13(My7)+ macrophages in BAL than the other three groups. Compared with IPF patients and healthy volunteers, patients with EAA had a significantly higher percentage of CD14(My4)+ macrophages, whereas in sarcoidosis patients the numbers were reduced. These observations suggest an increased influx of blood monocytes into the alveoli in interstitial lung disorders. Phenotypic differences were found between the BAL macrophage populations of the various interstitial diseases. These differences in alveolar macrophage phenotype may be due to local factors, depending on the type of inflammation.

In mixed connective tissue disease (MCTD) pulmonary involvement has been reported. In most patients diffuse interstitial pulmonary abnormalities are present. We describe an unusual pulmonary onset of MCTD in an 18-year-old woman. She presented with a bilateral pleural exudate containing many granulocytes (95%) and only a few monocytes (5%). High titers of antinuclear antibodies were found. One week after hospitalization, an erythema on both hands and forearms developed. Skin biopsy demonstrated discrete IgM-C3 depositions along the basal membrane of the epidermis, antinuclear antibodies in the nuclei of the keratocytes in the dermis and granular depositions of IgM in the blood vessel walls of the upper dermis. Lung function tests improved without corticosteroid treatment and diffusing capacity remained normal.

Using 3H-leukotriene D4, a specific receptor assay has been developed for human alveolar macrophages, obtained by broncho-alveolar lavage of patients undergoing fiberoptic bronchoscopy because of suspected bronchial carcinoma. Lavage was performed in a carcinoma-free lobe of the lung and alveolar macrophages were subsequently isolated and incubated for binding studies. 3H-Leukotriene D4 was found to bind specifically with high affinity (Kd = 3.8 nM), in a saturable manner (Bmax = 90 fmol/10(6) cells), reversible and selective. Specific binding was linear with protein concentration and equilibrium binding at 4 degrees C was reached at 50 min. Scatchard and Hill analysis revealed a single class of binding sites with no cooperativity among the sites. Displacement studies with LTD4, the selective SRS-A antagonist FPL 55712 and with leukotriene C4 revealed respective Ki values of 3.4; 16; and 110 nM. The data suggest that human alveolar macrophages may contain a specific receptor type for LTD4, which has a relatively low affinity for LTC4, and are discussed in relation to modulatory processes in the lung, apart from direct actions of LTD4 on smooth muscle receptors. From the data here acquired, it may be apparent that the study of characteristics of receptors specific for a broncho-active substance like LTD4 on human alveolar macrophages, which play an important role in immuno-inflammatory processes seen in many chronic lung diseases, may yield major insights into the pathogenesis and therapy decisions involved in these diseases.

Among patients with asthma or chronic obstructive pulmonary diseases the response to glucocorticoids varies considerably. To investigate the possible relationship between clinical response and number of glucocorticoid receptors in alveolar macrophages or their KD value a micro receptor assay was developed. Assay conditions were adjusted because of receptor occupancy by endogenous or therapeutically used glucocorticoids and high aspecific binding.

Ten human malignant mesothelioma cell lines from primary and metastatic sites were studied for the expression of c-sis (PDGF B-chain) and PDGF A-chain genes. Malignant mesothelioma cell lines expressed strongly the c-sis oncogene which is barely detectable in normal mesothelial cells. The PDGF A-chain gene expression was slightly elevated in malignant mesothelioma cell lines compared to the expression in normal mesothelial cells. Cytogenic and Southern blot analysis did not provide evidence for genomic amplification or rearrangement of the c-sis oncogene. These results suggest that malignant mesothelioma cell lines show constitutively enhanced expression of the c-sis and PDGF A-chain genes that could play a role in the etiology of this type of malignancy.

Gold-induced pneumonitis is a rare complication of gold salt therapy. We describe a patient with rheumatoid arthritis treated with gold salts, who developed bilateral interstitial pulmonary abnormalities and showed a dramatic response on corticosteroid therapy. Although after 4 weeks of treatment with corticosteroids the chest X-ray and lung function were still abnormal, bronchoalveolar lavage showed a normal cell distribution. Corticosteroid therapy was continued for 8 months since there was still improvement of pulmonary function studies. This case supports the view that in gold-induced pneumonitis a prolonged treatment with corticosteroids may be necessary, as lung function continued to improve.

Bronchoalveolar lavage (BAL) is an investigation which has already proven its value in the diagnosis and follow-up of patients with pulmonary sarcoidosis. It also appears to be a valuable contribution to the diagnosis of patients presenting with ocular sarcoidosis. We evaluated the findings in BAL in 16 cases with suspected ocular sarcoidosis (14 cases of uveitis, one with eyelid-swelling and one with an inflammatory process of the lacrimal gland). BAL was positive in 11 cases e.g. showed a lymphocytosis with predominantly T4+ helper lymphocytes. There was one patient with ocular signs very suspect for sarcoidosis (a perivasculitis with candle wax infiltrates) with a normal percentage T lymphocytes (2%) in BAL. In two cases BAL was positive and showed a subclinical alveolitis, whereas no changes were seen on the chest X-ray and in Angiotensin Converting Enzyme (ACE) level.

Seventeen human malignant mesothelioma cell lines were isolated from 61 samples (46 effusions, 9 biopsies and 6 tumors obtained at autopsy) collected from patients with a confirmed malignant mesothelioma. The method used is given in detail. Cytogenetic analysis of growing cultures is the best indicator to determine whether the observed proliferation concerns malignant or normal mesothelial cells. The addition of epidermal growth factor (EGF) and hydrocortisone (HC), or EGF alone, to the culture medium increases the chances of successful isolation of a malignant mesothelioma cell line.