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The two major fibrinolytic activators, urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA) may play role in tumor spread and metastasis. Malign pleural mesothelioma (MPM) is a kind of tumor with predominantly local invasion and low incidence of distant metastasis. In this study, u-PA, t-PA and PA activator-1 (PAI-1) antigen and activity were measured in plasma and pleural fluid samples from patients with MPM, lung cancer and benign effusion. When compared to the control group, in MPM group, plasma u-PA and t-PA antigen levels were higher, but plasma u-PA and t-PA activity were comparable. PAI-1 antigen was also higher in MPM group. These findings were in contrast to the lung cancer group, in which both activity and immunologic measurement of u-PA and t-PA were higher, but PAI-1 antigen was similar as compared to the control group. It is concluded that excess t-PA and u-PA are balanced in complexes with PAI-1 in MPM, whereas the amount of PAI-1 in plasma is insufficient to overcome the elevated t-PA and u-PA, in lung cancer. Based on these findings, it may be suggested that the balanced fibrinolytic system is responsible for the low incidence of distant metastasis in MPM.

In this study we analyzed the role of CA 125 serum levels in the diagnosis and follow-up of pleural metastases in breast cancer patients. CA 125 serum levels were measured in patients with lung and/or pleural metastases: a) at the time of detection of the metastases, b) 3 months thereafter during therapy and c) before and after drainage of pleural effusions. In all patients occurrence of metastases at other localisations was excluded. For CA 125 measurements ELISA sandwich assays were performed. In 76 patients with metastases CA 125 levels were elevated in 8% of patients with lung metastases, in 89% with pleural metastases and in 94% with-both sites of metastases. In patients with lung metastases, the CA 125 concentrations did not follow the clinical course of disease, while in patients with pleural metastases CA 125 levels followed the course of disease in 25 of 25 progressions and in 5 of 6 remissions. After the puncture of pleural effusions CA 125 levels decreased in 7 of 14 patients and remained stable in the other 7 patients.

We investigated the intraarterial concentration of CDDP following continuous hyperthermic pleural perfusion (CHPP, 43 degrees C for 30 to 60 minutes) with 100 mg CDDP diluted in distilled water or saline in 6 lung cancers (2 pleural dissemination, 1 malignant pleural effusion, 3 positive wash cytology), 2 metastatic lung cancer (from breast cancer, 1 rhabdomyosarcoma with pleural dissemination), and 1 metastatic pleural tumor (adenocarcinoma, unknown origin). The level of CDDP was 9.16 to 24.1 micrograms/ml (average 16.1) in perfusion fluid, 0.3 after 5 minutes, 0.41 to 0.85 after 60 minutes and 0.15 to 0.27 (average 0.22) after 24 hours. There were no severe side effects nor any difference in effects by dilution fluid between distilled water and saline. Only 1 patient suffered pleural effusion after this treatment. The results suggested that CHPP with CDDP diluted by saline was effective for prevention and treatment of pleural dissemination.

Malignant mesothelioma (MM) is a locally aggressive tumor that spreads by poorly understood mechanisms. Because neoplastic spread has been linked to altered fibrin turnover, we used immunohistochemistry of nine MM and three fibrous tumors of the pleura to confirm in vivo fibrin deposition and expression of selected coagulation and fibrinolytic reactants in MM. Tumor-associated fibrin was readily detectable at site of tissue invasion. Little fibrin was distributed within the tumor, but tissue factor and tissue factor pathway inhibitor, urokinase, urokinase receptor, and plasminogen activator inhibitors 1 and 2 were all detected in either epithelioid or sarcomatous areas of MM. We used the MS-1 human pleural mesothelioma cell line to determine how expression of these reactants is regulated. Fibrinolytic activity of MS-1 is mainly due to urokinase and is responsive to cytokine stimulation. Functional extrinsic activation and prothrombinase complexes assemble at the cell surface. MM express procoagulants as well as fibrinolytic reactants in vivo and in vitro that promote local fibrin formation and remodeling. Fibrin deposition occurs primarily at areas of tissue invasion and could promote local extension of this neoplasm. Sparsity of fibrin within the central portions of the tumor stroma suggests that local resorption of transitional fibrin occurs at sites of established MM.

The retrospective analysis of 250 breast cancer patients with disseminated disease provided evidence that the increase in CA 125 serum levels in these patients was caused by lung metastases or pleural effusions. Seven patients with lung metastases and pleural involvement had elevated CA 125 levels, while in four patients with lung metastases but without pleural effusions CA 125 levels remained normal. In patients with only bone or liver metastases CA 125 levels were usually not elevated. If these results are confirmed, CA 125 would be the first tumour marker in breast cancer whose levels could be associated with one single site of metastases.

Recurrent hypoglycemia occurred in a 48-year-old woman with a localized pleural mesothelioma. During hypoglycemia, serum high molecular weight insulin-like growth factor II (IGF-II) was elevated. The tumor also contained a high level of high molecular weight IGF-II. We propose that the primary cause of the hypoglycemia in this patient was the high molecular weight IGF-II produced by the tumor.

The half-life of interleukin-2 (IL-2) is short after intravenous bolus injections (6 to 10 minutes) and elevated doses are necessary for its anti tumour action on account of severe side-effects which limit its use. Studies have shown good tolerance and efficacy of elevated doses of recombinant IL-2 after intrapleural administration in the treatment of neoplastic pleurisy. After a phase one study to determine the maximum tolerated dose (24 x 10(6) IU/m2 per day), we have studied the pharmacokinetics of 21 x 10(6) IU/m2 per day of recombinant IL-2 administered as a continuous intrapleural infusion over 5 days in 6 patients who presented with a neoplastic pleurisy (3 had malignant mesotheliomas and 3 had adeno-carcinomas of unknown primary site). Three patients presented with a partial objective response and no toxic effects beyond grade 2 were noted. Specimens were taken from the pleura and blood following the infusion and were taken at 2, 6, 8, 32, 44, 56, 80 and 120 hours after the end of the infusion. After calibration with IL-2 (Roussel Uclaf) the concentrations were assessed using radio-immuno-assay (Amersham). Very elevated pleural levels were obtained for 5 patients with very significant areas under the curve (SSC). All the patients presented with diffuse lesions of the parietal pleura whose initial evaluation included thoracoscopy. The inverse was a patient who was suffering from pleural nodular lesions who had very low pleural levels at the lower limit of detectability. The blood concentrations were low in all patients and the area under the curve was 1000 times less elevated than for the pleura.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors report a case of pleural fibrosarcoma associated with severe hypoglycaemia. Chromatography of the patient's serum and tumour fragments revealed a substance with a high molecular weight and an insulin-like activity. Professor Poffengarger's laboratory identified this substance as Non Suppressible Insulin-Like Protein or NSILAp which induces insulin-like effects on various tissues. A review of the literature is presented in the light of this case.

A 64 year old woman with a long history of "drop attacks" and dizzy spells was found to have spontaneous hypoglycaemia. A slowly enlarging pleural mass had been present for at least five years. At thoracotomy the mass (weight 1.7 kg) was excised and the hypoglycaemia ceased. Histologically the tumour was a pleural fibroma, with no features of malignancy. Endocrine tests before surgery showed a subnormal growth hormone response to spontaneous hypoglycaemia, a reduced concentration of serum insulin like growth factor I (IGF-I), and an inappropriately high concentration of serum insulin like growth factor II (IGF-II). After resection of the tumour the growth hormone response to insulin induced hypoglycaemia and the IGF-I and IGF-II concentrations were normal. These data suggest that the hypoglycaemia was due to production of IGF-II by the tumour, causing increased glucose utilisation and an impaired growth hormone counterregulatory response to hypoglycaemia.

The pharmacokinetics and toxicity of cisplatin were investigated in 3 patients affected by malignant mesothelioma who received 90 mg/m2 of the drug intrapleurally. The mean area under the pleural Pt concentration versus time curve (AUC) [12.83 (S.D. 4.06) mg.min/ml] was about 50 times greater than that detected in plasma [0.27 (0.03) mg.min/ml], indicating a clear pharmacological advantage for this route of administration. The mean plasma total Pt concentration was 1.1 micrograms/ml and the apparent total body clearance was 268 (101) ml/min. Platinum plasma pharmacokinetic data measured following intrapleural cisplatin administration (4 patients) were compared with those observed in 7 patients treated intravenously with the same dose of cisplatin (90 mg/m2) under the same modalities of hydration. Intrapleural administration of cisplatin resulted in significantly lower plasma total partial AUC (P less than 0.05) and prolonged plasma levels of filterable Pt compared with intravenous administration. No difference between the two routes of cisplatin administration in the renal clearance (S.D.) of filterable Pt [132 (64) ml/min and 122 (39) ml/min for intravenous and intrapleural cisplatin, respectively] were observed. None of the mesothelioma patients developed clinical symptoms or signs of pleural inflammation. The intrapleural treatment did not produce haemotoxicity and the emetic toxicity was lower compared with that observed in patients receiving cisplatin intravenously.

We have reported the case of a 69-year-old woman with a hugh benign fibrous tumor of the left pleura and hypoglycemic seizures. Increased preoperative levels of insulin-like growth factor (IGF II) were present; insulin level was low and plasma levels of somatomedin C were normal. After resection of the 2,400 gm tumor, blood sugar level has remained normal, and IGF II has fallen to normal limits. This appears to be the first reported case documenting elevated serum IGF II in association with a benign fibrous pleural tumor.

Inflammatory pleurisies in the adult are particularly rich in CD4 lymphocytes, capable of inducing and facilitating the immune reaction. The aim of this study was to determine the percentage of CD4 and CD8 lymphocytes in pleural fluid and blood in 13 patients with tuberculous pleurisy and 12 patients with pleural neoplasms, to establish the diagnostic value of this analysis. Independent of the etiology of the effusion there is a concentration of CD4 T lymphocytes in the pleural fluid compared to the blood (49.52 +/- 12.36% and 39.28 +/- 6.74%, respectively, p value less than 0.001). However, there was a similar concentration for the two types of disorders studied with 59.92 +/- 7.26% for tuberculous pleurisies and 45.83 +/- 6.26% for neoplastic effusions, thus this technique does not make the diagnostic orientation any clearer.

Little has been reported concerning electrolyte changes among patients with mesothelioma. Two studies have suggested that hyponatraemia is particularly common among them and should lead to suspicion of inappropriate secretion of antidiuretic hormone in those patients (Perks et al. 1979; Siafakas et al. 1984). We reviewed serum electrolyte changes in three groups of patients: 48 cases of pleural mesothelioma, 89 of peritoneal mesothelioma, associated with asbestos exposure, and 149 of asbestosis. Five of 48 (10.4%) patients with pleural mesothelioma, 17 of 89 (19.1%) with peritoneal mesothelioma, and 23 of 149 (15.4%) patients with asbestosis without mesothelioma, had hyponatraemia. No statistically significant difference among the groups was found. These findings do not support the proposal that hyponatraemia is unusually common when mesothelioma is present, at least not among patients whose neoplasms are related to asbestos exposure.

Percentages of lymphocytes forming rosettes with sheep erythrocytes at 29 degrees C were determined in 10 cancer patients with metastases to the pleural cavity. Compared with normal controls, the patients showed a decreased proportion of rosette-forming cells (RFC) in the peripheral blood. The same patients had elevated levels of RFC in their metastatic pleural effusions. However, 2 patients with benign diseases had normal levels of RFC in their peripheral blood and pleural transudates. These observations suggested that in cancer patients some T-cells might migrate from the peripheral blood and accumulate in sites of tumor infiltration such as the pleural cavity.

Seven patients with advanced cancer underwent whole-body hyperthermia using a nylon and vinyl mesh, water-perfused suit. Treatments were given at 41.8 degrees C for 4 hours. Five patients received concomitant cyclophosphamide with hyperthermia. Compared to baseline (37 degrees C) conditions, there was a significant rise in pulse rate (P less than 0.001), a fall in diastolic pressure (P less than 0.02), and an increase in respiratory rate (P less than 0.001). Toxic effects included fatigue, extremity edema, diarrhea, nausea and vomiting, and respiratory depression in a patient with cerebral metastases. Compared to baseline values, there was a significant increase in serum glucose (P less than 0.02) and decreases in serum calcium (P less than 0.01) and phosphorus (P less than 0.01). Significant elevations in serum LDH and SGOT values occurred 24 hours following hyperthermia, suggesting hepatic sensitivity to heat. The methods used to induce whole-body hyperthermia, as described in this paper, are feasible, permit relatively easy access to the patient, and are potentially applicable in diverse hospital settings such as intensive care units, radiation therapy areas, and conventional rooms. The physiologic alterations that were observed and the toxic effects that were documented indicate that careful monitoring of patients is necessary.

Platelet counts were studied retrospectively in a series of 64 patients suspected of primary malignant pleural mesothelioma. Only platelet counts taken before chemotherapy and radiotherapy and surgery other than thoracocentesis were considered. Thirty-two patients had malignant pleural mesothelioma and 32 patients had other malignant disease in pleura. In both groups 34% had slightly elevated platelet counts. In a subgroup consisting of 18 patients with primary pulmonary adenocarcinoma 28% had thrombocytosis. The distribution of platelet counts did not differ in the diagnostic subgroups, and thrombocytosis had no differential diagnostic value in patients with malignant disease in any stage in the pleurae. The frequency of thromboembolic episodes was low.

The diagnostic value of hyaluronate concentration in effusions of malignant mesothelioma has been extensively reported but no information is available about serum hyaluronate in patients with this cancer. Using a new enzymoimmunologic assay based on hyaluronate-hyaluronectin interaction, serum levels of hyaluronate were measured in 16 patients with malignant pleural mesothelioma, 50 patients with other pleural effusions, and 94 healthy blood donors. The mean serum hyaluronate level in patients with mesothelioma (mean, 750 micrograms/l; range, 29 to 5833 micrograms/l) was significantly higher than in patients with other pleural effusions (mean, 56 micrograms/l; range, 4 to 137 micrograms/l) and than in blood donors (mean, 24 micrograms/l; range, 0 to 94 micrograms/l). Comparison of serum hyaluronate values observed in mesotheliomas with the clinical course of the disease suggests that serum hyaluronate might increase only at an advanced stage of the cancer. Therefore, serum hyaluronate determination has probably no clinical value for early detection of malignant mesothelioma, but might be useful to evaluate the clinical course of this malignancy.