Decreased expression of haem oxygenase-1 by alveolar macrophages in idiopathic pulmonary fibrosis.

Haem oxygenase (HO)-1 is an oxidative stress responsive protein that may be involved in the pathogenesis of interstitial lung disease. HO-1 expression in alveolar macrophages from bronchoalveolar lavage was investigated in 24 patients with idiopathic pulmonary fibrosis (IPF), 16 with sarcoidosis, 14 with hypersensitivity pneumonitis (HP) and 13 controls. Using immunocytochemistry, HO-1 expression in macrophages was scored semiquantitatively from 0-3 according to increasing intensity. The mean score of 100 macrophages was calculated. Macrophages were cultured and levels of interleukin (IL)-12 and IL-18 in the culture supernatants were measured by ELISA. The mean score of HO-1 was significantly lower in IPF (67) than in sarcoidosis (105), HP (106) or controls (106). There was no significant difference between sarcoidosis, HP and controls. The score of HO-1 correlated positively with the lymphocyte percentage in sarcoidosis and HP. Positive correlations were found between the score of HO-1 and the release of IL-12 and IL-18 by macrophages in IPF. The expression of haem oxygenase-1, a critical defender against oxidative stress, is decreased in macrophages of idiopathic pulmonary fibrosis patients compared with those with granulomatous lung disorders. This supports the hypothesis of an oxidant-antioxidant imbalance in the pathogenesis of idiopathic pulmonary fibrosis.

The differential effect of pentoxifylline on cytokine production by alveolar macrophages and its clinical implications.

The aim of this study was to investigate the effects of pentoxifylline (PTX) on the production of TNF-alpha, IL-1 beta, IL-6 and GM-CSF by lipopolysaccharide (LPS)-stimulated alveolar macrophages (AM). AM and peripheral blood monocytes (PBM) from 10 patients were cultured for 24 h in the presence of LPS (10 micrograms ml-1) and PTX at concentrations of 2.0 mM, 1.0 mM, 0.5 mM, 0.1 mM and 0.01 mM. TNF-alpha and GM-CSF were measured from the culture supernatants of both the AM and PBM from all 10 patients and IL-1 beta and IL-6 from the culture supernatants of the AM from five patients. The TNF-alpha production by AM was significantly suppressed in the presence of PTX at concentrations of 2.0 and 1.0 mM, while production of IL-1 beta, IL-6 and GM-CSF remained unaffected. In PBM cultures, PTX significantly suppressed the production of TNF-alpha and GM-CSF, at all tested concentrations. The present study provides evidence that PTX selectively suppresses the production of TNF-alpha by LPS-stimulated AM and may have a role in the treatment of lung diseases where TNF-alpha is involved. The mode of administration of PTX should take into account the suppressive effect of this drug on GM-CSF production by PBM.

Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages.

Tumor necrosis factor-alpha (TNF-alpha) is an important proinflammatory cytokine. Recently, pentoxifylline (POF) has been shown to suppress the synthesis of TNF-alpha from lipopolysaccharide (LPS)-stimulated human monocytes in cell cultures and in vivo. The aim of this study was to investigate whether POF-induced suppression of TNF-alpha secretion affects peripheral blood monocytes (PBM) and alveolar macrophages (AM) equally, and whether POF is able to suppress the spontaneous TNF-alpha production from AM in pulmonary sarcoidosis in vitro. In seven patients without interstitial lung disease we studied the effect of POF on LPS-stimulated PBM and AM cultured for 24 h. In six patients with sarcoidosis we investigated the effect of POF on the enhanced spontaneous TNF-alpha production by AM in vitro. POF induced a dose-dependent suppression of the LPS-stimulated TNF-alpha production which was not different for PBM and AM, respectively. In sarcoidosis, POF inhibited the spontaneous TNF-alpha production of AM at 0.1 mM by 91% and at 1 mM by 98%. In conclusion, POF inhibits LPS-induced TNF-alpha production from PBM and AM to a similar extent and can also inhibit the exaggerated spontaneous TNF-alpha production from AM in sarcoidosis in vitro. This may be the basis for further clinical trials to evaluate POF as an immunotherapeutic agent in sarcoidosis.

Weekly alternating non-cross-resistant chemotherapy for small cell lung cancer with a good prognosis: a study of the Hellenic Cooperative Oncology Group.

This trial was conducted by the Hellenic Cooperative Oncology Group to improve the responses and survival in small cell lung cancer with a good prognosis, using a weekly intensive chemotherapy with alternated non-cross-resistant myelosuppressive agents. Patients were classified into two groups; group A consisted of those who received the initial designed regimen (29 patients), and group B consisted of those who received the more intensified regimen that increased by 25% the doses of carboplatin, epirubicin, and ifosfamide, and by 33% the doses of etoposide given on days 1, 2, and 3 with prophylactic granulocyte colony-stimulating factor support. Chemotherapy in group A consisted of carboplatin 150 mg/m2 in 250 ml of 5% dextrose in water as an 1-hour infusion on day 1, etoposide 75 mg/m2 in 250 ml normal saline as an 1-hour infusion on days 1 and 2 alternating with epirubicin 30 mg/m2 intravenous push on day 8, and ifosfamide 2 g/m2 in 500 ml 5% dextrose in water as a 2-hour infusion with mesna protection on day 8. Responding patients with limited disease were also treated with thoracic irradiation. Those who achieved complete response received prophylactic cranial radiotherapy. In group A, the overall response rate was 79.3%, with a 27.6% complete response rate, a median time to progression of 5.71 months, and a median survival of 8.3 months. For patients with limited disease, the response rate was 75%, with a 40% complete response rate, a median time to progression of 5.87 months, and a median survival of 10.98 months. The respective numbers for extensive disease were 89% (only partial responses), 4.82 months, and 5.67 months. The toxicity was mild and manageable. There were no dose reductions or treatment delays. In view of the excellent tolerability and the rather low efficacy of the initial regimen, we decided to administer the more intensified one with granulocyte colony-stimulating factor support. In Group B, the overall response rate was 91.8%, with a 45.9% complete response rate, a median time to progression of 7.05 months, and a median survival of 10.16 months. For limited disease, the response rate was 93%, with a 52% complete response rate, a median time to progression of 7.05 months, and a median survival of 10.49 months. The respective numbers for extensive disease were 88% (25% complete response), 6.82 months, and 9.02 months. The toxicity of this more intensified regimen was more severe but acceptable. Myelosuppression was the main toxicity. However, grade 3-4 febrile neutropenia requiring hospitalization occurred only in 6% of patients. The relative dose intensity was 91%, probably the result of the prophylactic use of granulocyte colony-stimulating factor. The differences in response rate, time to progression, and survival were not statistically significant between the two groups. There were statistically significant differences in the response rate (p = 0.019) and survival rate (p = 0.001) between limited disease and extensive disease only in group A. In conclusion, this weekly, alternated regimen, specifically the intensified regimen, appears to be very active and well tolerated in patient who have small cell lung cancer with a good prognosis. However, despite the high efficacy, this study failed to show any survival advantage as compared with that obtained with the standard treatment for small cell lung cancer.

Respiratory muscle function in patients with asbestos-related pleural disease.

The effect of asbestos-related pleural disease (ARPD) on the generation of maximum respiratory pressure was investigated in 11 male patients with ARPD mean age 57 years, range 45-74, and mean duration of asbestos exposure of 9.9 years, range 5-16. There were three smokers, seven ex-smokers and one non-smoker. Breathlessness ranged from grade 1-3 on the MRC score. The extent of pleural disease was calculated using a score based on the ILO score for pleural disease. Full respiratory function tests, global respiratory muscle strength and diaphragmatic strength were assessed. Respiratory muscle strength, including diaphragm strength, was normal. Recoil pressure was high or at the upper limit of normal in four patients and correlated with chest radiograph score for pleural disease (r = 0.65, P < 0.02). There was no difference in either global respiratory muscle or diaphragmatic strength between patients with and without involvement of one or both costophrenic angles or between patients with mild or severe breathlessness. We conclude that respiratory muscle strength is not importantly reduced in ARPD, and it is unlikely that weakness contributes to breathlessness in these patients. By contrast reduced chest wall compliance is likely to be an important factor in breathlessness in some cases.

A comparative study of cisplatin and vinblastine versus ifosfamide, cisplatin and vinblastine in non-operable non-small-cell lung cancer. A study of the Hellenic Co-operative Oncology Group for Lung Cancer Trials.

PURPOSE: To evaluate the efficacy and toxicity of ifosfamide in combination with cisplatin and vinblastine in non-operable non-small-cell lung cancer (NSCLC). METHODS: A total of 136 patients with stage III or IV NSCLC were randomized to either PV (cisplatin, 120 mg/m2, and vinblastine, 6 mg/m2) or VIP (PV with the addition of ifosfamide, 3 g/m2) every 3 weeks. RESULTS: Patients receiving VIP had a higher response rate (31% vs. 10%), but the performance status (PS) was significantly worse in those receiving PV. No difference in survival can be demonstrated between the two treatment groups. The median survival was 8.4 months. In both groups, patients with stage III disease, good PS and no visceral involvement had better survivals. Nausea/vomiting and alopecia were more pronounced in the VIP group, although both chemotherapies were well tolerated. CONCLUSIONS: The addition of ifosfamide improved the response rate, but a survival advantage cannot be proven. The prognostic value of stage, PS and metastatic site is confirmed in this trial; further studies are required to select subgroups of patients who may have a survival benefit with combination chemotherapy. The response rate elicited by VIP makes it a candidate for neoadjuvant treatment.

Soluble interleukin-2 receptors (sIL-2R) and neuron specific enolase (NSE) in small cell lung carcinoma.

sIL-2R and NSE were measured in 24 patients with small cell carcinoma (NSCC) of the lung, in 25 patients with non small cell carcinoma (NSCC) and in 20 controls matched for age, sex and smoking habits. Significantly elevated values of sIL-2R and NSE were found in the SCC group (mean +/- SEM: 2103 +/- 314.4 U/ml and 44.5 +/- 7.3 ng/ml respectively), compared to those in the NSCC group (1079 +/- 104.5 U/ml and 3.64 +/- 0.8 ng/ml, p < 10(-7) respectively) and to controls (561 +/- 44.6 U/ml and 1.7 +/- 0.3 ng/ml p < 10(-5). In the SCC group, 83.3% of sIL-2R and 87.5% of NSE values were above cut-off (900 U/ml and 10 ng/ml respectively), while in the NSCC group, 48% of sIL-2R and only 8% of NSE values were above cut-off. In the controls, all values of both parameters were below cut-off. The results suggest that sIL-2R and NSE in concurrent measurements may help in decision making as regards treatment and prognosis.

Soluble interleukin-2 receptors and other markers in primary lung cancer.

Serum levels of soluble interleukin-2 receptors (sIL-2R), carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), beta-chorionic gonadotropin (beta-HCG), pregnancy-specific glycoprotein (SP1), and beta 2-microglobulin (beta 2M) were taken in 92 patients with primary lung cancer and 43 controls. The mean value of sIL-2R in the cancer group was twice as high as that of the controls (P less than 0.001) and the highest values were observed in those with small cell carcinoma (SCC) (P less than 0.0001). Of the cancer patients, 51.1% had CEA values higher than the cutoff level of 5 ng/ml. Extended-disease patients had a higher percentage of increased CEA values than those with limited disease. Adenocarcinoma (ADCC) and SCC groups had the highest percentages of increased CEA levels. There was no significant difference between the groups for beta-HCG, AFP, SP1, and beta 2M, and intermarker correlation was not seen. The results suggest that sIL-2R and CEA may be useful in monitoring the extent of disease and possibly indicate the histologic subtype, thus having a bearing on treatment and prognosis.

Assessment of asbestos-induced pleural disease by computed tomography--correlation with chest radiograph and lung function.

We compared computed tomography (CT) scanning with chest radiography in the assessment of asbestos-induced pleural disease (AIPD) in 20 patients (17 men and 3 women, mean age 55 years, range 43-74 years). Involved pleura was scored on plain chest radiographs according to the International Labour Office (ILO) method of evaluating AIPD. A CT score was calculated from the measurement, using a digital length probe, of the circumference of the chest wall involved by pleural disease in each slice. The maximum width of pleural disease was taken into account in a way analogous to the ILO method for the chest radiograph. The CT score correlated with the chest radiograph score (r = +0.82, P less than 0.0006). CT demonstrated discrete plaques in 95% of patients but these were identified only in 59% patients on the radiograph. Diffuse pleural thickening was evident on the CT scan in all patients and in 70% on the radiograph. There was more inter-reader agreement about the type of pleural disease on the CT scans than on the chest radiographs. CT and chest radiograph scores inversely correlated with all lung function measurements except KCO. We conclude that increasingly extensive pleural disease is associated with increasingly severe impairment of lung function. CT scanning demonstrates the type of AIPD better than plain chest radiography.

Pleural fluid and serum soluble interleukin-2 receptors in pleural effusions.

Pleural fluid and serum soluble Interleukin-2 receptors (sIL-2R) were measured by an enzyme-immunoassay in 13 patients with tuberculous pleurisy, in 28 patients with carcinomatous pleurisy and in 17 transudates from patients with congestive heart failure. Significantly higher values of sIL-2R were observed in exudative than in transudative (mean +/- SEM = 713 +/- 111 U/ml) pleural fluid samples, the highest being found in tuberculous (3777 +/- 501 U/ml) and the intermediate in carcinomatous exudates (1981 +/- 160 U/ml) (p less than 0.0001; on way ANOVA). Serum sIL-2R were significantly higher in carcinomatous and transudative groups than in age- and sex- matched controls (p less than 0.002; one way ANOVA), while there was no significant difference between the tuberculous group and controls. The pleural/serum sIL-2R ratio was significantly higher in tuberculous (5.32 +/- 0.60), than in carcinomatous pleurisy (2.67 +/- 0.20) and higher still than in transudates (0.76 +/- 0.10) (p less than 0.001; one way ANOVA). In conclusion, the pleura/serum sIL-2R ratio may be a helpful parameter in differentiating tuberculous from carcinomatous pleurisy and an additional confirmatory one for distinguishing transudates from exudates.