Docetaxel versus docetaxel/cisplatin in patients with advanced non-small-cell lung cancer: preliminary analysis of a multicenter, randomized phase III study.

The purpose of this study was to compare the efficacy and safety profile of docetaxel versus the combination of docetaxel/cisplatin as frontline treatment of patients with advanced or metastatic non-small-cell lung cancer (NSCLC) in a multicenter, randomized, prospective phase III trial. Patients with unresectable stage IIIB or metastatic stage IV NSCLC who had previously undergone no chemotherapy were allocated to receive either docetaxel (100 mg/m2 in a 1-hour intravenous infusion; group A) or the combination of docetaxel (100 mg/m2 day 1) and cisplatin (80 mg/m2 day 2) after adequate hydration (group B). Appropriate premedication was given before docetaxel infusion. All patients in group B received granulocyte colony-stimulating factor (150 microg/m2 subcutaneously) support from days 3 to 9 after treatment. Response and toxicity were assessed by World Health Organization criteria. From March 1999 to November 2001, 302 patients were randomly assigned to receive docetaxel (group A, n = 146) or docetaxel/cisplatin (group B, n = 156). The overall response rate was significantly higher in the combination arm (18% vs. 36%; P < 0.001). However, the 2 groups did not differ in median duration of response, time to progression (TTP), median overall survival (OS), or 1-year survival rate. Drug combination was associated with higher toxicity than single-agent therapy. Both regimens had comparable activity in terms of TTP and OS in chemotherapy-naive patients with advanced NSCLC; however, single-agent therapy had a more favorable toxicity profile.

Cisplatin-etoposide alternating with topotecan in patients with extensive stage small cell lung cancer (SCLC). A multicenter phase II study.

PURPOSE: In order to investigate the feasibility of a potentially non-cross resistant drug regimen, we alternated cycles of cisplatin-etoposide with topotecan as front-line treatment in patients with extensive stage small cell lung cancer (SCLC). PATIENTS AND METHODS: Thirty-six previously untreated patients with extensive stage SCLC received cisplatin 75 mg/m(2) IV on day 1 and etoposide 100 mg/m(2) IV on days 1-3 on cycles one, three, five and seven and topotecan 1.5 mg/m(2) IV on days 1-5 on cycles two, four, six and eight. Cycles were repeated every 21 days. Patients' median age was 60 years and performance status (WHO) was 0 for 13, 1 for 20 and 2 for three patients. All patients were evaluable for response and toxicity. RESULTS: Five (14%) patients achieved a complete response and 18 (50%) a partial response for an overall response rate of 64% (95% confidence interval: 48.2-79.6%). After a median follow up of 10 months, the median duration of response was 5.5 months, the time to tumor progression 8 months and the probability of 1-year survival 48.9%. A total of 126 cycles of cisplatin-etoposide and 117 cycles of topotecan were administered with a median number of 4 cycles/patient for each regimen. There were no toxic deaths. Treatment delays due to toxicity occurred in 13 (10%) cycles after cisplatin-etoposide and 16 (14%) cycles after topotecan while doses were reduced in seven (6%) and five (4%) cycles, respectively. Grade 3-4 neutropenia, thrombocytopenia and febrile neutropenia complicated 13, 1 and 3% of cisplatin-etoposide cycles and 28, 6 and 1% of topotecan, respectively. Non-hematologic toxicity was mild. The delivered dose intensity was 96% for cisplatin and etoposide and 98% for topotecan. CONCLUSIONS: The alternating administration of cisplatin-etoposide and topotecan is a feasible, active and well-tolerated regimen in patients with extensive stage SCLC.

Expression of mdm-2 protein in neoplastic, preneoplastic, and normal bronchial mucosa specimens: comparative study with p53 expression.

Loss of function of the p53 tumor supressor gene is involved in nearly all human cancer. Recently a cellular oncogene product, mdm2, has been shown to bind to p53 and eliminate its ability to function as a transcription factor. mdm2 and p53 immunohistochemical protein expression was studied in tumor tissues, preneoplastic lesions, and normal bronchial mucosa. The specimens were obtained during diagnostic bronchoscopy from 53 patients with lung cancer. In the tumor specimens, p53 nuclear staining was detected in 26 (49%) cases, mdm2 in 11 (20.7%), and simultaneous expression of both proteins in 6 (11.3%) cases. Thirty-five sections with preneoplastic lesions were found in 21 patients. p53 nuclear staining was found in 11 of 35 and mdm2 in 6 of 35 sections. In normal cells, mdm2 positive staining was found in 18 and p53 in 12 specimens. Simultaneous p53 and mdm2 expression was found in 4 specimens. Our results indicate that p53 expression is more frequent than mdm2 expression in lung cancer tissues. Alterations in these proteins are early events and may represent alternative pathways in carcinogenesis.

Immunohistochemical detection of p53 protein in neoplastic, preneoplastic and normal bronchial mucosa specimens obtained during diagnostic bronchoscopy.

The expression of p53 protein was evaluated immunochemically in cancer tissue, preneoplastic lesions and normal bronchial mucosa obtained during diagnostic bronchoscopy from 53 patients with lung cancer and 12 patients with benign lung diseases. In lung cancer patients, positive p53 staining was detected in 26/53 (49%) of the tumour specimens. In preneoplastic lesions p53 positive staining was found in 8 of 24 (33.3%) squamous metaplasia, 1 of 4 hyperplasia and 1 of 3 dysplasia lesions. In the same group of patients, 12 cases were found with positive p53 cells in normal bronchial mucosa. In patients with benign diseases, positive p53 staining was found in 1 of 4 cases with squamous metaplasia and in one normal mucosa. Our results provide evidence that somatic genetic alterations may occur in early stages of lung tumorigenesis, raising the possibility that molecular analyses is useful in the early diagnosis of precancerous lesions of the bronchial mucosa, and results indicate that p53 expression can be studied in small tissue specimens obtained during bronchoscopy.

Adenosine deaminase activity and lysozyme levels in bronchoalveolar lavage fluid in patients with pulmonary tuberculosis.

SETTING: The estimations of adenosine deaminase (ADA) activity and lysozyme (LYS) levels in pleural fluid have been proved useful tools in the diagnosis of tuberculous pleural effusions. Little is known about their usefulness when estimated in bronchoalveolar lavage fluid (BALF). OBJECTIVE: To evaluate whether both ADA activity and LYS levels in BALF could be employed in the diagnosis of pulmonary tuberculosis, and especially in active but acid fast bacilli (AFB) smear negative cases. DESIGN: ADA activity and LYS levels were determined in BALF and serum obtained on the same day in 28 patients with tuberculosis, 21 with interstitial lung diseases, 14 with lung cancer and 13 with infectious diseases. RESULTS: Patients with pulmonary tuberculosis had significantly higher ADA activity in BALF than patients with non-tuberculous lung diseases (P < 0.001). High BALF ADA activity in pulmonary tuberculosis patients suggests increased local production. In contrast, in this group of patients BALF LYS levels were not significantly higher than in the other groups of patients, but were in the group with interstitial lung diseases. CONCLUSION: BALF ADA activity seems to be a useful tool in the differentiation of tuberculosis from other lung diseases. Its estimation can be restricted to the detection of cases with AFB negative smears.

Evaluation of CYFRA 21-1 in malignant and benign pleural effusions.

CYFRA 21-1 was evaluated in 115 untreated patients with malignant pleural effusions (96 with primary lung cancer and 19 with non lung cancer) and 99 patients with benign pleural effusions. The levels of pleural fluid CYFRA 21-1 were from 1 to 385 times higher than those in serum, in all the examined patients. The mean level of pleural fluid CYFRA 21-1 was significantly higher in cancer patients than in patients with benign pleural effusion (96.1 ng/ml vs 26.2 ng/ml, p < 0.001). At 92% specificity for benign pleural effusion (> 50 ng/ml) the overall sensitivity of CYFRA 21-1 in malignant pleural effusions was 69.6%. When the histology was considered the highest sensitivity was found in squamous cell lung cancer (90%), followed by adenocarcinoma cell lung cancer (74%), non lung cancer (54%) and small cell lung cancer (25%). These results indicate that CYFRA 21-1 could be a useful pleural fluid marker in discriminating benign from malignant pleural effusion and particularly from those due to squamous and adenocarcinoma cell lung cancer.

HLA antigens and asthma in Greeks.

HLA-A and -B antigens were determined in a group of 76 Greek asthmatic patients: 35 children (1.5-15 years) and 41 adults (18-73 years). The results were compared to those of 400 healthy unrelated controls from the same population. The standard NIH lymphocytotoxicity test was applied. When all 76 patients were compared to the controls, a statistically significant lower frequency of HLA-B5 and -B35 antigens was noted. When adults were analysed alone, an increased frequency of HLA-B8 was found. On the other hand, in the asthmatic children sub-group, the HLA-A10 antigen was significantly higher and the HLA-B5 was significantly lower than in the controls. These data imply that different HLA antigens may be involved in the pathogenesis of several clinical forms of asthma and that, in order to study the role of immunogenetic factor(s) in the pathogenesis of this disease, more adequate grouping criteria are needed.

Tumour necrosis factor, interleukin-1 and adenosine deaminase in tuberculous pleural effusion.

Tumour necrosis factor (TNF) and interleukin-1 (IL-1) are powerful mediators with a key role in inflammation. This study was undertaken to study the presence of TNF and IL-1 in tuberculous effusion where there is marked inflammation and where examination of the pleural fluid may give information about the local inflammatory reaction. Adenosine deaminase activity (ADA, a marker of TB pleurisy) was also tested. Tumour necrosis factor, IL-1 and ADA levels were measured in the pleural fluid and serum of 97 patients; 33 with tuberculous effusion, 33 with malignant effusion, and 31 patients with benign non-tuberculous effusion. Pleural fluid TNF and ADA levels were higher in tuberculous (TB) patients than in patients with benign disorders or cancer (P < 0.01). Serum TNF levels were also higher in TB patients than other benign (P < 0.01) or malignant (P < 0.05) effusions. There was a positive correlation between serum and pleural fluid values (r = 0.998-0.999, P < 0.001) although pleural fluid concentration was higher (P < 0.001), possibly suggesting local production in the pleural cavity. Pleural fluid IL-1 levels were not raised in any patient group but there was a positive correlation between TNF and IL-1. In addition, a positive correlation was found between TNF and ADA levels, probably indicating some common production mechanism. Furthermore, ADA sensitivity in the diagnosis of tuberculous effusion was augmented by the combined use of TNF and ADA. The use of both these markers may prove useful in the differential diagnosis of TBC pleurisy.

Recurrent respiratory papillomatosis with malignant transformation in a young adult.

The term 'papilloma' was first used by Mackenzie 100 years ago, who claimed that this was the most benign tumour of the larynx. Today papillomas are considered to be caused by the Human Papilloma Virus group (H.P.V.). The majority of patients suffering from this disease which is also referred to as 'recurrent respiratory papillomatosis' require multiple surgical operations for tumour removal. Malignant transformation of papillomas, which is a rare condition, is considered to occur mainly to irradiated patients. The following report describes the case of a male patient, with a history of vocal cord papillomas since his first year of age, who developed bronchial and pulmonary spread of the disease. He died at the age of 26 years because of squamous cell carcinoma which was related to the malignant transformation of the pulmonary papillomas.

Expression of IGF-I, TGF-alpha and p53 protein in imprint smears of bronchial biopsy specimens of lung cancer.

The expression of insulin-like growth factor-I (IGF-I), transforming growth factor-alpha (TGF-alpha) and p53 protein was examined in bronchial biopsy imprint smears of patients with primary lung cancer and benign lung disorders, by immunohistochemistry. Of the 44 malignant imprint smears, 26 (59%) were positively stained for IGF-I, 18 (41%) for TGF-alpha and 29 (66%) for p53 protein. In contrast, of the 36 benign imprint smears none was positively stained for IGF-I (p<0.001), whereas 7 were positively stained for TGF-alpha (p>0.05) and 3 for p53 protein (p<0.001). There was no correlation between the expression of the examined markers and the histological type of lung cancer. The most sensitive indicator of malignancy was p53 overexpression (65.9%), the most specific was IGF-I (100%) whereas both revealed 77.5% accuracy. The combination of IGF-I and p53 revealed 75% sensitivity, 91.6% specificity and 82.5% accuracy. When one marker was positive the relative possibility of lung cancer was 67.1%. This possibility increased to 77.7% when two markers were positive and to 100% when three markers were positive. These results suggest that the evaluation of IGF-I and p53 in imprint smears could be of value in diagnosis of lung cancer.

Expression of ras p21 and myc p64 oncoproteins in imprint smears of lung-cancer.

The expression of ras p21 and myc p64 was examined in imprint smears of 52 patients with lung cancer and 44 patients with benign disorders, by immunochemistry. Imprint smears were-taken from fresh bronchial biopsies during diagnostic bronchoscopy. Both ras and mye oncoproteins were found to give negative reaction in all benign examined cases; Of the 52 malignant bronchial tissue imprint smears, 28 (54%) and 30 (58%) were positively stained with ms p21 and mye p64 antibodies respectively. Positive staining of ras p21 was demonstrated in 54.5% of squamous cell carcinoma, in 80% of adenocarcinoma and in 0% of small cell carcinoma imprint smears. Positive staining of myc p64 was demonstrated in 45.4% of squamous cell carcinoma, in 50% of adeno-carcinoma and in 100% of small cell carcinoma. The results of this study indicate that both ras and myc oncoproteins detected in bronchial biopsies, may play a crucial role in lung cancer.

Diagnostic usefulness of 5 tumor-markers in patients with primary lung-cancer.

Thymidine kinase (TK), carbohydrate antigen 19-9 (CA 19-9), carbohydrate antigen 125 (CA 125), squamous cell carcinoma antigen (SCC) and tissue polypeptide antigen (TPA), were evaluated in 104 untreated patients with primary lung cancer acid 55 patients with benign lung disease. The mean concentrations of TPA and CA 125 were significantly higher in lung cancer patients than in benign controls (p<0.001). The concentrations of all the tumor markers were well correlated with the stage of lung cancer. In respect to sensitivity, specificity and accuracy, TPA was superior to the other tumor markers tested (70.2%, 88.8% and 75.8% respectively). When TPA was combined with the other markers, sensitivity increased from 70.2% to 98%, but as the number of combined markers became larger, specificity decreased (from 88.8% to 40%). Nevertheless, the combination of TPA and CA 19-9 showed significantly higher sensitivity in patients with resectable non small eel lung cancer (NSCLC) and limited small cell lung cancer (SCLC) than TPA alone (87% vs 49% and 88.8% vs 44.4% respectively) without significant differences in specificity. The relative possibility of lung cancer was 15% when one tumor marker was positive. This possibility increased to 82%-100% when more than three markers were positive.

HLA-A and -B antigens in chronic bronchitis.

The A- and B- types of Human Leucocyte Antigens (HLA) were examined in a group of Greek patients with a diagnosis of chronic bronchitis. The results were compared to those of 400 healthy unrelated controls (smokers and non-smokers) from the same population. A statistically significant increase of HLA-A1 and HLA-B17 was noted; a similar increase was also noted when only healthy smokers were utilized as a control group. These results support the hypothesis that genetic factors are also involved in the pathogenesis of this common disease.

The effects of salmeterol and salbutamol on ciliary beat frequency of cultured human bronchial epithelial cells, in vitro.

Studies investigating mechanisms of mucociliary clearance have suggested that beta 2-adrenergic agents may significantly influence ciliary activity of epithelial cells and therefore play a vital role in the maintenance of functional integrity of the airways. We have cultured human bronchial epithelial cells, from surgical explants and investigated the effects of salbutamol and salmeterol, in a time- and dose-dependent manner, on the ciliary beat frequency (CBF) of these cells. Prior to and at several times after exposure to either salbutamol (10(-8) to 10(-3) M) or salmeterol (10(-8) to 10(-4) M), the epithelial cells were monitored for CBF and on the basis of data obtained from these studies, the effect of 10(-6) M propranolol was investigated in the presence of optimal concentrations of salbutamol and salmeterol. Salbutamol was optimally active at a concentration of 10(-4) M and caused a transient but significant increase in the CBF from baseline level of 8.6 +/- 0.4 to 9.6 +/- 0.5 Hz (P < 0.05), after 2 h incubation. In contrast, salmeterol was maximally active at a concentration of 10(-6) M and caused a significantly rapid and prolonged increase in CBF from a baseline value of 9.2 +/- 0.4 to 10.9 +/- 0.6 Hz (P < 0.02) and 10.6 +/- 0.8 Hz (P < 0.05) after 15 min and 24 h incubation, respectively. Propranolol (10(-6) M) abrogated the salbutamol- but not the salmeterol-induced increases in CBF.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical evaluation of four tumor markers in malignant and benign pleural effusions.

Total sialic acid (TSA), lipid-bound sialic acid (LSA), ferritin and carcinoembryonic antigen (CEA) were evaluated in 55 patients with malignant pleural effusions and in 32 patients with benign (exudative) pleural effusions. No significant differences were found in the pleural fluid TSA, LSA and ferritin levels between malignant and benign conditions. CEA levels in malignant effusions were significantly higher than those in benign effusions (43.13 +/- 72.8 ng/ml versus 2.6 +/- 5.56 ng/ml, p less than 0.01). At a cut-off level of 5 ng/ml, 60% of the patients with cancer showed elevated pleural fluid CEA levels. The specificity and diagnostic accuracy of CEA in distinguishing malignant from benign pleural exudates were both very high (91% and 71% respectively). Therefore, of the four markers investigated, only CEA could be a valuable tool in the detection of pleural malignancy.

Five tumor markers in lung cancer: significance of total and "lipid"-bound sialic acid.

Total sialic acid (TSA) and "lipid-bound" sialic acid (LSA) were evaluated in comparison to carcinoembryonic antigen (CEA) and ferritin and neuron specific enolase (NSE) in 152 untreated patients with primary lung cancer, 107 benign pulmonary disease patients and 207 notmal controls. The mean concentrations of TSA, LSA and CEA in lung cancer patients, were significantly higher than in benign and normal controls (p less than 0.001), while the mean ferritin and NSE levels were significantly higher than in normal controls only (p less than 0.001). At the designated cut-off serum levels, sensitivities of the five markers for lung cancer were in decreasing order: TSA 86.5% (greater than 80 mg/dL), LSA 77% (greater than 20 mg/dL), CEA 46.4% (greater than 5 ng/mL), ferritin 36% (greater than 300 ng/mL) and NSE 34.5% (greater than 12.5 ng/mL). Using the benign pulmonary values as negative controls the specificity of each marker was as follows: CEA 88%, ferritin 72%, NSE 58%, TSA 44% and LSA 44%. In small cell lung cancer (SCLC) patients, NSE mean concentrations and sensitivity were significantly higher than in non-small lung cancer (NSCLC) patients (9.63 +/- 4.4 versus 23.54 +/- 16.9, p less than 0.001 and 74% versus 21.4% respectively). While in NSCLC patients only CEA levels correlated well with the stage of the disease, in SCLC patients concentrations of TSA, LSA and ferritin were significantly higher in extensive than in limited disease stages. These preliminary data suggest that, although TSA and LSA are highly sensitive markers in lung cancer, their specificity is low.

HLA antigens and bronchogenic carcinoma in the Greek population.

The distribution of HLA antigens was studied in 85 Greek patients with bronchogenic carcinoma. Fifty-seven specific HLA antisera were used to determine 27 HLA-A and B antigens, with the two-stage standard NIH microlymphocytotoxicity assay. The results were compared with those in a control group, consisting of 400 healthy individuals. In the whole group of patients there was a significantly higher frequency of HLA-AW19 and HLA-A29 (p less than 0.003 and p less than 0.006 respectively) and a lower frequency of HLA-A2 and HLA-A3 (p less than 0.014 and p less than 0.006 respectively) than in the control population. In patients with squamous cell carcinoma there was a significantly higher frequency of HLA-AW19 and lower frequency of HLA-A2 (p less than 0.02 and p less than 0.05 respectively). In small cell carcinoma patients there was a significantly lower frequency of HLA-A3 (p less than 0.04) than among the controls. In patients with adenocarcinoma no significant change of HLA antigen frequencies was observed when compared to the controls.

A study of beta-thromboglobulin and platelet factor-4 plasma levels in steady state sickle cell patients.

To evaluate the platelet function in sickle cell syndromes we measured the beta-thromboglobulin (beta-TG) and platelet factor 4 (PF-4) plasma values of 45 patients suffering from homozygous sickle cell anaemia (10) and sickle cell beta-thalassaemia (35) in steady state. The results were compared to those of 32 normal controls. Both the beta-TG and PF-4 levels were found to be significantly higher in patients than in controls but the beta-TG:PF-4 ratio was significantly lower in the patients group. This finding and the absence of any statistical correlation between platelet number and beta-TG or PF-4 indicate that platelets seem to be somehow activated in sickle cell syndromes, both in homozygotes and sickle cell/beta-thalassaemia heterozygotes. This platelet activation seems to exist even in steady state sickle cell disease patients, regardless of the functional status of the spleen.