Expression of DNA topoisomerase IIalpha and topoisomerase IIbeta genes predicts survival and response to chemotherapy in patients with small cell lung cancer.

Drug resistance is a major problem in patients with small cell lung cancer; in fact, most die of resistant disease, despite an initial response. Several markers of drug resistance have been described in preclinical models, but the mechanism of drug resistance in lung cancer patients remains unknown. The objective of this study was to evaluate the role of the expression of a number of markers of drug resistance, proliferation, and apoptosis in relation to response to chemotherapy and survival in patients with small cell lung cancer. Tumor samples were derived from 93 previously untreated patients who were randomized in a Phase III study to receive cyclophosphamide, epirubicine, and etoposide or cyclophosphamide, epirubicine and vincristine alternating with carboplatin and etoposide. Paraffin-embedded samples, derived from the primary tumor site prior to chemotherapy, were analyzed by immunohistochemistry for expression of markers implicated in drug resistance [topoisomerase (topo) IIalpha, topo IIbeta, and multidrug resistance-associated protein], apoptosis (p53, p21, and bcl-2), or proliferation (Ki67). Response prediction was analyzed by chi2 test and logistic regression analysis; overall and disease-free survival curves were compared by log-rank test and Cox regression analysis. Shorter survival was observed in patients with extensive disease (P = 0.037) and poorer performance status (P = 0.028) and in patients whose tumors expressed high topo IIalpha levels (P = 0.01) and high Ki67 (P = 0.024). By multivariate analysis, the following factors were found to be predictive for worse survival: high expression levels of topo IIalpha, Ki67, and bcl-2; male sex; and extensive disease. High topo IIbeta expression was found to be predictive for lower overall and complete response rate. No relationship between apoptotic pathway markers or MRP and response to chemotherapy was observed. In conclusion, high expression of topo IIalpha was predictive of worse survival, and high expression of topo IIbeta was predictive of lower response rates. Furthermore, lower survival probability was observed in patients with bcl-2-positive tumors. Immunohistochemical assessment of these markers in diagnostic biopsies may give important prognostic information and may help selecting patients in the worse prognostic categories for new therapeutic strategies.

Identical efficacy of terbutaline multidose dry powder inhaler prior to and after 4 weeks of use by asthmatic patients.

We investigated whether the terbutaline multidose dry powder inhaler (Turbuhaler) has the same efficacy after routine daily use as it has when new. Thirty-three adult asthmatic patients were tested on two occasions. The bronchodilatory effect of inhalations of 0.5, 0.5 and 1.0 mg terbutaline at 40-min intervals from the same device was determined prior to and after using the device at least three times a day for 4 weeks. When tested for the second time, 116-186 doses had been inhaled. Although baseline forced expiratory volume in 1 s (FEV1) was slightly higher after the 4-week treatment period, the bronchodilatory effect of the inhaled terbutaline doses was identical. We conclude that the multidose dry powder inhaler is as effective in delivering terbutaline after a period of routine daily use as it is when new.

A study on the clinical equivalence and patient preference of fluticasone propionate 250 microg twice daily via the Diskus/Accuhaler inhaler or the Diskhaler inhaler in adult asthmatic patients.

The Diskus/Accuhaler inhaler (D/A) is a new multidose powder inhaler, designed to deliver all asthma drugs. This study was carried out to establish clinical equivalence between FP 250 microg twice daily (b.i.d.) via the D/A and FP 250 microg b.i.d. via the current powder inhaler, the Diskhaler (DH). Also, device handling and patient preference for both devices were determined. This was a multicenter, randomized, double-blind, double-dummy, parallel-group study. Adult asthmatics (364, aged 18-79) requiring inhaled corticosteroids in a daily dosage of 400 microg up to and including 1000 microg and demonstrating a mean morning peak expiratory flow rate (PEFR) calculated from the last 7 days of the run-in of less than 85% of the response after salbutamol, a baseline forced expiratory volume in 1 sec (FEV1) between 50 and 90% of their predicted normal value, and an ability to correctly use both devices, were randomized to a 12-week treatment period. No statistically significant differences between the two devices were seen for mean morning PEFR (p = 0.76), mean evening PEFR (p = 0.88), median daytime and nighttime symptom score (p = 0.57 and p = 0.47), median percentage of rescue-free days and nights (p = 0.43 and p = 0.24), and clinic visit lung function. No differences in the safety profile of FP were seen. Patients found the D/A easier to use and easier with respect to assessing the number of doses remaining (both p < 0.001). Sixty-five percent of the patients expressed an overall preference for the D/A over the DH (p < 0.001). The results show that FP 250 microg b.i.d. via the D/A is clinically equivalent to delivery via the DH. Both treatments proved to be equally safe and were well tolerated. The D/A was easier to use and patients preferred the D/A over the DH.