p21WAF1 expression in invasive breast cancer and its association with p53, AP-2, cell proliferation, and prognosis.

AIMS: To evaluate the expression and prognostic relevance of p21(WAF1) in breast cancer and to investigate its association with p53, activator protein 2 (AP-2), and cell proliferation (as assessed by Ki-67 expression). METHODS: p21(WAF1) expression was analysed immunohistochemically in a large prospective, consecutive series of 420 patients with breast cancer diagnosed and treated between 1990 and 1995 at Kuopio University Hospital, Kuopio, Finland. Inter-relations between p21(WAF1) expression and p53, AP-2, and Ki-67 were evaluated. The expression of p21(WAF1) was also compared with clinicopathological parameters and the patients' survival. RESULTS: In general, nuclear p21(WAF1) expression was low in carcinomas (median, 2.5%; range, 0-70%). Expression was lowest in lobular carcinomas (chi(2) = 7.4; p = 0.025). p21(WAF1) positive tumours were more often p53 positive (chi(2) = 4.2; p = 0.041) but expression of p21(WAF1) did not correlate with AP-2 expression or Ki-67 in the whole patient group. In addition, the combined expression of p21 and p53 was not associated with AP-2 expression. High nuclear p21(WAF1) positivity (n = 160; 38%) was associated with poor differentiation (chi(2) = 8.1; p = 0.017). In the univariate analyses, p21(WAF1) expression had no prognostic value for predicting breast cancer related survival (BCRS) or recurrence free survival (RFS) in the whole patient group or in the subgroups investigated. However, in postmenopausal patients with lymph node metastases, and oestrogen receptor (ER) and/or progesterone receptor (PR) positive tumours, high p21(WAF1) expression predicted response to adjuvant hormonal treatment with antioestrogens. In the univariate analysis, the significant factors for predicting BCRS were Ki-67 expression, stage, lymph node status, histological grade, ER and PR status, and those for RFS were Ki-67 expression, stage, and lymph node status. In the multivariate analysis, the independent predictors of shorter BCRS were high cell proliferation activity measured by Ki-67 expression (p < 0.001), advanced stage (p < 0.001), and poor differentiation (p = 0.048). Shorter RFS was independently predicted by high cell proliferative activity (p < 0.001) and advanced stage (p < 0.001). CONCLUSIONS: The regulation of p21(WAF1) seems to occur independently of p53 or AP-2 and analysing p21(WAF1) expression provided no prognostic information for patients with breast cancer.

Flow cytometric analysis of tumor DNA profile related to response to treatment and survival in small-cell lung cancer.

Flow cytometric (FCM) analysis of tumor DNA ploidy and S-phase fraction (SPF) has been widely used to predict prognosis and treatment response in many malignant tumors, but rarely in small-cell lung cancer (SCLC). In the present study, tumor DNA ploidy and SPF were measured from paraffin-embedded tumor biopsy samples of 36 small-cell lung cancer patients treated with combination chemotherapy and radiotherapy. Aneuploidy was detected in 69% of the tumors. There was a statistically non-significant trend towards more aneuploidy among extensive disease (ED) patients as compared to patients with limited disease (LD): 80% versus 65%, respectively (p = 0.69). The mean SPF was 21.3% (+/-7.6) in patients with LD and 29.0% (+/-5.3) in patients with ED, the difference (7.6%) being statistically significant (p = 0.008, 95% CI for the difference 2.2-13.1). No significant differences was detected in the survival of aneuploid and diploid patients or patients with low (< or = 24.9%) and high (> 24.9%) SPF. Similarly, no significant difference was observed between aneuploid and diploid cases in relation to response to treatment or response duration. It is concluded that the difference detected in the SPF with LD and ED of SCLC may indicate the biological aggressiveness of extensive SCLC.

An overview of randomised studies comparing 5-HT3 receptor antagonists to conventional anti-emetics in the prophylaxis of acute chemotherapy-induced vomiting.

Ten years after it was demonstrated in the ferret that cisplatin-induced emesis could be blocked by the selective 5-HT3 receptor antagonist MDL 72222, 5-HT3 receptor antagonists have become routine anti-emetic agents for chemotherapy-induced emesis. However, although in association with highly emetogenic, mainly cisplatin-containing regimens, the use of these agents is well justified, the net benefit of 5-HT3 receptor antagonists in association with moderately emetogenic regimens has not been that well clarified. Here, we present an overview of 30 randomised studies comparing 5-HT3 antagonists with the conventional anti-emetics in the prophylaxis of acute vomiting induced by cytotoxic chemotherapy. A meta-analysis showed that 5-HT3 antagonists reduce the risk of acute vomiting in comparison to conventional anti-emetics both with cisplatin treatments (15 trials; odds ratio 0.60; 95% confidence interval 0.51-0.70) and with moderately emetogenic treatments (11 trials; odds ratio 0.47; 95% confidence interval 0.39-0.58). The risk of acute vomiting seems to be further reduced when 5-HT3 antagonists are combined with dexamethasone.

Effects of granisetron with doxorubicin or epirubicin on ECG intervals.

Commercially available serotonin-type 3 (5-HT3) receptor antagonists (ondansetron, granisetron, and tropisetron) have shown no clinically significant adverse effects on the cardiovascular system. In the dose-ranging evaluation of dolasetron, computer-generated ECGs revealed clinically asymptomatic prolongations of ECG intervals. We performed a clinical trial in which the possible changes in ECG intervals following a single 3-mg i.v. injection of granisetron and an injection of either doxorubicin or epirubicin were registered using computerized ECG analysis in cancer patients. A total of 30 patients who were designated to receive 3 mg granisetron i.v. for the prophylaxis of emesis induced by doxorubicin or epirubicin were entered into the study. Computer-generated ECG tracings were obtained before treatment, following the injection of 3mg granisetron, and immediately after doxorubicin or epirubicin injection. The mean PR interval duration increased from 160 to 166 ms after granisetron infusion (P=0.02). Doxorubicin and epirubicin did not potentiate this change. There was no statistically significant change in cardiac rhythm, QRS duration, or QTc intervals. The observed minor changes in the PR time following i.v. injection of granisetron do not seem to be of clinical relevance.

Prognostic significance of TGF-alpha expression in breast cancer.

A series of breast cancer biopsies from 204 women were analysed immunohistochemically for the expression of transforming growth factor alpha (TGF-alpha). Expression of TGF-alpha was intense in 119 cases (58%), weak in 63 (31%), and totally absent in 22 (11%) of the cases. No correlation was observed between the expression of TGF-alpha and tumour size, metastasis at diagnosis, histological type and grade, ER and PR status, DNA index, S-phase fraction or the expression of TGF-beta1 or beta2. However, the expression of TGF-alpha was significantly related to axillary lymph node metastasis and to low survival probability during the follow-up. These data support the earlier observations on the in vitro studies, suggesting that TGF-alpha most probably exerts an in vivo growth stimulation of female breast cancer cells.

5-HT3 receptor antagonists in the prophylaxis of acute vomiting induced by moderately emetogenic chemotherapy--a randomised study.

166 patients receiving moderately emetogenic chemotherapy were entered into a randomised prospective study in which the efficacy of single dose ondansetron 8 mg, tropisetron 5 mg and granisetron 3 mg in the prophylaxis of acute vomiting was evaluated. 130 patients were evaluable for analysis. During the 24 h following the start of chemotherapy complete control of vomiting was achieved in 80% [95% confidence interval (CI) 73.1; 86.9] of patients receiving granisetron compared with 75% (95% CI 67.1; 82.1) of those on tropisetron and 69% (95% CI 60.5; 76.5) on ondansetron. The patients experienced significantly fewer failures with granisetron (6.2%, 95% CI 2.1; 10.3) than with either ondansetron (14.6%, 95% CI 8.5; 20.6) or tropisetron (13.8%, 95% CI 7.9; 19.7). When asked, 34 (26%) patients out of 130 expressed no preference, 54 (42%) preferred granisetron, 22 (17%) preferred ondansetron and 20 (15%) preferred tropisetron. All the 5-HT3 receptor antagonists were highly effective in the prophylaxis of acute vomiting induced by moderately emetogenic chemotherapy. The observed differences in the control of emesis, although statistically significant, may not have clinical significance.

Comparison of ondansetron with customary treatment in the prophylaxis of nausea and emesis induced by non-cisplatin containing chemotherapy.

One hundred cancer patients receiving non-cisplatin containing chemotherapy were entered in a prospective study in which the efficacy of ondansetron was compared with standard antiemetic treatments in the prophylaxis of nausea and emesis. During the first 24 h, 77% of patients on ondansetron reported complete control of emesis compared with 56% of those on customary treatments (p = 0.03). However, no statistically significant difference was observed between ondansetron and customary treatments in control of delayed emesis on days 2-5. Nor was any statistically significant difference seen between ondansetron and customary treatments in preventing acute or delayed nausea.

Ondansetron and tropisetron with dexamethasone in the prophylaxis of acute vomiting induced by non-cisplatin-containing chemotherapy.

Forty-seven patients receiving non-cisplatin-containing chemotherapy were entered in a prospective study in which the efficacy of ondansetron plus dexamethasone and tropisetron plus dexamethasone in the prophylaxis of acute vomiting was evaluated. Thirty-nine patients were evaluable for cross-over analysis. During the 24 hours following the start of chemotherapy, 97% of patients on ondansetron plus dexamethasone reported total control of vomiting compared with 82% of those on tropisetron plus dexamethasone (p = 0.026). Thus, both 5-HT3- receptor antagonists combined with dexamethasone were highly effective in controlling acute vomiting induced by non-cisplatin-containing chemotherapy. The observed difference between the treatments may be caused by different dose schedules of ondansetron and tropisetron. A double-blind design with equal number of placebo-controlled administrations is needed to ascertain whether there is a significant pharmacological difference between ondansetron and tropisetron.