First-line therapy with moderate dose capecitabine in metastatic breast cancer is safe and active: results of the MONICA trial.

BACKGROUND: To determine activity and safety of capecitabine at a moderate dose of 2000 mg/m(2) as first-line therapy for metastatic breast cancer. METHODS: In this prospective phase II trial, patients with HER2-negative metastatic breast cancer received first-line capecitabine 2000 mg/m(2) on days 1-14 every 3 weeks. The primary aim was to exclude a time to progression (TTP) <6 months. Secondary end-points were overall response rate, overall survival (OS), toxicity and quality of life. RESULTS: Median age of the 161 included patients was 65 years. Median TTP and OS were 7.3 months [95% (confidence interval) CI: 6.2-8.4] and 17.1 months (95% CI: 14.0-20.3), respectively. An overall response rate of 26.1%, including 13 complete remissions was observed. Patients developing grade I-III hand-foot syndrome had a significantly longer TTP and OS and patients >65 years also achieved a significantly longer TTP. Haematological grade I-IV toxicities were leucopenia (64.0%), anaemia (50.9%) and thrombocytopenia (28.0%). Relevant non-haematological toxicities were hand-food-syndrome (37.3%), fatigue (34.2%), nausea (29.8%) and diarrhoea (20.5%). Quality of life assessment revealed an improved emotional function, but worsening of nausea and vomiting from cycle 1-10. CONCLUSIONS: Capecitabine at a dose of 2000 mg/m(2) is active and safe as first-line treatment of patients with metastatic breast cancer.

Vasectomy, serum assays, and coronary heart disease symptoms and risk factors.

We compared three serum assays (two antisperm antibody assays and one assay for circulating immune complexes) and a number of CHD-related variables in 69 vasectomized (V) and 126 non-vasectomized (NV) participants in the Portland Center for the Multiple Risk Factor Intervention Trial. Significant differences between the V and NV men were found in sperm agglutination (SA) and sperm immobilization (SI) titers, as well as in several CHD risk factors, symptoms, and treatments; men in the V group had higher titers for SA and SI, smoked more, and had lower diastolic and systolic blood pressure than men in the NV group. Differences between V and NV in SA and SI activity remained even after we controlled for any effects that CHD risk factors, symptoms, and treatments may have had on the serum assays. Antibody development tended to decrease with age-at-vasectomy and increase with time-post-vasectomy. In the case of SA the antibodies clearly increased with time-post-vasectomy.

PIP: A comparative study of 69 vasectomized and 126 nonvasectomized men enrolled in the Portland (Oregon, US) Center for the Multiple Risk Factor Intervention Trial evaluated vasectomy as a risk factor for cardiovascular disease. In animal studies, atherosclerosis development has been linked to circulating anti-sperm antibodies and immune complexes formed in response to sperm breakdown products released in the body after vasectomy. Vasectomized men smoked more and had lower diastolic and systolic blood pressure than men in the control group. As expected, both sperm immobilization and sperm agglutination assays were significantly higher among vasectomized men than controls; 29.4% of vasectomized men compared with only 2.5% of nonvasectomized men had sperm immobilization values of 0.3 or less, while 54.1% of vasectomized men compared with 12.5% of nonvasectomized men had sperm agglutination values of 20.0 or above. These significant differences persisted even when a variety of coronary heart disease risk factors and treatments were controlled. Multivariate analysis showed that antibody development tended to decrease with age at vasectomy and increase with time since vasectomy. In the case of sperm agglutination, the antibodies clearly increased with time since vasectomy.

Reproductive health counseling for young men: what does it do?

A reproductive health intervention combining a highly explicit half-hour slide-tape program with a personal health consultation was provided to male patients aged 15-18 at a large health maintenance organization. A test of the consultation's impact against a control group provides no support for the argument that highly explicit instruction in contraception encourages early initiation of intercourse. In fact, the consultation may have reduced pressure to become sexually active among young men who had never had sexual intercourse. There is also some evidence that the consultation helped improve the effectiveness of contraceptive practice among the men who were sexually active at follow-up; those exposed to the consultation were more likely than those who were not to report that their last intercourse was protected by the pill and that their main method of contraception in the previous year was the pill. Compared with those in the control group, patients who received the health consultation scored higher on measures of fertility knowledge and knowledge of the prevention of sexually transmitted diseases, including AIDS. Furthermore, the young men who had the consultation were more likely to have practiced testicular self-examination. In many cases, however, the positive effects of the consultation were stronger or were only statistically significant among those who had not been sexually active at the time of the baseline survey.

PIP: This case-control study examined the effects of a reproductive health intervention directed to 15-18 year old adolescent male members of a US health maintenance organization. The intervention combined an explicit slide-tape program with a personal health consultation designed to improve contraceptive practice and knowledge of fertility, prevent sexually transmitted diseases, increase the practice of testicular self-examination, and ameliorate coercive sexual attitudes. Comparison with controls revealed that the intervention did not encourage early initiation of intercourse but may, in fact, have reduced pressure to become sexually active. There was some evidence at follow-up that the intervention improved the effectiveness of contraceptive practice among the men who were sexually active. Cases scored higher than controls on measures of knowledge in the subjects covered by the intervention. The intervention had the greatest impact on young men who were not sexually active at the time of the baseline survey. This implies that additional efforts should be directed to young men who are already sexually active and use contraceptives in an inconsistent manner (or not at all). The breadth of the topics covered in the intervention and the use of audiovisual materials are possible reasons for its success.

Comparison of single administration with an ovule of 600 mg fenticonazole versus a 500 mg clotrimazole vaginal pessary in the treatment of vaginal candidiasis.

Fenticonazole is an imidazole derivative with a broad spectrum of antimycotic activity. The therapeutic activity and tolerability of 600 mg fenticonazole versus 500 mg clotrimazole were evaluated in an investigator-blind trial in 80 patients with mycologically confirmed vaginal candidiasis. Fenticonazole was administered as an ovule and clotrimazole as a vaginal pessary, both in a single administration. Therapeutic efficacy was assessed by microbiological and clinical criteria 7 days after the start of treatment. Patients cured at the end of the trial were rechecked 4-5 weeks after the start of therapy in order to identify and evaluate possible relapse. Both treatments resulted in a statistically significant reduction in vaginal symptoms (erythema, itching, discharge and oedema) and in elimination of Candida albicans in about 90% of patients. The tolerance of both treatments was excellent since no local or systemic signs or symptoms of toxicity were reported. An equally high efficacy and safety for both drugs in the elimination of symptoms and objective evidence of vaginal candidiasis was indicated.

Augmentation of the response of mouse uterine epithelial cells to estradiol by uterine stroma.

The effect of estrogen on the in vitro growth of mouse uterine epithelial cells was assessed. Epithelial cells from the immature mouse uterus were successfully cultivated in a 1:1 mixture of Dulbecco's Modified Eagle's Medium and Ham's F-12 supplemented with insulin (5 micrograms/ml), transferrin (10 micrograms/ml), hydrocortisone (10(-7) M), BSA (2 mg/ml), and fetuin (1 mg/ml). Addition of 17 beta-estradiol in the range of 1-100 nM did not significantly change the total DNA content of the epithelial cells. A binding component of [3H]estradiol by cultured uterine cells was shown to be specific, saturable, and of high affinity. Kd values for specific binding by epithelial and stromal cells were 1.0-1.7 x 10(-10) M. Maximal specific binding was 0.74 and 2.3 fmol/micrograms DNA for epithelial and stromal cells, respectively. Treatment of epithelial and stromal cells for 4 days with 10 nM estradiol led to a 2- to 6-fold increase in progesterone receptor concentration. Treatment of epithelial and stromal cells in mixed culture for 4 days with 10 nM estradiol resulted in a significant increase in total DNA. That epithelial-stromal contact was critical for estradiol stimulation was shown by the fact that if the cell types were separated into two compartments which still allowed free media mixing, total DNA was not enhanced by estradiol. These observations are organized into a model for mitogenic action of estradiol that seems to reconcile observed disparities in the action of the hormone in vivo and in vitro.

Short-term treatment of vaginal candidiasis with fenticonazole ovules: a three-dose schedule comparative trial.

In an unblinded, randomized parallel group trial three different therapeutic dose schedules of fenticonazole (vaginal ovules) were compared in the treatment of vaginal candidiasis. A total of 60 patients, aged 17-71 years, affected by mycologically confirmed symptomatic vaginal candidiasis were included and randomly allocated to three treatment groups: 200 mg daily, for 3 days; 600 mg in a single administration; and 1000 mg in a single administration. Therapeutic efficacy was assessed by microbiological and clinical criteria 7 days after the end of the treatment. All mycologically cured patients were re-checked, microbiologically and clinically, 2 weeks after the end of treatment to identify and evaluate possible relapses. The results obtained indicate that vaginal application of fenticonazole ovules is highly effective in producing both symptomatic relief and mycological sterilization of vaginal swabs in 75-85% of treated patients. No relapses were noted at the time of re-check. The three administration schedules tested appear to be equally effective and well tolerated. In one case only of the group given 200 mg and two cases of those given 1000 mg, a local burning sensation was noted. These results show that short-term treatment of vaginal candidiasis with fenticonazole ovules is effective and well tolerated.

[Toxic shock syndrome toxin-1 producing strains of Staphylococcus aureus in vaginal smears]. / Toxic-shock-Syndrom Toxin-1-produzierende Staphylococcus-aureus-Stämme in Vaginal-abstrichen.

21 Staphylococcus aureus strains were isolated from 391 vaginal swabs. This corresponds to a frequency of 5.3%. In females using tampons this frequency was 7%, in users of napkins 2.4%. 2 out of these 21 S. aureus strains produced toxic shock syndrome toxin-1 (TSST-1). Both strains originated from women using tampons. Therefore, 5 out of 1000 women must be expected to carry TSST-1-producing S. aureus strains within their vagina.

[Induction of fetal lung maturation using ambroxol and betamethasone. Results of an open multicenter study]. / Induktion der fetalen Lungenreifung durch Ambroxol und Betamethason. Ergebnisse einer offenen Multicenter-Studie.

In a randomized open multicenter study the results of antenatal prophylaxis against neonatal RDS by administration of betamethasone were compared with those obtained with the bromhexine VIII metabolite Ambroxol. Ambroxol was administered for a maximum of 5 days - 1000 mg in an infusion solution; betamethasone was injected intramuscularly in 2 daily doses of 8 mg. One of these two substances was given to 123 pregnant women for pulmonary maturation in the fetus, in accordance with a randomization plan. The patients were either being treated for premature labor or pregnancy was terminated on the basis of indication between the 28th and 36th week. Therapy had to be discontinued in 4 cases in each group, because of continued labor and birth, and in one case because of an amniotic infection syndrome. A full analysis of the treatment records of 57 pregnancies in the Ambroxol group was carried out; the corresponding figure for the betamethasone group was 58. In 39 patients the duration of pregnancy was 37 weeks or more, so that no assessment on the basis of neonatal pulmonary maturity was possible. In the remaining pregnancies, RDS morbidity was estimated on the basis of clinical and radiological findings and blood gas analysis. Related to a maximum duration of pregnancy of 34 weeks, RDS morbidity after Ambroxol therapy was 18.2% (2 out of 11), as opposed to 35.7% (5 out of 14) after betamethasone treatment. The results confirm that antenatal administration of Ambroxol can bring about a reduction in neonatal RDS corresponding to that achieved with betamethasone therapy. However, with Ambroxol the occurrence of side-effects is potentially lower; it therefore has advantages over betamethasone while being equally efficacious.

Ovarian carcinoma: increase in clinical validity by simultaneous determination of SRA and CA 125.

Ovarian carcinomas are distinguished by their polyclonality, i.e., heterogeneity and polymorphism of their tissue. There is no marker available complying with the clinical demands in the case of ovarian carcinoma regarding satisfactory sensitivity and specificity. Therefore, we have simultaneously determined two entirely distinct tumor markers, serum ribonuclease activity (SRA) and cancer antigen 125 (CA 125), recommended in the literature with respect to ovarian carcinoma. After evaluation by logistic regression analysis, we found a specificity of 93% together with a sensitivity of 97% for the simultaneous determination of SRA and CA 125 (37 ovarian carcinomas, 11 cases without pathological findings after treatment, 11 benign tumors of the ovary, 61 controls). The patients are not exposed to increased stress by this simultaneous determination method compared to the determination of a single marker. The increased clinical validity justifies the recommendation of routine simultaneous determinations of SRA and CA 125 for diagnosis and monitoring of patients with ovarian carcinoma.

[Effect of subpartal tocolysis on maternal cardiovascular parameters with subsequent cesarean section in general anesthesia]. / Zum Einfluss einer subpartualen Tokolyse auf das mütterliche Herz-Kreislaufverhalten bei nachfolgender Sectio caesarea in Allgemeinanästhesie.

The influence of subpartal beta-sympathicomimetic tocolysis on a subsequent Caesarean section with halothane as inhalational anaesthetic was examined in 42 pregnant women. Alterations in the heart rate, blood pressure and heart action during the operation were measured. 23 patients (group "bolus") received fenoterol monotherapy. In 19 patients (group "iv-tocolysis") fenoterol was combined with the cardioselective beta-1-blocking agent metoprolol. In comparison with these two groups, 25 pregnant women without tocolysis were examined as controls. There were only slight differences in heart rate and blood pressure between the three groups. Arrhythmias were registered in 42 percent of the cases, in most cases during light anaesthesia before delivery. Sinus tachycardias with a heart rate of 130 beats per minute or more were observed most frequently. Arrhythmias of ectopic origin and sinus bradycardias, however, were found seldom. The incidence of arrhythmias in the three groups during Caesarean section did not differ significantly. There was no evidence for an increased occurrence of arrhythmias following beta-sympathicomimetic tocolysis.

Serum ribonuclease activity in patients with ovarian tumors.

The RNase activities have been assayed in 1678 serum samples from a total of 209 patients. 52 with histologically confirmed ovarian carcinoma, 13 with benign tumors of the ovary, and 144 patients without any clinically detectable malignancy. The serum RNase activity is unequivocally increased in the group with ovarian cancer (p less than 0.01). Considering the distribution of the RNase activities with a margin at 300 ngeqvs/ml serum we find 8.3% false negative and 4.9% false positive results. The serum RNase activity does not display any evident relationship with tumor spread, histology, clinical grading (TNM), nor metastasis at the time of the blood taking. It is concluded that the serum RNase activity is a meaningful criterion together with the careful clinical examination for the diagnosis and the surveillance of ovarian cancer.

Protein kinase stimulation of steroidogenesis in rat luteal cell mitochondria.

The regulatory role of cAMP-dependent protein kinase in steroidogenesis was examined in luteal cell mitochondria prepared from heavily luteinized prepubertal rat ovaries. The cAMP-dependent protein kinase, localized in luteal mitochondria, comprised 5.5% of the total cellular protein kinase activity (cAMP-dependent). Intact mitochondria supported by a suitable electron-donor substrate and inhibited by isoxazole converted cholesterol to a single steroid product, pregnenolone. Neither (Bu)2 cAMP nor a crude preparation of cytosolic protein kinase stimulated pregnenolone production from cholesterol when added to intact luteal cell mitochondria; however, mitochondria treated with 10 mM CaCl2 became responsive to both (Bu)2 cAMP and protein kinase by showing increased pregnenolone production. Likewise, the addition of cytosol protein kinase to incubations of cholesterol and crude cholesterol sidechain cleavage enzyme (cytochrome P-450cscc) isolated from luteal mitochondria, also stimulated pregnenolone production. Cholesterol-poor mitochondria, depleted of endogenous sterol by prolonged preincubation, when subsequently incubated with Ca+2 plus (Bu)2 cAMP and protein kinase showed significantly increased pregnenolone production. Conversely, mitochondria with greatly increased intramitochondrial cholesterol after preincubation with 200 microM cholesterol and a cytochrome P-450cscc inhibitor (aminoglutethimide) synthesized pregnenolone in significantly higher amounts than either normal or cholesterol-poor mitochondria after removal of the aminoglutethimide block. However, addition of (Bu)2cAMP or protein kinase to Ca+2-treated cholesterol-rich mitochondria failed to additionally stimulate pregnenolone synthesis. We conclude from these observations that the mitochondrial membrane normally excludes protein kinase and (Bu)2cAMP from any stimulatory action on cholesterol side-chain cleavage. Disruption of the mitochondrial membrane by high Ca+2 concentrations eliminates this barrier and permits (Bu)2cAMP and protein kinase stimulation of the CSCC enzyme system. The mechanism of stimulation is not clear. It could involve direct action on the CSCC enzyme. Alternatively, an increase in either intramitochondrial transport or binding of cholesterol substrate to the CSCC enzyme could be facilitated by protein kinase action. Direct stimulation of the enzyme by protein kinase seems less likely, since increased enzyme activity was not observed in the presence of high concentrations of intramitochondrial cholesterol substrate.

[Cost-benefit studies of 2 equivalent forms of therapy in cervical cancer in the pretherapeutic T 1b stage]. / Kosten-Nutzen-Untersuchungen zu zwei gleichwertigen Therapieformen beim Kollumkarzinom im prätherapeutischen Stadium T 1b.

Patients suffering from a collum carcinoma stage T 1b can be treated either by operation according to Wertheim and Meigs, or by radiotherapy. The results with regard to post operationem complications, five-year-survival and recidivation are equivalent in both methods. Therefore, an analysis of the indirect benefit and the costs of both therapies was performed. Surgery was superior to radiotherapy in all analysed dimensions of indirect benefit. Over and above this, expenses for an operation were 2.7 times lower than for radiotherapy.

Biliary concentrations of temocillin.

Serum and bile concentrations of temocillin were measured after intravenous administration of 1g twice daily to 16 patients with biliary tract infections. The concentration of temocillin in the bile showed high inter-individual variations; however, in patients drug concentrations were attained which were considerably higher than the minimum inhibitory concentrations of the biliary tract pathogens identified throughout the study period. All the patients admitted to the study were treated successfully by temocillin, with the tolerance of the drug being very good, and no side effects or drug-related deteriorations of laboratory data being reported.