Differences in the frequency and distribution of BRCA1 and BRCA2 mutations in breast/ovarian cancer cases from the Basque country with respect to the Spanish population: implications for genetic counselling.

The prevalence of unique and recurrent BRCA1 and BRCA2 pathogenic mutations and unclassified variants varies among different populations. Two hundred and thirty-six breast and/or ovarian cancer patients were analysed to clarify the role of these genes in the Basque Country. We also studied 130 healthy women from the general population from the same region. Fifteen different pathological mutations were found in 16 index cases: 10 truncating mutations, 4 missense mutations and 1 splicing mutation. c.3002_3003insT and c.5788_5789delGT, both in exon 11 of BRCA2 have not previously been described. No pathological mutations were found in cases of sporadic juvenile breast cancer. There are no recurrent mutations in our population; apart from the mutation c.9254_9258del5, which appears in only two index cases. We have also found a lot of variants whose effect is unknown. From these variants, 17 have not previously been described: 6 missenses, 6 synonymous and 5 alterations in intronic regions. We would like to highlight the fact that 14.3% of patients with 3 or more cases of breast cancer in the family, and 16.7% of patients with family history of breast and ovarian cancer, present a pathological mutation in BRCA1 or BRCA2. This manuscript demonstrates that each population can have different mutations and due to this, Genetic Counselling and selection criteria must be different for each population. Furthermore, this article describes for the first time some new mutations and unclassified variants found in our population.

Increasing levels of estradiol are deleterious to embryonic implantation because they directly affect the embryo.

OBJECTIVE: To investigate whether the deleterious effect of E(2) on embryonic implantation is due to a direct effect on the endometrium, on the embryo, or both. DESIGN: Prospective, controlled in vitro study. SETTING: Tertiary infertility center. PATIENT(S): Fertile patients in the luteal phase with histologically normal endometrium who were attending the infertility clinic as oocyte donors (n = 14). INTERVENTION(S): E(2) dose-response (0, 10(-8), 10(-7), 10(-6), 10(-5), and 10(-4) M) and time course (day 2 vs. day 5) experiments were performed in an in vitro embryo adhesion assay composed of human polarized endometrial epithelial cells obtained from fertile patients and mouse embryos. MAIN OUTCOME MEASURE(S): Blastocyst formation rate and embryo adhesion rate. RESULTS: Monolayers of polarized endometrial epithelial cells expressed ERalpha at the mRNA level. The E(2) dose response of blastocysts with polarized endometrial epithelial cells (n = 235) demonstrated a progressive reduction in embryonic adhesion that was statistically significant at 10(-6) M. When polarized endometrial epithelial cells were treated alone with increasing doses of E(2) for 3 days and E(2) was then removed and blastocysts added (n = 410), embryonic adhesion was not significantly reduced, except at 10(-4) M. When 2-day mouse embryos (n = 609) were treated with increasing E(2) concentrations until day 5, the rate of blastocyst formation significantly decreased at a concentration >or= 10(-6) M, and embryonic adhesion decreased when blastocysts (n = 400) were obtained at a concentration >or= 10(-7) M. Time course experiments of embryos cultured for 2 days with polarized endometrial epithelial cells (n = 426) showed that the adhesion rate was higher at E(2) levels of 10(-7), 10(-6) and 10(-5) M compared with embryos cultured for 5 days (n = 495). CONCLUSION(S): High E(2) levels are deleterious to embryo adhesion in vitro, mainly because they have a direct toxic effect on the embryo that may occur at the cleavage stage.

Use of intrauterine contraceptive devices in nulliparous women: personal experience over a 12-year period.

OBJECTIVE: To evaluate the use of intrauterine contraceptive devices (IUDs) in nulliparous women compared to their use in parous women. METHODS: A comparative cross-sectional study was carried out to determine the reasons for removal of IUDs inserted between 1985 and 1996 in a sample of 227 nulliparous women and 2080 parous women. The statistical analysis was performed using the chi 2 test; the differences were considered to be significant when p < 0.05. RESULTS: The reasons for removal of IUDs in the two groups were: expiry, 49.1% in the nulliparous group vs. 48.2% in the parous group; planned pregnancy, 21.7% vs. 15.4%; accidental pregnancy, 4.8% vs. 6.3%; expulsion, 1.6% vs. 5.1%; pelvic inflammatory disease, 1.6% vs. 1.1%; pain and/or bleeding, 14.5% vs. 10.2%; other, 6.4% vs. 6.3%; vasectomy or tubal sterilization, 0% vs. 7%. CONCLUSION: Our data suggest that nulliparity is not a contraindication for the use of an IUD, and that the use of an IUD in nulliparous women is as safe and effective as in parous women.

Phase II trial of weekly IV vinorelbine in first-line advanced breast cancer chemotherapy.

PURPOSE: The study investigated the therapeutic effect of single-agent IV weekly vinorelbine (Navelbine, Pierre Fabre Oncologie, Boulogne, France) a semi-synthetic vinca-alkaloid, in women who had received no prior treatment for advanced or metastatic breast cancer. PATIENTS AND METHODS: Fifty-four patients with assessable advanced or metastatic breast cancer who had received no prior chemotherapy were entered into the study. Fifty patients were evaluable for toxicity and response by WHO criteria; 4 patients were not evaluated because they did not meet the eligibility criteria of the study. Vinorelbine was given as a weekly 30 mg/m2 short IV infusion; and treatment was continued until disease progression or the occurrence of unacceptable toxicity. RESULTS: The overall response rate was 50% (complete response 2%, partial response 48%). The response rate according to target was: lymph nodes 64%; liver 28%; lung 66%; local recurrence 60%. The median duration of response was 9 months, the median time to treatment failure was 5 months and the median survival was 15 months. TOXICITY: Six-hundred thirty cycles were given to 54 patients (53 assessable for tolerance). At least one episode of WHO grade 3/4 granulocytopenia was seen in each of 71% of the patients. Significant nausea/vomiting (WHO grade 3) was seen in less than 1% of cycles and other side effects were uncommon. CONCLUSION: This study confirms that vinorelbine has major single-agent anti-tumour activity as front-line therapy in advanced breast cancer. Given its excellent tolerance profile and low morbidity, it should be considered for inclusion in first-line combination chemotherapy regimens.