Safety of MF59-adjuvanted A/H1N1 influenza vaccine in pregnancy: a comparative cohort study.

OBJECTIVE: The 2009-2010 A/H1N1 pandemic provided a unique setting to study the safety of MF59-adjuvanted vaccination in pregnancy. STUDY DESIGN: This was an observational cohort study of the safety of an MF59-adjuvanted A/H1N1 vaccine (Focetria) conducted among 4508 pregnant women (2295 vaccinated vs 2213 unvaccinated), with 3 month follow-up of neonates. RESULTS: No maternal deaths or abortions occurred among the vaccinated women. No differences between the vaccinated and unvaccinated cohorts were observed for gestational diabetes, preeclampsia, stillbirth, low birthweight, neonatal deaths, or congenital malformations. The risk of premature birth was significantly decreased among the vaccinated women (adjusted proportional hazard, 0.69; 95% confidence interval, 0.51-0.92). No differences were observed in rates of congenital malformations after vaccination in the first (2.1%), second (2.7%), or third (2.1%) trimesters. CONCLUSION: There was no evidence of a safety risk for MF59-adjuvanted A/H1N1 vaccination in pregnant women; protection was observed against premature birth.

Future Prospects in Breast Cancer Research - Cancer Stem Cells.

Breast cancer is one of the leading causes of cancer deaths among women. Although significant advances in the prevention, diagnosis and management are made, still every year half a million women die of breast cancer. Personalised treatment has the potential to increase treatment efficacy, and hence decrease mortality rates. Moreover, understanding cancer biology and translating this knowledge to the clinic, will improve the breast cancer therapy regime tremendously. Recently, it has been proposed that cancer stem cells (CSC) play an important role in tumour biology. CSC have the ability for self-renewal and are pivotal in setting the heterogeneous character of a tumour. Additionally, CSC possess several characteristics that make them resistant and more aggressive to the conventional chemo- and radiotherapy. Nowadays, breast cancer therapy is focused on killing the differentiated tumour cells, leaving the CSC unharmed, potentially causing recurrence of the disease and metastasis. Specific targeting of the CSC will improve the disease-free survival of breast cancer patients. In this article, two methods are described, aiming at specifically attacking the differentiated tumour cells ('Apoptosis chip') and the cancer stem cell. For this, microfluidics is used.

Cancer prevalence in osteoporotic women with low serum vitamin D levels.

OBJECTIVE: The aim of this study was to assess the role of vitamin D in cancer development in postmenopausal osteoporotic women. METHODS: A cross-sectional and in vitro study was carried out, with statistical analysis with odds ratios and 95% CIs presented. Human estrogen receptor-positive breast cancer cells (MCF-7) were studied in vitro. The apoptosis-to-proliferation (A/P) ratio was also determined. RESULTS: A total of 885 women were included in this study. Any kind of cancer was found in 112 (12.7%) of all women. Breast cancer was the most prevalent malignancy, representing half of the cases (n = 56, 50%). The prevalence of any kind of cancer and breast cancer in women with low 25-hydroxyvitamin D3 levels (25OHD; <50 nmol/L) was higher than in women with high 25OHD levels (≥ 50 nmol/L). The in vitro study demonstrated a statistically significant increased A/P ratio of 5.27 (95% CI, 4.054-6.493) with a high concentration of 1α,25-dihydroxyvitamin D (10 µM) after 96 hours. CONCLUSIONS: Osteoporotic women with low serum levels of 25OHD (<50 nmol/L) have an increased prevalence of any kind of cancer and breast cancer; however, these differences are not statistically significant. 1α,25-dihydroxyvitamin D induced an increased A/P ratio in MCF-7 breast cancer cells in vitro.

Viability analysis and apoptosis induction of breast cancer cells in a microfluidic device: effect of cytostatic drugs.

Breast cancer is the leading cause of cancer deaths among non-smoking women worldwide. At the moment the treatment regime is such that patients receive different chemotherapeutic and/or hormonal treatments dependent on the hormone receptor status, the menopausal status and age. However, in vitro sensitivity testing of tumor biopsies could rationalize and improve the choice of chemo- and hormone therapy. Lab-on-a-Chip devices, using microfluidic techniques, make detailed cellular analysis possible using fewer cells, enabling working with a patients' own cells and performing chemo- and hormone sensitivity testing in an ex vivo setting. This article describes the development of two microfluidic devices made in poly(dimethylsiloxane) (PDMS) to validate the cell culture properties and analyze the chemosensitivity of MCF-7 cells (estrogen receptor positive human breast cancer cells) in response to the drug staurosporine (SSP). In both cases, cell viability was assessed using the life-stain Calcein-AM (CAAM) and the death dye propidium iodide (PI). MCF-7 cells could be statically cultured for up to 7 days in the microfluidic chip. A 30 min flow with SSP and a subsequent 24 h static incubation in the incubator induced apoptosis in MCF-7 cells, as shown by a disappearance of the aggregate-like morphology, a decrease in CAAM staining and an increase in PI staining. This work provides valuable leads to develop a microfluidic chip to test the chemosensitivity of tumor cells in response to therapeutics and in this way improve cancer treatment towards personalized medicine.

Breast cancer and climacteric complaints: weighing up risks of hormone therapy against quality of life.

Women with severe menopausal symptoms can, at their request, be treated effectively with hormone therapy. Good information about the advantages and disadvantages of hormone therapy should precede this decision. For women with breast cancer or an inherited increased risk of breast cancer and severe, often therapy-related climacteric symptoms, a high degree of reticence is appropriate in relation to hormone therapy. If the quality of life is seriously affected in these often-young women with these iatrogenic climacteric complaints, then careful consideration must be given to the various treatment modalities.

Treatment of dysfunctional uterine bleeding in the perimenopause: the effects of adding combined estradiol/norethisterone acetate therapy to goserelin acetate treatment--a randomized, placebo-controlled, double-blind trial.

OBJECTIVE: To assess the effects of adding combined estradiol/norethisterone acetate therapy (CENT) to goserelin acetate treatment (GA) of dysfunctional uterine bleeding (DUB) in perimenopausal women. METHODS: In a randomized, placebo-controlled, double-blind trial followed by an open follow-up study, 31 perimenopausal women with DUB were recruited from gynecological outpatient departments of two Dutch hospitals and randomized for treatment with either GA/placebo or GA/CENT for 6 months followed by 18 months of GA/CENT for all. The main outcome measures were abdominal pain, number of bleeding days, double-layer endometrial thickness (DET), Greene climacteric score (GCS), visual analog scale for well-being, bone mineral density (BMD) and mammographic density (BI-RAD score). RESULTS: Abdominal pain, number of bleeding days and DET decreased in both groups, the between-group difference in decrease not being statistically significant. GCS initially showed significant improvement in the GA/CENT group. BMD decreased significantly in the GA/placebo group (-4.1%) compared with the GA/CENT group (-0.3%). Another 18 months of GA/CENT did not result in a lasting difference in BMD between groups. BI-RAD scores did not differ significantly between or within the two groups. CONCLUSIONS: Adding CENT to GA treatment for DUB in perimenopausal women initially prevented BMD loss and improved climacteric complaints, while having no negative impact on vaginal bleeding, abdominal pain or BI-RAD scores. However, prolonged treatment did not result in a lasting prevention of bone loss.

Gonadal protection by a gonadotropin-releasing hormone agonist depot in young women with Hodgkin's disease undergoing chemotherapy.

OBJECTIVE: To explore the effects of a gonadotropin-releasing hormone (GnRH) agonist depot (goserelin acetate) in women with Hodgkin's disease receiving chemotherapy while taking a continuous combined estrogen-progestin preparation as add-back on the prevention of premature ovarian failure (POF). METHODS: In a prospective pilot study, five premenopausal women with Hodgkin's disease received a GnRH agonist depot plus add-back until polychemotherapy was completed. Every 4 weeks during treatment and thereafter, a hormonal profile (follicle-stimulating hormone (FSH), luteinizing hormone, 17beta-estradiol, progesterone and inhibin B) was measured until resumption of menstruation or the development of a hypergonadotropic state (2 x FSH > 30 U/l). RESULTS: All patients reached prepubertal status during treatment. After discontinuation of goserelin acetate, one patient developed a hypergonadotropic state and four patients resumed menstruation. One of those patients became pregnant and delivered a healthy son. CONCLUSIONS: The effectiveness of GnRH agonist plus add-back on the prevention of POF during polychemotherapy in women with Hodgkin's disease needs further elucidation in randomized controlled trials. The results of our pilot study are promising.

Differential effects of progestogens on breast cancer cell lines.

Our in vitro results indicate that not all progestogens act equally on breast cancer cells. Some progestogens (medroxyprogesterone acetate (MPA), norethisterone acetate (NETA) and dienogest) alone or combined with estradiol (E2) stimulate proliferation of breast cancer cells, while others (dihydrodydrogesterone (DHD), the active metabolite of dydrogesterone, tibolone and progesterone (Prog)) alone or combined with estradiol induce apoptosis. Further pharmacological and clinical studies should be initiated to evaluate these findings in vivo.

Oral, more than transdermal, estrogen therapy improves lipids and lipoprotein(a) in postmenopausal women: a randomized, placebo-controlled study.

OBJECTIVE: To assess the effects of low-dose oral and transdermal estrogen therapy on the lipid profile and lipoprotein(a) [Lp(a)] levels in healthy, postmenopausal women and to study the additional influence of gestodene administration. DESIGN: In a multicenter, randomized, double-blind, placebo-controlled study, 152 healthy, hysterectomized, postmenopausal women received daily either placebo (n = 49), 50 microg transdermal 17beta-estradiol (tE2, n = 33), 1 mg oral 17beta-estradiol (oE2, n = 37), or 1 mg oE2 combined with 25 microg gestodene (oE2 + G, n = 33) for 13 cycles of 28 days, followed by 4 cycles of placebo in each group. Fasting serum concentrations of total, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, triglycerides, and Lp(a) were measured at baseline and in cycles 4, 13, and 17. RESULTS: In cycle 13, a significant mean percentage decrease from baseline was found in all treatment groups compared with placebo in total cholesterol (tE2, -4.7%; oE2, -6.9%; oE2 + G, -10.5%) and LDL cholesterol (tE2, -5.8%; oE2, -12.6%; oE2 + G, -13.6%). For both oral groups, the reductions were already significant in cycle 4. None of the treatment groups showed a significant change in HDL cholesterol or triglycerides. In cycle 13, Lp(a) was decreased compared with placebo in the oE2 group (-6.6%) and the oE2 + G group (-8.2%). After washout, all observed changes had returned to baseline level, except for the decreases in total and LDL cholesterol in the oE2 + G group. CONCLUSIONS: Oral E2 and E2 + G, and to a lesser extent transdermal E2, decreased total and LDL cholesterol. Lp(a) was lowered only by the oral treatments.

Effects of low-dose oral and transdermal estrogen replacement therapy on hemostatic factors in healthy postmenopausal women: a randomized placebo-controlled study.

OBJECTIVE: This study was undertaken to investigate the effect of transdermal and oral estrogen replacement therapy in healthy postmenopausal women on markers of coagulation and fibrinolysis associated with coronary artery disease. STUDY DESIGN: In a randomized, placebo-controlled, double-blind study, healthy hysterectomized postmenopausal women received daily either placebo (n=49), transdermal 17beta-estradiol (E(2)) 50 microg (tE(2) group, n=33), oral E(2) 1 mg (oE(2) group, n=37), or oral E(2) 1 mg combined with gestodene 25 microg (oE(2)+G group, n=33) for thirteen 28-day treatment cycles. Hemostatic variables were measured in blood samples collected at baseline and in cycles 4 and 13. RESULTS: No significant changes versus baseline and placebo were found in the tE(2) group, except for plasminogen activator inhibitor type-1 (PAI-1) in cycle 13 (-32.4%, P=.01). In the oE(2) group, significant percentage changes from baseline versus placebo in cycle 13 were found in fibrinogen, -5.4% (P<.05); factor VII, -7.3% (P<.05); thrombin-antithrombin III complexes, -13.3% (P<.05); tissue-type plasminogen activator (t-PA), -17.3% (P<.001); and PAI-1, -54.3% (P<.001). In the oE(2)+G group, respective changes were factor VII, -17.6% (P<.001); t-PA, -14.5% (P=.01); PAI-1, -36.4% (P<.01); and D-dimer, +21.8% (P<.05). No significant changes were observed in prothrombin fragment 1+2 and plasmin-alpha(2)-antiplasmin complexes. CONCLUSION: Low-dose oral estradiol therapy was associated with an increase in fibrinolysis and small decreases in procoagulant variables. Transdermal therapy had minor effects.