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emas OBGYN NEWS is a service that Serge Rozenberg, intends to share with you in EMAS' efforts to exchange research and knowledge. The selection of the articles is arbitrary, but there are no commercial interests involved and no conflict of interest.


N° 859 Topic: A 17β-Estradiol–Progesterone Oral Capsule for Vasomotor Symptoms in Postmenopausal Women: A Randomized Controlled Trial
Lobo, et al Obstetrics & Gynecology: July 2018 - Volume 132 - Issue 1 - p 161–170 doi: 10.1097/AOG.0000000000002645 evaluated efficacy, endometrial safety, and overall safety of a single-capsule 17β-estradiol–progesterone (TX-001HR) for treating menopausal moderate-to-severe vasomotor symptoms in a phase 3, 12-month, RCT (n=1845 women). Frequency and severity of vasomotor symptoms significantly decreased from baseline with 1 mg estradiol and 100 mg progesterone and 0.5 mg estradiol and 100 mg progesterone compared with placebo at week 4 (frequency: by 40.6 and 35.1 points [1 mg and 100 mg and 0.5 mg and 100 mg, respectively] vs 26.4 points [placebo]; severity: by 0.48 and 0.51 vs 0.34 points) and week 12 (by 55.1 and 53.7 vs 40.2; severity: by 1.12 and 0.90 vs 0.56); 0.5 mg estradiol and 50 mg progesterone improved (P<.05) frequency and severity at week 12, and 0.25 mg estradiol and 50 mg progesterone frequency but not severity at weeks 4 and 12.
No endometrial hyperplasia was observed while single-capsule estradiol–progesterone provided clinically meaningfully improvements in moderate-to-severe vasomotor symptoms. This estradiol–progesterone formulation may represent a new option, using naturally occurring hormones, for the estimated millions of women using nonregulatory-approved, compounded hormone therapy.


N° 858 Topic: Platelet Counts during Pregnancy
Reese,et al (N Engl J Med 2018; 379:32-43 DOI: 10.1056/NEJMoa1802897) evaluated platelet counts throughout pregnancy in women who delivered at Oklahoma University Medical Center between 2011 - 2014. These platelet counts were compared with those of nonpregnant women who were included in the National Health and Nutrition Examination Survey from 1999 through 2012.
Women who had uncomplicated pregnancies, had lower mean platelet count in the first trimester (mean gestation, 8.7 weeks) 251,000 per cubic millimeter, than nonpregnant women (273,000 per cubic millimeter) (P<0.001). At the time of delivery, 9.9% of the women with uncomplicated pregnancies had a platelet count below 150,000 per cubic millimeter. During the course of the uncomplicated pregnancies and deliveries, only 45 women (1.0%) had a platelet count below 100,000 per cubic millimeter. Among the 12 women with uncomplicated pregnancies who had a platelet count below 80,000 per cubic millimeter, only 5 (0.1%, among whom the range of platelet counts was 62,000 to 78,000 per cubic millimeter; median, 65,000) were identified by medical record review as having no alternative cause for the thrombocytopenia. Platelet counts of less than 150,000 per cubic millimeter at the time of delivery were more common among women who had pregnancy-related complications than among women who had uncomplicated pregnancies (11.9% vs. 9.9%, P=0.01). Throughout their pregnancies and deliveries, 59 women (2.3%) with pregnancy-related complications had a platelet count below 100,000 per cubic millimeter, and 31 (1.2%) had a platelet count below 80,000 per cubic millimeter.
CONCLUSIONS
Mean platelet counts decreased during pregnancy in all the women, beginning in the first trimester. In women who have a platelet count of less than 100,000 per cubic millimeter, a cause other than pregnancy or its complications should be considered

N° 857 Topic: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet: Supplemented with Extra-Virgin Olive Oil or Nuts
Estruch,et al for the PREDIMED Study (June 13, 2018 DOI: 10.1056/NEJMoa1800389) Investigators*assigned in a multicenter trial in Spain, 7447 participants (55-80 years of age, 57% women) who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was a major cardiovascular event (myocardial infarction, stroke, or death from cardiovascular causes). After a median follow-up of 4.8 years, the trial was stopped on the basis of a prespecified interim analysis. The authors have withdrawn their previously published report and now report revised effect estimates based on analyses that do not rely exclusively on the assumption that all the participants were randomly assigned.
RESULTS
A primary end-point event occurred in 288 participants; there were 96 events in the group assigned to a Mediterranean diet with extra-virgin olive oil (3.8%), 83 in the group assigned to a Mediterranean diet with nuts (3.4%), and 109 in the control group (4.4%). In the intention-to-treat analysis including all the participants and adjusting for baseline characteristics and propensity scores, the HR was 0.69 (95% CI, 0.53- 0.91) for a Mediterranean diet with extra-virgin olive oil and 0.72 (95% CI, 0.54- 0.95) for a Mediterranean diet with nuts, as compared with the control diet. Results were similar after the omission of 1588 participants whose study-group assignments were known or suspected to have departed from the protocol.

N° 856 Topic: Lifepristone Pretreatment for the Medical Management of Early Pregnancy Loss
Schreiber, et al (N Engl J Med 2018; 378:2161-2170) randomly assigned 300 women who had an anembryonic gestation or in whom embryonic or fetal death was confirmed to receive pretreatment with 200 mg of mifepristone, administered orally, followed by 800 μg of misoprostol, administered vaginally (mifepristone-pretreatment group), or 800 μg of misoprostol alone, administered vaginally (misoprostol-alone group). Complete expulsion after one dose of misoprostol occurred in 124/148 women (83.8%; 95% CI 76.8-89.3) in the mifepristone-pretreatment group and in 100/ 149 women (67.1%; 95% CI, 59.0-74.6) in the misoprostol-alone group (RR : 1.25; 95% CI, 1.09 to 1.43). Uterine aspiration was performed less frequently in the mifepristone-pretreatment group than in the misoprostol-alone group (8.8% vs. 23.5%; RR: 0.37; 95% CI, 0.21 to 0.68). Bleeding that resulted in blood transfusion occurred in 2.0% of the women in the mifepristone-pretreatment group and in 0.7% of the women in the misoprostol-alone group (P=0.31); pelvic infection was diagnosed in 1.3% of the women in each group.

N° 855 Topic: Vuvodynia
Gabapentin for the Treatment of Vulvodynia: A Randomized Controlled Trial
Brown, Candace, et al for the Gabapentin (GABA) Study Group Obstetrics & Gynecology: June 2018 - Volume 131 - Issue 6 - p 1000–1007 doi: 10.1097/AOG.0000000000002617 evaluated whether extended-release gabapentin is more effective than placebo among women with vulvodynia.using a multicenter double-blind, placebo-controlled randomized crossover trial, gabapentin (1,200–3,000 mg/d) was compared with a placebo. In this cohort, extended-release gabapentin, as compared with a placebo, did not reduce tampon test pain. These data do not support the recommendation of gabapentin alone as treatment for vulvodynia.

N° 854 Topic: Risk of Gynecologic Cancer According to the Type of Endometriosis
Saavalainen, Liisu, et al (Obstetrics & Gynecology: June 2018 - Volume 131 - Issue 6 - p 1095–1102 doi: 10.1097/AOG.0000000000002624) assed the risks of gynecologic cancer according to the type of endometriosis in women with surgically verified endometriosis,using  a population-based study retrieved from the Finnish Hospital Discharge Register 1987–2012 (N=49,933); the subtypes of ovarian (n=23,210), peritoneal (n=20,187), and deep infiltrating (n=2,372) endometriosis were analyzed separately. Gynecologic cancers were obtained from the Finnish Cancer Registry. In this study, endometriosis was associated with increased risk of ovarian cancer (standardized incidence ratio 1.76 [95% CI 1.47–2.08]), especially with endometrioid (3.12 [2.15–4.38]) and clear cell (5.17 [3.20–7.89]) histologic type and to a lesser extent with serous type (1.37 [1.02–1.80]). The risk of ovarian cancer was highest among women with ovarian endometriosis and especially for endometrioid (4.72 [2.75–7.56]) and clear cell (10.1 [5.50–16.9]) ovarian cancer, occurring 5–10 years after the index surgery. The overall risk of ovarian cancer was not increased among women with peritoneal and deep infiltrating endometriosis. However, peritoneal endometriosis was associated with a twofold increase in risk of endometrioid histology. The risk of endometrial cancer was not altered in the entire cohort. The standardized incidence ratio for precancerous cervical lesions was 0.81 (0.71–0.92) and for invasive squamous cell carcinoma of the cervical cancer 0.46 (0.20–0.91). CONCLUSION: The excess risk of ovarian cancer among women with ovarian endometriosis translates into two excess cases per 1,000 patients followed for 10 years. Acknowledging these risks is important when planning long-term management of women with endometriosis.

N° 853 Topic: The impact of menopausal hormone therapy (MHT) on cardiac structure and function: Insights from the UK Biobank imaging enhancement study
Sanghvi et al ( PLoS One. 2018 Mar 8;13(3):e0194015. doi: 10.1371/journal.pone.0194015. eCollection 2018.) examined in a cross-sectional study the impact of MHT on left ventricular (LV) and left atrial (LA) structure and function, alterations which are markers of subclinical cardiovascular disease, in a population-based cohort.

METHODS:
Post-menopausal women who had never used MHT and those who had used MHT ≥3 years participating in the UK Biobank who had undergone cardiovascular magnetic resonance (CMR) imaging and free of known cardiovascular disease were included. Multivariable linear regression was performed to examine the relationship between cardiac parameters and MHT use ≥3 years. To explore whether MHT use on each of the cardiac outcomes differed by age, multivariable regression models were constructed with a cross-product of age and MHT fitted as an interaction term.
RESULTS:
Of 1604 post-menopausal women, 513 (32%) had used MHT ≥3 years. In the MHT cohort, median age at menopause was 50 (IQR: 45-52) and median duration of MHT was 8 years. In the non-MHT cohort, median age at menopause was 51 (IQR: 48-53). MHT use was associated with significantly lower LV end-diastolic volume (122.8 ml vs 119.8 ml, effect size = -2.4%, 95% CI: -4.2% to -0.5%; p = 0.013) and LA maximal volume (60.2 ml vs 57.5 ml, effect size = -4.5%, 95% CI: -7.8% to -1.0%; p = 0.012). There was no significant difference in LV mass. MHT use significantly modified the effect between age and CMR parameters; MHT users had greater decrements in LV end-diastolic volume, LV end-systolic volume and LA maximal volume with advancing age.

CONCLUSIONS:
MHT use was not associated with adverse, subclinical changes in cardiac structure and function. Indeed, significantly smaller LV and LA chamber volumes were observed which have been linked to favourable cardiovascular outcomes. These findings represent a novel approach to examining MHT's effect on the cardiovascular system.

N° 852 Topic: Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging.
Mosconi et al (Neurology. 2017 Sep 26;89(13):1382-1390. doi: 10.1212/WNL.0000000000004425. Epub 2017 Aug 30.) investigated in an observational multimodality brain imaging study emergence of endophenotypes of late-onset Alzheimer disease (AD) risk during endocrine transition states in a cohort of clinically and cognitively normal women (15 asymptomatic perimenopausal by age [CNT], 13 perimenopausal [PERI], and 14 postmenopausal [MENO]) and age-matched men (18 age- and education-matched men).
All patients had volumetric MRI, 18F-fluoro-2-deoxyglucose (FDG)-PET (glucose metabolism), and Pittsburgh compound B-PET scans (β-amyloid [Aβ] deposition, a hallmark of AD pathology).
As expected, the MENO group was older than the PERI and CNT groups. Otherwise, groups were comparable on clinical and neuropsychological measures and APOE4 distribution. Compared to CNT women and to men, and controlling for age, PERI and MENO groups exhibited increased indicators of AD endophenotype, including hypometabolism, increased Aβ deposition, and reduced gray and white matter volumes in AD-vulnerable regions (p < 0.001). AD biomarker abnormalities were greatest in MENO, intermediate in PERI, and lowest in CNT women (p < 0.001). Aβ deposition was exacerbated in APOE4-positive MENO women relative to the other groups (p < 0.001).
CONCLUSIONS:
Multimodality brain imaging indicates sex differences in development of the AD endophenotype, suggesting that the preclinical AD phase is early in the female aging process and coincides with the endocrine transition of perimenopause. These data indicate that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process

N° 851 Topic: Efficacy of Vaginal Estradiol or Vaginal Moisturizer vs Placebo for Treating Postmenopausal Vulvovaginal Symptoms
Caroline M. Mitchell et al (JAMA Intern Med. doi:10.1001/jamainternmed.2018.0116) compared the efficacy of a low-dose vaginal estradiol tablet and a vaginal moisturizer, each vs placebo, for treatment of moderate-to-severe postmenopausal vulvovaginal symptom,which affects nearly half of postmenopausal women
This 12-week multicenter randomized clinical trial enrolled postmenopausal women with moderate to severe symptoms of vulvovaginal itching, pain, dryness, irritation, or pain with penetration.
Women received either  vaginal 10-μcg estradiol tablet (daily for 2 weeks, then twice weekly) plus
placebo gel (3 times a week) (n = 102) vs placebo tablet plus vaginal moisturizer (n = 100) vs
dual placebo (n = 100).
The results suggested that neither prescribed vaginal estradiol tablet nor over-the-counter vaginal moisturizer provides additional benefit over placebo vaginal tablet and gel in reducing postmenopausal vulvovaginal symptoms.

N° 850 Topic: Screening in the community to reduce fractures in older women (SCOOP): a randomised controlled trial
Lee Shepstone et al (Lancet Volume 391, No. 10122, p741–747, 24 February 2018) conducted an RCT in women aged 70–85 years to compare a screening programme using FRAX with usual management to test whether it would reduce fractures. Women were recruited from 100 GP practices in the UK: Women who were currently on prescription anti-osteoporotic drugs and any individuals deemed to be unsuitable to enter a research study were excluded. In the screening group, treatment was recommended in women at high hip fracture risk.
12 483 eligible women were identified and participated in the trial, and 6233 women randomly assigned to the screening group. Treatment was recommended in 898 (14%) of 6233 women. Use of osteoporosis medication was higher at the end of year 1 in the screening group compared with controls (15% vs 4%), with uptake particularly high (78% at 6 months) in the screening high-risk subgroup. Screening did not reduce the primary outcome of incidence of all osteoporosis-related fractures (HR 0·94, 95% CI 0·85–1·03, p=0·178), nor the overall incidence of all clinical fractures (0·94, 0·86–1·03, p=0·183), but screening reduced the incidence of hip fractures (0·72, 0·59–0·89, p=0·002). There was no evidence of differences in mortality, anxiety levels, or quality of life.
Interpretation
Systematic, community-based screening programme of fracture risk in older women in the UK is feasible, and could be effective in reducing hip fractures.

N° 849 Topic: Intraperitoneal
Willemien J. van Driel et al (N Engl J Med 2018; 378:230-240January 18, 2018DOI: 10.1056/NEJMoa1708618) conducted a multicenter, open-label, phase 3 trial in 245 patients, to investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer.
In the intention-to-treat analysis, events of disease recurrence or death occurred in 110 of the 123 patients (89%) who underwent cytoreductive surgery without HIPEC (surgery group) and in 99 of the 122 patients (81%) who underwent cytoreductive surgery with HIPEC (surgery-plus-HIPEC group) (HR for disease recurrence or death, 0.66; 95% CI], 0.50 to 0.87; P=0.003). The median recurrence-free survival was 10.7 months in the surgery group and 14.2 months in the surgery-plus-HIPEC group. At a median follow-up of 4.7 years, 76 patients (62%) in the surgery group and 61 patients (50%) in the surgery-plus-HIPEC group had died (HR, 0.67; 95% CI, 0.48 to 0.94; P=0.02). The median overall survival was 33.9 months in the surgery group and 45.7 months in the surgery-plus-HIPEC group. The percentage of patients who had adverse events of grade 3 or 4 was similar in the two groups (25% in the surgery group and 27% in the surgery-plus-HIPEC group, P=0.76).
CONCLUSIONS
Among patients with stage III epithelial ovarian cancer, the addition of HIPEC to interval cytoreductive surgery resulted in longer recurrence-free survival and overall survival than surgery alone and did not result in higher rates of side effects.

N° 848 Topic: Transfer of Fresh versus Frozen Embryos in Ovulatory Women
Yuhua Shi, M.D., et al N Engl J Med 2018; 378:126-136January 11, 2018DOI: 10.1056/NEJMoa1705334
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BACKGROUND
Elective frozen-embryo transfer has been shown to result in a higher live-birth rate than fresh-embryo transfer among anovulatory women with the polycystic ovary syndrome. It is uncertain whether frozen-embryo transfer increases live-birth rates among ovulatory women with infertility.
Yuhua Shi, et al conducted a RCT  (2157 women who were undergoing their first IVF cycle) to undergo either fresh-embryo transfer or embryo cryopreservation followed by frozen-embryo transfer.
The live-birth rate did not differ significantly between the frozen-embryo group and the fresh-embryo group (48.7% and 50.2%, respectively;RR, 0.97; 95% CI, 0.89- 1.06; P=0.50). There were also no significant between-group differences in the rates of implantation, clinical pregnancy, overall pregnancy loss, and ongoing pregnancy. Frozen-embryo transfer resulted in a significantly lower risk of the ovarian hyperstimulation syndrome than fresh-embryo transfer (0.6% vs. 2.0%;RR, 0.32; 95% CI, 0.14 -0.74; P=0.005). The risks of obstetrical and neonatal complications and other adverse outcomes did not differ significantly between the two groups.

N° 846 Topic: Does hormonal contraception during molar pregnancy follow-up influence the risk and clinical aggressiveness of gestational trophoblastic neoplasia after controlling for risk factors?
Does hormonal contraception during molar pregnancy follow-up influence the risk and clinical aggressiveness of gestational trophoblastic neoplasia after controlling for risk factors?
Dantas PRS et al (Gynecol Oncol. 2017 Nov;147(2):364-370. doi: 10.1016/j.ygyno.2017.09.007. Epub 2017 Sep 18) evaluated whether hormonal contraception (HC) influences the development and clinical aggressiveness of gestationaltrophoblastic neoplasia (GTN) and the time for normalization of human chorionic gonadotropin (hCG) levels using a retrospective cohort study followed at the Rio de Janeiro Trophoblastic Disease Center, between January 2005 and January 2015. The occurrence of postmolar GTN and the time for hCG normalization between users of HC or barrier methods (BM) during the postmolar follow-up or GTN treatment were evaluated.
Among 2828 patients, 2680 (95%) used HC and 148 (5%) used BM. The use of HC did not significantly influence the occurrence of GTN (ORa: 0.66, 95% CI: 0.24-1.12, p=0.060), despite different formulations: progesterone-only (ORa: 0.54, 95% CI: 0.29-1.01, p=0.060) or combined oral contraception (COC) (ORa: 0.50, 95% CI: 0.27-1.01, p=0.60) or with different dosages of ethinyl estradiol: 15mcg (ORa, 1.33, 95% CI 0.79-2.24, p=0.288), 20mcg (ORa: 1.02, 95% CI: 0.64-1.65, p=0.901), 30mcg (ORa: 1.17, 95% CI: 0.78-1.75, p=0.437) or 35mcg (ORa: 0.77, 95% CI: 0.42-1.39, p=0.386). Time to hCG normalization ≥10weeks (ORa: 0.58, 95% CI: 0.43-1.08, p=0.071) or time to remission with chemotherapy≥14weeks (ORa: 0.60, 95% CI: 0.43-1.09, p=0.067) did not significantly differ among HC users when compared to patients using BM, when controlling for other risk factors using multivariate logistic regression.
CONCLUSIONS:
The use of HC during postmolar follow-up or GTN treatment does not seem to increase the risk of GTN or its severity and does not postpone the normalization of hCG levels.

N° 845 Topic: Comparisons of Interventions for Preventing Falls in Older AdultsA Systematic Review and Meta-analysi
Andrea C. Tricco, et al JAMA. 2017;318(17):1687-1699. doi:10.1001/jama.2017.15006
assessed what types of fall-prevention programs may be effective for reducing injurious falls in older people.  In a network meta-analysis including 54 studies and 41 596 participants, exercise (odds ratio [OR], 0.51), combined exercise, vision assessment and treatment, and environmental assessment and modification (OR, 0.30), combined exercise, and vision assessment and treatment (OR, 0.17), and combined clinic-level quality-improvement strategies, multifactorial assessment and treatment, calcium supplementation, and vitamin D supplementation (OR, 0.12) were significantly associated with reductions in injurious falls.
Meaning  The analysis identified combinations of interventions likely to be more effective than usual care for preventing injurious falls.

N° 844 Topic: 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years
ErikssoHongchao Pan et al for the EBCTCG* (N Engl J Med 2017; 377:1836-1846November 9, 2017DOI: 10.1056/NEJMoa1701830)
In this meta-analysis of the results of 88 trials involving 62,923 women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy, the authors assess the associations of tumor diameter and nodal status (TN), tumor grade, and other factors with patients’ outcomes during the period from 5 to 20 years.
RESULTS

Breast-cancer recurrences occurred at a steady rate throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status. Among the patients with stage T1 disease, the risk of distant recurrence was 13% with no nodal involvement (T1N0), 20% with one to three nodes involved (T1N1–3), and 34% with four to nine nodes involved (T1N4–9); among those with stage T2 disease, the risks were 19% with T2N0, 26% with T2N1–3, and 41% with T2N4–9. The risk of death from breast cancer was similarly dependent on TN status, but the risk of contralateral breast cancer was not. Given the TN status, the factors of tumor grade (available in 43,590 patients) and Ki-67 status (available in 7692 patients), which are strongly correlated with each other, were of only moderate independent predictive value for distant recurrence, but the status regarding the progesterone receptor (in 54,115 patients) and human epidermal growth factor receptor type 2 (HER2) (in 15,418 patients in trials with no use of trastuzumab) was not predictive. During the study period from 5 to 20 years, the absolute risk of distant recurrence among patients with T1N0 breast cancer was 10% for low-grade disease, 13% for moderate-grade disease, and 17% for high-grade disease; the corresponding risks of any recurrence or a contralateral breast cancer were 17%, 22%, and 26%, respectively.
CONCLUSIONS

After 5 years of adjuvant endocrine therapy, breast-cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status, with risks ranging from 10 to 41%, depending on TN status and tumor grade.


N° 843 Topic: Genetic Associations with Gestational Duration and Spontaneous Preterm Birth
Ge Zhang, M.DN (Engl J Med 2017; 377:1156-1167September 21, 2017DOI: 10.1056/NEJMoa1612665) performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. They used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10−8) or an association with suggestive significance (P<1.0×10−6) in the discovery set.
In this genomewide association study, They found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement.

N° 842 Topic: Low-Fat Dietary Pattern and Breast Cancer Mortality in the WHI RCT.
Patients and Methods :The trial randomly assigned 48,835 postmenopausal women with normal mammograms and without prior breast cancer from 1993 to 1998 at 40 US clinical centers to a dietary intervention with goals of a reduction of fat intake to 20% of energy and an increased intake of fruits, vegetables, and grains (40%; n = 19,541) or to a usual diet comparison (60%; n = 29,294).
Results : In the dietary group, fat intake and body weight decreased (all P < .001). During the 8.5-year dietary intervention, with 1,764 incident breast cancers, fewer deaths occurred as a result of breast cancer in the dietary group, which was not statistically significant (27 deaths [0.016% per year] v 61 deaths [0.024% per year]; HR= 0.67; 95% CI, 0.43 to 1.06; P = .08).
During the same period, deaths after breast cancer (n = 134) were significantly reduced (40 deaths [0.025% /year] v 94 deaths [0.038%/ year]; HR, 0.65; 95% CI, 0.45 to 0.94; P = .02) by the dietary intervention.
During the 16.1-year follow-up, with 3,030 incident breast cancers, deaths after breast cancer also were significantly reduced (234 deaths [0.085% / year] v 443 deaths [0.11%/ year]; HR, 0.82; 95% CI, 0.70 to 0.96; P = .01) in the dietary group.
Conclusion Compared with a usual diet comparison group, a low-fat dietary pattern led to a lower incidence of deaths after breast cancer.
Chlebowski J Clin Oncol. 2017 Sep 1;35(25):2919-2926.

The authors CONCLUSIONS were that :
Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years

N° 841 Topic: Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials.

A recent analysis of th Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials focused on all-cause and cause-specific mortality. Manson JE  et al JAMA. 2017 Sep 12;318(10):927-938. doi: 10.1001/jama.2017.11217.

The authors CONCLUSIONS were that :
Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years

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N° 840 Topic: Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data
Jolliffe et al (Lancet Respiratory medicine DOI: http://dx.doi.org/10.1016/S2213-2600(17)30306-5)

A previous aggregate data meta-analysis of randomised controlled trials showed that vitamin D supplementation reduces the rate of asthma exacerbations requiring treatment with systemic corticosteroids. Whether this effect is restricted to patients with low baseline vitamin D status is unknown.
This systematic review identified 483 unique studies, eight of which were eligible randomised controlled trials. Vitamin D supplementation reduced the rate of asthma exacerbation requiring treatment with systemic corticosteroids among all participants (adjusted incidence rate ratio [aIRR] 0·74, 95% CI 0·56–0·97; p=0·03; 955 participants in seven studies; high-quality evidence). Subgroup analyses of the rate of asthma exacerbations treated with systemic corticosteroids revealed that protective effects were seen in participants with baseline 25(OH)D of less than 25 nmol/L (aIRR 0·33, 0·11–0·98; p=0·046; but not in participants with higher baseline 25(OH)D levels (aIRR 0·77, 0·58–1·03; p=0·08)
Interpretation
Vitamin D supplementation reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids overall. The authors did not find definitive evidence that effects of this intervention differed across subgroups of patients.

N° 839 Topic: Use of Bisphosphonates and Risk of Breast Cancer in a French Cohort of PostmenopausalWomen.
Fournier A1, et al (J Clin Oncol. 2017 Jul 14:JCO2016714337. doi: 10.1200/JCO.2016.71.4337. [Epub ahead of print]) assessed whether bisphosphonate (BP) use is associated with decreased breast cancer incidence in a cohort of postmenopausalwomen using the French E3N study population (n= 64,438 postmenopausal women).
Over an average of 7.2 years of follow-up, 2,407 first primary breast cancer cases were identified. The HR of breast cancer associated with exposure to BPs was 0.98 (95% CI, 0.85 to 1.12).
They observed a decrease in breast cancer risk restricted to the year after treatment initiation (HR, 0.56; 95% CI, 0.36 to 0.87), which was likely explained by healthy screening bias.
Finally, they did not find any variation in HRs across breast carcinomas defined by their estrogen receptor or invasive or in situ status.
Conclusion In this observational cohort of postmenopausal women BP use was not associated with decreased breast cancer incidence.

N° 838 Topic: Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis
Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption.
Kenneth G. Saag, et al (NEJM 11.9.17 DOI: 10.1056/NEJMoa1708322) enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1:1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open-label alendronate in both groups.
Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2046 patients]) than in the alendronate-to-alendronate group (11.9% [243 of 2047 patients]) (P<0.001). Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of 2047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (P<0.001). The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [10.6%]; P=0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients [2.5%] vs. 38 of 2014 patients [1.9%]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed.
In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. (Funded by Amgen and others; ARCH ClinicalTrials.gov number, NCT01631214.)


N° 837 Topic: Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist
Hugh S. Taylor, et al (N Engl J Med 2017; 377:28-40July 6, 2017DOI: 10.1056/NEJMoa1700089) performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix (an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist )— 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) — as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain.
A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P=0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings.


N° 836 Topic: Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia
Daniel L. Rolnik, M.D., et al  (NEJM June 28, 2017DOI: 10.1056/NEJMoa1704559) conducted a  multicenter, double-blind, placebo-controlled trial, (n= 1776 women with singleton pregnancies who were at high risk for preterm preeclampsia to receive aspirin, 150 mg/ day, or placebo from 11 to 14 weeks of gestation until 36 weeks of gestation). The primary outcome was delivery with preeclampsia before 37 weeks of gestation. The analysis was performed according to the intention-to-treat principle. At the end there were 798 participants in the aspirin group and 822 in the placebo group. Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as compared with 35 (4.3%) in the placebo group (OR in the aspirin group, 0.38; 95%CI, 0.20 to 0.74; P=0.004).
Treatment with low-dose aspirin in women at high risk for preterm preeclampsia resulted in a lower incidence of this diagnosis than placebo.

N° 835 Topic: Hysterosalpingography using oil or water –based contrast ?
Daniel L. Rolnik, M.D., et al  (NEJM June 28, 2017DOI: 10.1056/NEJMoa1704559) conducted a  multicenter, double-blind, placebo-controlled trial, (n= 1776 women with singleton pregnancies who were at high risk for preterm preeclampsia to receive aspirin, 150 mg/ day, or placebo from 11 to 14 weeks of gestation until 36 weeks of gestation). The primary outcome was delivery with preeclampsia before 37 weeks of gestation. The analysis was performed according to the intention-to-treat principle. At the end there were 798 participants in the aspirin group and 822 in the placebo group. Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as compared with 35 (4.3%) in the placebo group (OR in the aspirin group, 0.38; 95%CI, 0.20 to 0.74; P=0.004).
Treatment with low-dose aspirin in women at high risk for preterm preeclampsia resulted in a lower incidence of this diagnosis than placebo.ps.

N° 834 Topic: Bone-Density Testing Interval and Transition to Osteoporosis in Older Women
Gourlay et al (N Engl J Med 2012; 366:225-233 January 19, 2012) studied 4957 women, 67 years of age or older, with normal BMD (T score at the femoral neck and total hip, −1.00 or higher) or osteopenia (T score, −1.01 to −2.49) and with no history of hip or clinical vertebral fracture or of treatment for osteoporosis, and followed prospectively for up to 15 years. The BMD testing interval was defined as the estimated time for 10% of women to make the transition to osteoporosis before having a hip or clinical vertebral fracture, with adjustment for estrogen use and clinical risk factors. Transitions from normal BMD and from three subgroups of osteopenia (mild, moderate, and advanced) were analyzed with the use of parametric cumulative incidence models. Incident hip and clinical vertebral fractures and initiation of treatment with bisphosphonates, calcitonin, or raloxifene were treated as competing risks.
The estimated BMD testing interval was 16.8 years (95% CI, 11.5- 24.6) for women with normal BMD, 17.3 years (95% CI, 13.9 to 21.5) for women with mild osteopenia, 4.7 years (95% CI, 4.2 to 5.2) for women with moderate osteopenia, and 1.1 years (95% CI, 1.0 to 1.3) for women with advanced osteopenia.
The authors concluded that osteoporosis would develop in less than 10% of older, postmenopausal women during rescreening intervals of approximately 15 years for women with normal bone density or mild osteopenia, 5 years for women with moderate osteopenia, and 1 year for women with advanced osteopenia.

N° 833 Topic: Systematic review on “The management of menopause in women with a history of endometriosis”
L.C. Gemmell et al (Hum Reprod Update May 2017,  https://doi.org/10.1093/humupd/dmx011) conducted systematic review on “The management of menopause in women with a history of endometriosis”
They concluded that due to the lack of high-quality studies, it remains unclear how to advise women with a history of endometriosis regarding the management of menopausal symptoms. The absolute risk of disease recurrence and malignant transformation cannot be quantified, and the impact of HRT use on these outcomes is not known, calling for multicentre randomized trials or large observational studies.

N° 832 Topic: alternative treatment to MHT.
Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial

Julia K Prague et al  Lancet 2017; 389: 1809–20 evaluated in a phase 2 RCT, double-blind-crossover trial whether a Neurokinin 3 receptor antagonism reduces vasomotor symptoms in postmenopausal women. Neurokinin B signalling is increased in menopausal women, and has been implicated as an important mediator of hot flushes. Participants received 4 weeks of MLE4901 (40 mg, orally, twice daily) or placebo  in random order separated by a 2 week washout period. 68 women were screened, of which 37 were randomly assigned and included in an intention-to-treat analysis. 28 participants completed the trial and were included in a per-protocol analysis. MLE4901 significantly reduced the total weekly number of hot flushes by 45 percentage points (95% CI 22–67) compared with the placebo (intention-to-treat adjusted means: placebo 49·01 [95% CI 40·81–58·56] vs MLE4901 19·35 [15·99–23·42]; adjusted estimate of difference 29·66 [17·39–42·87], p<0.001. Treatment was well tolerated. Three participants developed a transaminase rise with a normal bilirubin 28 days after starting MLE4901, which normalised within 90 days. Interpretation Treatment with a neurokinin 3 receptor antagonist (MLE4901) could be practice changing as it safely and effectively relieves hot flush symptoms without the need for oestrogen exposure. Larger scale studies of longer duration are now indicated.

N° 831 Topic: The ACOG issued a committee opinion about Hormone Therapy in Primary Ovarian Insufficiency
(Obstet Gynecol. 2017 May;129(5):e134-e141. doi: 10.1097/AOG.0000000000002044.)

…. In women with primary ovarian insufficiency, systemic hormone therapy (HT) is an effective approach to treat the symptoms of hypoestrogenism and mitigate long-term health risks if there are no contraindications to treatment. Hormone therapy is indicated to reduce the risk of osteoporosis, cardiovascular disease, and urogenital atrophy and to improve the quality of life of women with primary ovarian insufficiency.
Although exogenous estrogen replacement is recommended for women with primary ovarian insufficiency, data comparing various hormonal regimens for disease prevention, symptom amelioration, and safety are lacking in this population. As a first-line approach, HT (either orally or transdermally) that achieves replacement levels of estrogen is recommended. Combined hormonal contraceptives prevent ovulation and pregnancy more reliably than HT; despite only modest odds of spontaneous pregnancy in women with primary ovarian insufficiency, this is a critical consideration for those who deem pregnancy prevention a priority. Treatment for all women with primary ovarian insufficiency should continue until the average age of natural menopause is reached (age 50-51 years). Finally, considering the challenges that adolescents and young women may face in coping with the physical, reproductive, and social effects of primary ovarian insufficiency, comprehensive longitudinal management of this condition is essential.

N° 830 Topic: Quadrivalent HPV Vaccination and the Risk of Adverse Pregnancy Outcomes
Nikolai M. Scheller et al (N Engl J Med 2017; 376:1223-1233March 30, 2017DOI: 10.1056/NEJMoa1612296)

evaluated the safety of the quadrivalent HPV vaccine during pregnancy, since some women will have inadvertent exposure to vaccination during early pregnancy.  Using nationwide registers, they linked information on vaccination, adverse pregnancy outcomes, and potential confounders among women in the national cohort. Women who had vaccine exposure during the prespecified time windows were matched for propensity score in a 1:4 ratio with women who did not have vaccine exposure during the same time windows. Outcomes included spontaneous abortion, stillbirth, major birth defect, small size for gestational age, low birth weight, and preterm birth.
In matched analyses, exposure to the quadrivalent HPV vaccine was not associated with significantly higher risks than no exposure for major birth defect
CONCLUSIONS
Quadrivalent HPV vaccination during pregnancy was not associated with a significantly higher risk of adverse pregnancy outcomes than no such exposure.


N° 829 Topic: A clinical model for identifying the short-term risk of breast cancer.
Eriksson M  et al (Breast Cancer Res. 2017 Mar 14;19(1):29. doi: 10.1186/s13058-017-0820-y.) describe a model that could be used at most mammography screening units without adding substantial cost to individual risk of the disease.
The study was based on the Karma cohort, which included 70,877 participants. Mammograms were collected up to 3 years following the baseline mammogram. A prediction protocol was developed using mammographic density, computer-aided detection of microcalcifications and masses, use of hormone replacement therapy (HRT), family history of breast cancer, menopausal status, age, and body mass index. Relative risks were calculated using conditional logistic regression. Absolute risks were calculated using the iCARE protocol.

Comparing women at highest and lowest mammographic density yielded a fivefold higher risk of breast cancer for women at highest density. When adding microcalcifications and masses to the model, high-risk women had a nearly ninefold higher risk of breast cancer than those at lowest risk. In the full model, taking HRT use, family history of breast cancer, and menopausal status into consideration, the AUC reached 0.71.

CONCLUSIONS:
Measures of mammographic features and information on HRT use, family history of breast cancer, and menopausal status enabled early identification of women within the mammography screening program at such a high risk of breast cancer that additional examinations are warranted. In contrast, women at low risk could probably be screened less intensively.

N° 828 Topic: Computerised interpretation of fetal heart rate during labour (INFANT): a randomised controlled trial
By The INFANT Collaborative Group (Lancet DOI: http://dx.doi.org/10.1016/S0140-6736(17)30568-8) aimed to establish whether the addition of decision-support software to assist in the interpretation of cardiotocographs affected the number of poor neonatal outcomes.
Using an unmasked RCT they recruited women in labour having continuous electronic fetal monitoring, with a singleton or twin pregnancy, and at 35 weeks' gestation or more at 24 maternity units. Women were randomly assigned (1:1) to decision support with the INFANT system or no decision support. The primary outcomes were poor neonatal outcome (intrapartum stillbirth or early neonatal death excluding lethal congenital anomalies, or neonatal encephalopathy, admission to the neonatal unit within 24 h for ≥48 h with evidence of feeding difficulties, respiratory illness, or encephalopathy with evidence of compromise at birth), and developmental assessment at age 2 years in a subset of surviving children. Analyses were done by intention to treat. This trial is completed and is registered with the ISRCTN Registry, number 98680152.
47 062 women were randomly assigned  and 46 042 were analysed (22 987 in the decision-support group and 23 055 in the no-decision-support group). There was no difference in the incidence of poor neonatal outcome between the groups—172 (0·7%) babies in the decision-support group compared with 171 (0·7%) babies in the no-decision-support group (adjusted risk ratio 1·01, 95% CI 0·82–1·25). At 2 years, no significant differences were noted in terms of developmental assessment.

N° 827 Topic: Effects of Calcium, Vitamin D, and Hormone Therapy on Cardiovascular Disease Risk Factors in the Women's Health Initiative: A Randomized Controlled Trial
Schnatz, et al Obstetrics & Gynecology. 129(1):121-129, January 2017 analyzed the treatment effect of calcium+vitamin D supplementation, hormone therapy, or both, and neither on cardiovascular disease risk factors.


N° 826 Topic: Fish Oil‐Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring
Fish Oil‐Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring
Reduced intake of n−3 long-chain polyunsaturated fatty acids (LCPUFAs) may be a contributing factor to the increasing prevalence of wheezing disorders. Hans Bisgaard, et al  evaluated the effect of supplementation with n−3 LCPUFAs in pregnant women on the risk of persistent wheeze and asthma in their offspring (N Engl J Med 2016; 375:2530-2539December 29, 2016DOI: 10.1056/NEJMoa1503734) using a RCT (736 pregnant women at 24 weeks of gestation to receive 2.4 g of n−3 LCPUFA (fish oil) or placebo (olive oil) per day) Their children were followed prospectively with extensive clinical phenotyping. Neither the investigators nor the participants were aware of group assignments during follow-up for the first 3 years of the children’s lives, after which there was a 2-year follow-up period during which only the investigators were unaware of group assignments. The primary end point was persistent wheeze or asthma, and the secondary end points included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization.
The risk of persistent wheeze or asthma in the treatment group was 16.9%, versus 23.7% in the control group (HR, 0.69; 95%CI 0.49 to 0.97; P=0.035), corresponding to a relative reduction of 30.7%.
Prespecified subgroup analyses suggested that the effect was strongest in the children of women whose blood levels of eicosapentaenoic acid and docosahexaenoic acid were in the lowest third of the trial population at randomization: 17.5% versus 34.1% (hazard ratio, 0.46; 95% CI, 0.25 to 0.83; P=0.011). Analyses of secondary end points showed that supplementation with n−3 LCPUFA was associated with a reduced risk of infections of the lower respiratory tract (31.7% vs. 39.1%; HR, 0.75; 95% CI, 0.58 to 0.98; P=0.033), but there was no statistically significant association between supplementation and asthma exacerbations, eczema, or allergic sensitization.

N° 825 Topic: Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women 
Annalene Nel, et al N Engl J Med 2016; 375:2133-2143December 1, 2016DOI: 10.1056/NEJMoa1602046
evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in women, using a RCT in a 2:1 ratio. The incidence of HIV-1 infection was 31% lower in the dapivirine group than in the placebo group (HR, 0.69; 95%CI, 0.49 to 0.99; P=0.04).

N° 824 Topic: There have been several recent papers on the influence of sex-pecific risk factors on stroke incidence and mortality.
One Systematic Review and Meta-analysis conducted by Poorthuis and al. (JAMA Neurol. 2016 Nov 14. doi: 10.1001/jamaneurol.2016.3482.) included 78 studies, comprising 10 187 540 persons.
We report some of their results: The authors observed a 80% increased risk related to hypertensive disorder in pregnancy (HDP) (gestational hypertension [GH], preeclampsia, or eclampsia) (RR=1.80 (95% CI, 1.49-2.18). They also observed an association between hemorrhagic stroke and late menopause (RR= 2.24 (95% CI, 1.19-4.21) in women with menopause > 55 years vs 50 to 54 years, an increased risk with Gestational diabetes (RR= 5.08 (95% CI, 1.80-14.34), with oophorectomy vs no oophorectomy (RR of any stroke=1.42 (95% CI, 1.34-1.50), a reduced risk after hysterectomy vs no hysterectomy  (0.88 (95% CI, 0.85-0.90). The pooled relative risk of stroke mortality was 1.57 (95% CI, 1.04-2.39) after GH vs no GH.

Another interesting paper was published by Thurston et al (Stroke. 2016 Nov 10. pii: STROKEAHA.116.014674. [Epub ahead of print] Menopausal Hot Flashes and Carotid Intima Media Thickness Among Midlife Women.
These authors tested whether hot flashes, measured via state-of-the-art physiologic methods, were associated with greater subclinical atherosclerosis as assessed by carotid ultrasound.
A total of 295 nonsmoking women free of clinical CVD underwent ambulatory physiologic hot flash assessments were assessed.
The authors observed that more frequent physiologic hot flashes were associated with higher carotid intima media thickness and plaque among women reporting daily hot flashes; associations were not accounted for by CVD risk factors or by estradiol. Among women reporting hot flashes, hot flashes accounted for more variance in intima media thickness than most CVD risk factors.
These authors concluded that among women reporting daily hot flashes, frequent hot flashes may provide information about a woman's vascular status beyond standard CVD risk factors and estradiol. Frequent hot flashes may mark a vulnerable vascular phenotype among midlife women.
Finally, we want to draw the attention of our community of readers towards a review article published by R. Lobo in Nat Rev Endocrinol. (2016 Oct 7. doi: 10.1038/nrendo.2016.164. [Epub ahead of print] Hormone-replacement therapy: current thinking.) debating the role of hormone-replacement therapy (HRT) and coronary heart disease (CHD).
Contributed by Serge Rozenberg
References
Poorthuis and al. Female- and Male-Specific Risk Factors for Stroke: A Systematic Review and Meta-analysis. (JAMA Neurol. 2016 Nov 14. doi: 10.1001/jamaneurol.2016.3482.)
2. Thurston et al (Stroke. 2016 Nov 10. pii: STROKEAHA.116.014674. [Epub ahead of print] Menopausal Hot Flashes and Carotid Intima Media Thickness Among Midlife Women.
 R. Lobo in Nat Rev Endocrinol. (2016 Oct 7. doi: 10.1038/nrendo.2016.164. [Epub ahead of print] Hormone-replacement therapy: current thinking.) 


N° 823 Topic: Breast-Cancer Tumor Size, Overdiagnosis, and Mammography Screening Effectiveness
H. Gilbert Welch, et al N Engl J Med 2016; 375:1438-1447October 13, 2016DOI: 10.1056/NEJMoa1600249 used data from the Surveillance, Epidemiology, and End Results (SEER) program, 1975 through 2012, to calculate the tumor-size distribution and size-specific incidence of breast cancer among women 40 years of age or older. They then calculated the size-specific cancer case fatality rate for two time periods: a baseline period before the implementation of widespread screening mammography (1975 through 1979) and a period encompassing the most recent years for which 10 years of follow-up data were available (2000 through 2002).
Results
After the advent of screening mammography, the proportion of detected breast tumors that were small (invasive tumors measuring <2 cm or in situ carcinomas) increased from 36% to 68%; the proportion of detected tumors that were large (invasive tumors measuring ≥2 cm) decreased from 64% to 32%. However, this trend was less the result of a substantial decrease in the incidence of large tumors (with 30 fewer cases of cancer observed per 100,000 women in the period after the advent of screening than in the period before screening) and more the result of a substantial increase in the detection of small tumors (with 162 more cases of cancer observed per 100,000 women). Assuming that the underlying disease burden was stable, only 30 of the 162 additional small tumors per 100,000 women that were diagnosed were expected to progress to become large, which implied that the remaining 132 cases of cancer per 100,000 women were overdiagnosed (i.e., cases of cancer were detected on screening that never would have led to clinical symptoms). The potential of screening to lower breast cancer mortality is reflected in the declining incidence of larger tumors. However, with respect to only these large tumors, the decline in the size-specific case fatality rate suggests that improved treatment was responsible for at least two thirds of the reduction in breast cancer mortality.
Conclusions
Although the rate of detection of large tumors fell after the introduction of screening mammography, the more favorable size distribution was primarily the result of the additional detection of small tumors. Women were more likely to have breast cancer that was overdiagnosed than to have earlier detection of a tumor that was destined to become large. The reduction in breast cancer mortality after the implementation of screening mammography was predominantly the result of improved systemic therapy.

N° 822 Topic: Adjunctive Azithromycin Prophylaxis for Cesarean Delivery
Alan T.N. Tita, et al for the C/SOAP Trial Consortium*
N Engl J Med 2016; 375:1231-1241September 29, 2016DOI: 10.1056/NEJMoa1602044 evaluated the addition of azithromycin to standard regimens for antibiotic prophylaxis before cesarean delivery to reduce the rate of postoperative infection.
The trial included 2013 women who had a singleton pregnancy with a gestation of 24 weeks or more and who were undergoing cesarean delivery during labor or after membrane rupture. Women were randomly assigned to receive 500 mg of intravenous azithromycin and 994 to receive placebo. All the women were also scheduled to receive standard antibiotic prophylaxis. The primary outcome was a composite of endometritis, wound infection, or other infection occurring within 6 weeks.
The primary outcome occurred in 62 women (6.1%) who received azithromycin and in 119 (12.0%) who received placebo (RR  0.51; 95% CI 0.38 to 0.68; P<0.001).

N° 821 Topic: Romosozumab Treatment in Postmenopausal Women with Osteoporosis
Romosozumab, a monoclonal antibody that binds sclerostin, increases bone formation and decreases bone resorption. 7180 postmenopausal women who had a T score of –2.5 to –3.5 at the total hip or femoral neck were enrolled and randomized to receive subcutaneous injections of romosozumab (at a dose of 210 mg) or placebo monthly for 12 months; thereafter, patients in each group received denosumab for 12 months, at a dose of 60 mg, administered subcutaneously every 6 months. At 12 months, new vertebral fractures had occurred in 16 of 3321 patients (0.5%) in the romosozumab group, as compared with 59 of 3322 (1.8%) in the placebo group (representing a 73% lower risk with romosozumab; P<0.001). Clinical fractures had occurred in 58 of 3589 patients (1.6%) in the romosozumab group, as compared with 90 of 3591 (2.5%) in the placebo group (a 36% lower risk with romosozumab; P=0.008). Nonvertebral fractures had occurred in 56 of 3589 patients (1.6%) in the romosozumab group and in 75 of 3591 (2.1%) in the placebo group (P=0.10). At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3325 patients] in the romosozumab group vs. 2.5% [84 of 3327] in the placebo group, a 75% lower risk with romosozumab; P<0.001). Adverse events, including instances of hyperostosis, cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and two cases of osteonecrosis of the jaw were observed in the romosozumab group.
CONCLUSIONS In postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months. The lower risk of clinical fracture that was seen with romosozumab was evident at 1 year.


N° 820 Topic: Association of Age at Onset of Menopause and Time Since Onset of Menopause With Cardiovascular Outcomes, Intermediate Vascular Traits, and All-Cause Mortality: A Systematic Review and Meta-analysis.

Muka T et al JAMA Cardiol. 2016 Sep 14. doi: 10.1001/jamacardio.2016.2415. [Epub ahead of print] conducted a systematical review and meta-analyze studies evaluating the effect of age at onset of menopause and duration since onset of menopause on intermediate CVD end points, CVD outcomes, and all-cause mortality.

Of the initially identified references, 32 studies were selected that included 310 329 non-overlapping women. Outcomes were compared between women who experienced menopause younger than 45 years and women 45 years or older at onset;

the RR (95% CIs) were 1.50 (1.28-1.76) for overall CHD, 1.11 (1.03-1.20) for fatal CHD, 1.23 (0.98-1.53) for overall stroke, 0.99 (0.92-1.07) for stroke mortality, 1.19 (1.08-1.31) for CVD mortality, and 1.12 (1.03-1.21) for all-cause mortality.

Outcomes were also compared between women between 50 and 54 years at onset of menopause and women younger than 50 years at onset; there was a decreased risk of fatal CHD (relative risk, 0.87; 95% CI, 0.80-0.96) and no effect on stroke.

Time since onset of menopause in relation to risk of developing intermediate cardiovascular traits or CVD outcomes was reported in 4 observational studies with inconsistent results.
Conclusions and Relevance:

The findings of this review indicate a higher risk of CHD, CVD mortality, and overall mortality in women who experience premature or early-onset menopause.


N° 819 Topic: 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer
Fatima Cardoso, M.D., Laura J. van’t Veer, Ph.D., Jan Bogaerts, Ph.D., Leen Slaets, Ph.D., Giuseppe Viale, M.D., Suzette Delaloge, M.D., Jean-Yves Pierga, M.D., Ph.D., Etienne Brain, M.D., Ph.D., Sylvain Causeret, M.D., Mauro DeLorenzi, Ph.D., Annuska M. Glas, Ph.D., Vassilis Golfinopoulos, M.D., Ph.D., Theodora Goulioti, M.D., Susan Knox, M.A., Erika Matos, M.D., Bart Meulemans, M.Sc., Peter A. Neijenhuis, M.D., Ulrike Nitz, M.D., Ph.D., Rodolfo Passalacqua, M.D., Peter Ravdin, M.D., Isabel T. Rubio, M.D., Mahasti Saghatchian, M.D., Tineke J. Smilde, M.D., Ph.D., Christos Sotiriou, M.D., Ph.D., Lisette Stork, M.Sc., Carolyn Straehle, Ph.D., Geraldine Thomas, Ph.D., Alastair M. Thompson, M.D., Jacobus M. van der Hoeven, M.D., Ph.D., Peter Vuylsteke, M.D., René Bernards, Ph.D., Konstantinos Tryfonidis, M.D., Emiel Rutgers, M.D., Ph.D., and Martine Piccart, M.D., Ph.D., for the MINDACT Investigators* (N Engl J Med 2016; 375:717-729August 25, 2016DOI: 10.1056/NEJMoa1602253)
Background
The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer.
They sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical–pathological criteria in selecting patients for adjuvant chemotherapy.
Methods
In this randomized, phase 3 study, they enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher.
Results
A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor–positive, human epidermal growth factor receptor 2–negative, and either node-negative or node-positive disease.
Conclusions
Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy.

N° 818 Topic: Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years
Treatment with an aromatase inhibitor for 5 years as up-front monotherapy or after tamoxifen therapy is the treatment of choice for hormone-receptor–positive early breast cancer in postmenopausal women. Extending treatment with an aromatase inhibitor to 10 years may further reduce the risk of breast-cancer recurrence.
Paul E. Goss, et al (N Engl J Med 2016; 375:209-219July 21, 2016DOI: 10.1056/NEJMoa1604700) published the results of a double-blind, placebo-controlled trial, involving 1918 women, to assess the effect of the extended use of letrozole for an additional 5 years, evaluating disease-free survival.. After a median follow-up of 6.3 years, there were 165 events involving disease recurrence or the occurrence of contralateral breast cancer (67 with letrozole and 98 with placebo) and 200 deaths (100 in each group). The 5-year disease-free survival rate was 95% (95% [CI], 93 to 96) with letrozole and 91% (95% CI; 89 to 93) with placebo (HR, 0.66; P=0.01). The rate of 5-year overall survival was not different. The annual incidence rate of contralateral breast cancer in the letrozole group was 0.21% (95% CI, 0.10 to 0.32), and the rate in the placebo group was 0.49% (95% CI, 0.32 to 0.67) (HR, 0.42; P=0.007). Bone-related toxic effects occurred more frequently among patients receiving letrozole than among those receiving placebo, including a higher incidence of bone pain, bone fractures, and new-onset osteoporosis. No significant differences between letrozole and placebo were observed in scores on most subscales measuring quality of life.
Conclusions
The extension of treatment with an adjuvant aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than those with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo.


N° 817 Topic: Danazol Treatment for Telomere Diseases
BACKGROUND
Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene. Danielle M. Townsley et al (N Engl J Med 2016; 374:1922-1931May 19, 2016DOI: 10.1056/NEJMoa1515319) administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months in a phase 1–2 prospective study involving patients with telomere diseases. The goal of treatment was the attenuation of accelerated telomere attrition, After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol — elevated liver-enzyme levels and muscle cramps — of grade 2 or less occurred in 41% and 33% of the patients, respectively.
CONCLUSIONS
In this study, treatment with danazol led to telomere elongation in patients with telomere diseases.


N° 816 Topic: Dietary Patterns and Fractures in Postmenopausal Women Results From the Women’s Health Initiative
Bernhard Haring, et al
JAMA Intern Med. Published online March 28, 2016. doi:10.1001/jamainternmed.2016.0482
A Post hoc analysis was conducted of longitudinal data from the Women’s Health Initiative (WHI) observational study. Participants included 93 676 women who were eligible for the WHI if they were aged 50 to 79 years. The WHI food frequency questionnaire was used to derive nutrient and food intake at baseline. Diet quality and adherence were assessed by scores on the alternate Mediterranean Diet (aMED), a 9-category measure of adherence to a Mediterranean dietary pattern; the Healthy Eating Index 2010 (HEI-2010), a 100-point measure of 12 food components; the 11-item Alternate Healthy Eating Index 2010 (AHEI-2010); or the 8-component Dietary Approaches to Stop Hypertension (DASH) diet score.
Of the 93 676 participants, 90 014 were included in the analysis (mean [SD] age, 63.6 [7.4]) years. During a median follow-up time of 15.9 years, there were 2121 cases of hip fractures and 28 718 cases of total fractures. Women scoring in the highest quintile (Q5) of the aMED index had a lower risk for hip fractures (HR, 0.80; 95% CI, 0.66-0.97), with an absolute risk reduction of 0.29% and a number needed to treat of 342 (95% CI, 249-502). No association between the aMED score and total fractures was observed (Q5 HR, 1.01; 95% CI, 0.95-1.07). Higher HEI-2010 or DASH scores tended to be inversely related to hip fracture risk, but the results were nonsignificant (Q5 HR, 0.87; 95% CI, 0.75-1.02; and Q5 HR, 0.89; 95% CI, 0.75-1.06, respectively). The AHEI-2010 score was associated with neither hip nor total fractures.

N° 815 Topic: Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol
Howard N. Hodis et al report the ¡°Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol¡±( N Engl J Med 2016; 374:1221-1231March 31, 2016DOI: 10.1056/NEJMoa1505241). A total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ¡Ý10 years [late postmenopause]) and were randomly assigned to receive either oral 17ŠÂ-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intimašCmedia thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen.
Results: After a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P=0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P=0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P=0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum.
Conclusions
Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum.



N° 814 Topic: Active commuting and obesity in mid-life: cross-sectional, observational evidence from UK Biobank
E Flint &S Cummins, (Lancet http://dx.doi.org/10.1016/S2213-8587(16)00053-X) examined the relation between active commuting and obesity in mid-life using objectively measured anthropometric data a Cross-sectional, observational study in the UK. Final complete case sample sizes were 72 999 men and 83 667 women for the BMI outcome and 72 139 men and 82 788 women for the percentage body fat outcome. Active commuting was significantly and independently associated with reduced BMI and percentage body fat for both sexes, with a graded pattern apparent across the seven commuting categories. In fully adjusted models, compared with their car-only counterparts, mixed public and active transport commuters had significantly lower BMI and lower percentage body fat.
These findings support the case for interventions to promote active travel as a population-level policy response for prevention of obesity in mid-life.


N° 813 Topic: A Randomized Trial of a Cervical Pessary to Prevent Preterm Singleton Birth
Kypros H. Nicolaides, et al (N Engl J Med 2016; 374:1044-1052March 17, 2016DOI: 10.1056/NEJMoa1511014) conducted a multicenter, randomized, controlled trial comparing pessary placement with expectant management (control) in girls and women who were pregnant with singletons (singleton pregnancies) and who had a cervical length of 25 mm or less at 20 weeks 0 days to 24 weeks 6 days of gestation. Participants in either group who had a cervical length of 15 mm or less, at randomization or at subsequent visits, received treatment with vaginal progesterone. The primary outcome was spontaneous delivery before 34 weeks of gestation. In an intention-to-treat analysis, there was no significant difference between the pessary group (465 participants) and the control group (467 participants) in the rate of spontaneous delivery before 34 weeks (12.0% and 10.8%, respectively; OR in the pessary group, 1.12; 95%CI, 0.75 to 1.69; P=0.57). There were no significant differences in the rates of perinatal death (3.2% in the pessary group and 2.4% in the control group, P=0.42), adverse neonatal outcome (6.7% and 5.7%, respectively; P=0.55), or neonatal special care (11.6% and 12.9%, respectively; P=0.59). The incidence of new or increased vaginal discharge was significantly higher in the pessary group than in the control group.


N° 812 Topic: A Randomized Trial of a Cervical Pessary to Prevent Preterm Singleton Birth
JoAnn E. Manson and Andrew M. Kaunitz report in a paper entitled “PERSPECTIVE of Menopause Management — Getting Clinical Care Back on Track” (NEJM 3.3.16) that the use of systemic hormone therapy has decreased by as much as 80% among U.S. women since the initial findings of the WHI in 2002, leading to anxiety and confusion. The results of this trial are being used inappropriately in making decisions about treatment for women in their 40s and 50s who have distressing vasomotor symptoms. Moreover, the new generation of medical graduates and primary care providers often lacks training and competence in management of menopausal patients.





N° 811 Topic: The ACOG Committee Opinion about the Use of Vaginal Estrogen in Women With a History of Estrogen-Dependent Breast Cancer
The ACOG Committee Opinion about the Use of Vaginal Estrogen in Women With a History of Estrogen-Dependent Breast Cancer has been published (Obstet Gynecol. 2016 Mar;127(3):e93-6. doi: 10.1097/AOG.0000000000001351.)
They suggest to use first nonhormonal approaches, vaginal estrogen should be reserved for those patients who are unresponsive to nonhormonal remedies. The decision to use vaginal estrogen may be made in coordination with a woman's oncologist. Additionally, it should be preceded by an informed decision-making and consent process in which the woman has the information and resources to consider the benefits and potential risks of low-dose vaginal estrogen.
They write, however, that data do not show an increased risk of cancer recurrence among women currently undergoing treatment for breast cancer or those with a personal history of breast cancer who use vaginal estrogen to relieve urogenital symptoms.

N° 810 Topic: The ACOG Committee Opinion about the Use of Vaginal Estrogen in Women With a History of Estrogen-Dependent Breast Cancer
Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial
Jane Elizabeth Norman for the OPPTIMUM study group
DOI: http://dx.doi.org/10.1016/S0140-6736(16)00350-0
did a double-blind, randomised, placebo-controlled trial of vaginal progesterone, 200 mg daily taken from 22šC24 to 34 weeks of gestation, on pregnancy and infant outcomes in women at risk of preterm birth (because of previous spontaneous birth at ¡Ü34 weeks and 0 days of gestation, or a cervical length ¡Ü25 mm, or because of a positive fetal fibronectin test combined with other clinical risk factors for preterm birth [any one of a history in a previous pregnancy of preterm birth, second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical procedure to treat abnormal smears]).
The objective of the study was to determine whether vaginal progesterone prophylaxis given to reduce the risk of preterm birth affects neonatal and childhood outcomes.
They randomly assigned 1228 women to the placebo group (n=610) and the progesterone group (n=618). After correction for multiple outcomes, progesterone had no significant effect on the primary obstetric outcome (OR adjusted for multiple comparisons 0,86, 95% CI 0,61šC1,22) or neonatal outcome (OR 0,62, 0,38šC1,03), nor on the childhood outcome Maternal or child serious adverse events were reported in 70 (11%) of 610 patients in the placebo group and 59 (10%) of 616 patients in the progesterone group (p=0¡€27).
Interpretation
Vaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age.


N° 809 Topic: PERSPECTIVE of Menopause Management — Getting Clinical Care Back on Track
Jiangrong Wang, et al (BMJ 2016; 352 doi: http://dx.doi.org/10.1136/bmj.i276 (Published 11 February 2016) Cite this as: BMJ 2016;352:i276) investigated the risks of invasive cervical cancer after detection of atypical glandular cells (AGC) during cervical screening using a Nationwide population based cohort study in Sweden between 1 January 1980 and 1 July 2011 who had any record of cervical cytological testing at ages 23-59. They found that the prevalence of cervical cancer was 1.4% for women with AGC, which was lower than for women with HSIL (2.5%) but higher than for women with LSIL (0.2%); adenocarcinoma accounted for 73.2% of the prevalent cases associated with AGC. The incidence rate of invasive cervical cancer after AGC was significantly higher than for women with normal results on cytology for up to 15.5 years and higher than HSIL and LSIL for up to 6.5 years. The incidence rate of adenocarcinoma was 61 times higher than for women with normal results on cytology in the first screening round after AGC, and remained nine times higher for up to 15.5 years. Incidence and prevalence of invasive cervical cancer was highest when AGC was found at ages 30-39. Only 54% of women with AGC underwent histology assessment within six months, much less than after HSIL (86%). Among women with histology assessment within six months, the incidence rate of cervical cancer after AGC was significantly higher than that after HSIL for up to 6.5 years.
Conclusions AGC found at cervical screening is associated with a high and persistent risk of cervical cancer for up to 15 years, particularly for cervical adenocarcinoma and women with AGC at age 30-39. Compared with the reduction in risk of cancer seen after HSIL management, management of AGC seems to have been suboptimal in preventing cervical cancer. Research to optimise management is needed, and a more aggressive assessment strategy is warranted.

N° 808 Topic: Predicting the risk of malignancy in adnexal masses based on the Simple Rules from the International Ovarian Tumor Analysis (IOTA) group
Accurate methods to preoperatively characterize adnexal tumors are pivotal for optimal patient management. A recent meta-analysis concluded that the International Ovarian Tumor Analysis (IOTA) algorithms such as the Simple Rules are the best approaches to preoperatively classify adnexal masses as benign or malignant.
Dirk Timmerman et al (2016) (DOI: http://dx.doi.org/10.1016/j.ajog.2016.01.007 article in press) developed and validated a model to predict the risk of malignancy in adnexal masses using the ultrasound features in the Simple Rules using International cross-sectional cohort study involving 22 oncology centers, They included consecutive patients with an adnexal tumor who underwent a standardized transvaginal ultrasound examination and were selected for surgery. Data on 5020 patients were recorded in three phases between 2002 and 2012. The five Simple Rules features indicative of a benign tumor (B-features) and the five features indicative of malignancy (M-features) are based on the presence of ascites, tumor morphology, and degree of vascularity at ultrasonography. Gold standard was the histopathologic diagnosis of the adnexal mass (pathologist blinded to ultrasound findings). Logistic regression analysis was used to estimate the risk of malignancy based on the ten ultrasound features and type of center. The diagnostic performance was evaluated by area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive and negative likelihood ratios (LR+, LR-), positive and negative predictive values (PPV, NPV) and calibration curves.
Results
Data on 4848 patients were analyzed. The malignancy rate was 43% (1402/3263) in oncology centers and 17% (263/1585) in other centers. The AUC on validation data was very similar in oncology centers (0.917, 95% CI 0.901 to 0.931) and other centers (0.916, 95% CI 0.873 to 0.945). Risk estimates showed good calibration. 23% of patients in the validation data set had a very low estimated risk (<1%), 48% had a high estimated risk (≥30%). For the 1% risk cutoff, sensitivity was 99.7%, specificity 33.7%, LR+ 1.5, LR- 0.010, PPV 44.8% and NPV 98.9%. For the 30% risk cutoff, sensitivity was 89.0%, specificity 84.7%, LR+ 5.8, LR- 0.13, PPV 75.4% and NPV 93.9%.
Conclusion
Quantification of the risk of malignancy based on the Simple Rules has good diagnostic performance both in oncology centers and other centers. A simple classification based on these risk estimates may form the basis of a clinical management system. Patients with a high risk may benefit from surgery by a gynecological oncologist, while patients with a lower risk may be managed locally.


N° 807 Topic: A novel intravaginal ring to prevent HIV-1, HSV-2, HPV, and unintended pregnancy.
Ugaonkar SR et al ( J Control Release. 2015 Jun 17;213:57-68. doi: 10.1016/j.jconrel.2015.06.018. [Epub ahead of print]) described a novel core-matrix intravaginal ring (IVR), the MZCL IVR. The results demonstrated proof-of-concept of a novel core-matrix IVR for sustained and simultaneous delivery of diverse molecules for the prevention of HIV, HSV-2 and HPV acquisition, as well as unintended pregnancy.

N° 806 Topic: Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus
Argyro Syngelaki, et al (N Engl J Med 2016; 374:434-443February 4, 2016DOI: 10.1056/NEJMoa1509819) randomized in this double-blind, placebo-controlled trial, ipregnant women with a BMI of more than 35 to receive metformin, (3.0 g per day, or placebo (225 women in each group) from 12 to 18 weeks of gestation until delivery. There was no significant between-group difference in the median neonatal birth-weight z score . The median maternal gestational weight gain was lower in the metformin group than in the placebo group (4.6 kg [interquartile range, 1.3 to 7.2] vs. 6.3 kg [interquartile range, 2.9 to 9.2], P<0.001), as was the incidence of preeclampsia (3.0% vs. 11.3%; OR, 0.24; 95%CI, 0.10 to 0.61; P=0.001). The incidence of side effects was higher in the metformin group than in the placebo group. There were no significant between-group differences in the incidence of gestational diabetes, large-for-gestational-age neonates, or adverse neonatal outcomes.
Conclusions
Among women without diabetes who had a BMI of more than 35, the antenatal administration of metformin reduced maternal weight gain but not neonatal birth weight.


N° 805 Topic: Acupuncture for Menopausal Hot Flashes: A Randomized Trial
Carolyn Ee, et al (Ann Intern Med. Published online 19 January 2016 doi:10.7326/M15-1380) assessed the efficacy of Chinese medicine acupuncture against sham acupuncture for menopausal HFs in a stratified, blind (participants, outcome assessors, and investigators, but not treating acupuncturists), parallel, randomized, sham-controlled trial with equal allocation in women, meeting criteria for Chinese medicine diagnosis of kidney yin deficiency. 327 women older than 40 years in the late menopausal transition or postmenopause with at least 7 moderate HFs daily, were randomly assigned to acupuncture (n = 163) or sham acupuncture (n = 164) and treated for 8 weeks (10 sessions). At the end of treatment, 16% of participants in the acupuncture group and 13% in the sham group were lost to follow-up. Mean HF scores at the end of treatment were 15.36 in the acupuncture group and 15.04 in the sham group (mean difference, 0.33 [95% CI, −1.87 to 2.52]; P = 0.77). No serious adverse events were reported.

Conclusion: Chinese medicine acupuncture was not superior to noninsertive sham acupuncture for women with moderately severe menopausal HFs.

N° 804 Topic: Maternal Immunization With an Investigational Trivalent Group B Streptococcal Vaccine: A Randomized Controlled Trial.

Donders, Gilbert et al (Obstetrics & Gynecology:
Post Author Corrections: January 07, 2016
doi: 10.1097/AOG.0000000000001190) evaluated the safety and immunogenicity of an investigational trivalent group B streptococcal vaccine in pregnant women and antibody transfer to their newborns using an observer-blind, randomized study.

Published Ahead-of-Print

From September 2011 to October 2013, 86 pregnant women were allocated in a 3:2 ratio to receive an investigational group B streptococcal vaccine containing glycoconjugates of serotypes Ia, Ib, and III or placebo. Demographics were similar across groups. Transfer ratios were 66-79% and maternal geometric mean concentrations increased 16-, 23-, and 20-fold by delivery against serotypes Ia, Ib, and III, respectively, Women with no detectable antibodies at inclusion had lower responses than those with detectable antibodies. Three months after birth, infant antibody concentrations were 22-25% of birth levels. Antidiphtheria geometric mean concentrations were similar across groups. In the vaccine and placebo groups, 32 of 51 women (63%) and 26 of 35 women (74%) reported adverse effects, respectively.

CONCLUSION: The investigational vaccine was well-tolerated without safety signals in recipients and their infants or interference with routine infant diphtheria vaccination, although further studies on safety and effectiveness are needed. The investigational vaccine was immunogenic for all serotypes, particularly among women with detectable antibody levels at baseline. Antibody transfer to neonates was at similar levels to other maternally administered polysaccharide vaccines.

N° 803 Topic: Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia
The ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is elevated in pregnant women before the clinical onset of preeclampsia, but its predictive value in women with suspected preeclampsia is unclear.

Harald Zeisler, et al (N Engl J Med 2016; 374:13-22January 7, 2016DOI: 10.1056/NEJMoa1414838) performed a prospective, multicenter, observational study to derive and validate a ratio of serum sFlt-1 to PlGF that would be predictive of the absence or presence of preeclampsia in the short term in women with singleton pregnancies in whom preeclampsia was suspected (24 weeks 0 days - 36 weeks 6 days).

In the development cohort (500 women), theyidentified an sFlt-1:PlGF ratio cutoff of 38 as having important predictive value. In a subsequent validation study among an additional 550 women, an sFlt-1:PlGF ratio of 38 or lower had a negative predictive value (i.e., no preeclampsia in the subsequent week) of 99.3% (95%CI, 97.9-99.9), with 80.0% sensitivity (95% CI, 51.9- 95.7) and 78.3% specificity (95% CI, 74.6- 81.7). The positive predictive value of an sFlt-1:PlGF ratio above 38 for a diagnosis of preeclampsia within 4 weeks was 36.7% (95% CI, 28.4 to 45.7), with 66.2% sensitivity (95% CI, 54.0 to 77.0) and 83.1% specificity (95% CI, 79.4 to 86.3).

Conclusions

An sFlt-1:PlGF ratio of 38 or lower can be used to predict the short-term absence of preeclampsia in women in whom the syndrome is suspected clinically.

N° 802 Topic: Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth
Ditte Mølgaard-Nielsen, et al (JAMA. 2016;315(1):58-67. doi:10.1001/jama.2015.17844) studied the association between oral fluconazole exposure during pregnancy and the risk of spontaneous abortion and stillbirth using nationwide register-based cohort in Denmark (n=1 405 663 pregnancies), oral fluconazole–exposed pregnancies were compared with up to 4 unexposed pregnancies matched on propensity score, maternal age, calendar year, and gestational age (based on gestational age at first day of treatment with eligible controls surviving through this date). To test for confounding by indication, pregnancies exposed to intravaginal formulations of topical azoles were used as an additional comparator group. Among 3315 women exposed to oral fluconazole from 7 through 22 weeks’ gestation, 147 experienced a spontaneous abortion, compared with 563 among 13 246 unexposed matched women. There was a significantly increased risk of spontaneous abortion associated with fluconazole exposure (HR, 1.48; 95% CI, 1.23-1.77). Among 5382 women exposed to fluconazole from gestational week 7 to birth, 21 experienced a stillbirth, compared with 77 among 21 506 unexposed matched women. There was no significant association between fluconazole exposure and stillbirth (HR, 1.32 [95% CI, 0.82-2.14]). Using topical azole exposure as the comparison, 130 of 2823 women exposed to fluconazole vs 118 of 2823 exposed to topical azoles had a spontaneous abortion (HR, 1.62 [95% CI, 1.26-2.07]); 20 of 4301 women exposed to fluconazole vs 22 of 4301 exposed to topical azoles had a stillbirth (HR, 1.18 [95% CI, 0.64-2.16]).
Conclusions and Relevance In this nationwide cohort study in Denmark, use of oral fluconazole in pregnancy was associated with a statistically significant increased risk of spontaneous abortion compared with risk among unexposed women and women with topical azole exposure in pregnancy. Until more data on the association are available, cautious prescribing of fluconazole in pregnancy may be advisable. Although the risk of stillbirth was not significantly increased, this outcome should be investigated further.

N° 801 Topic: Ovarian Suppression With Triptorelin During Adjuvant Breast Cancer Chemotherapy and Long-term Ovarian Function, Pregnancies, and Disease-Free Survival: A RCT
Matteo Lambertini, et al; for the GIM Study Group (JAMA. 2015;314(24):2632-2640. doi:10.1001/jama.2015.17291) evaluated long-term results of LHRHa-induced ovarian suppression during breast cancer chemotherapy in premenopausal women with stage I to III hormone receptor–positive or hormone receptor–negative breast cancer . Patients were randomized to receive adjuvant or neoadjuvant chemotherapy alone (control group) or chemotherapy plus triptorelin (LHRHa group).
A total of 281 women (median age, 39 [range, 24-45] years) were randomized. Median follow-up was 7.3 years (interquartile range, 6.3-8.2 years). The 5-year cumulative incidence estimate of menstrual resumption was 72.6% (95% CI, 65.7%-80.3%) among the 148 patients in the LHRHa group and 64.0% (95% CI, 56.2%-72.8%) among the 133 patients in the control group (hazard ratio [HR], 1.28 [95% CI, 0.98-1.68]; P = .07; age-adjusted HR, 1.48 [95% CI, 1.12-1.95]; P = .006). Eight pregnancies (5-year cumulative incidence estimate of pregnancy, 2.1% [95% CI, 0.7%-6.3%]) occurred in the LHRHa group and 3 (5-year cumulative incidence estimate of pregnancy, 1.6% [95% CI, 0.4%-6.2%]) in the control group (HR, 2.56 [95% CI, 0.68-9.60]; P = .14; age-adjusted HR, 2.40 [95% CI, 0.62-9.22]; P = .20). Five-year DFS was 80.5% (95% CI, 73.1%-86.1%) in the LHRHa group and 83.7% (95% CI, 76.1%-89.1%) in the control group (LHRHa vs control: HR, 1.17 [95% CI, 0.72-1.92]; P = .52).

Conclusions and Relevance Among premenopausal women with either hormone receptor–positive or hormone receptor–negative breast cancer, concurrent administration of triptorelin and chemotherapy, compared with chemotherapy alone, was associated with higher long-term probability of ovarian function recovery, without a statistically significant difference in pregnancy rate. There was no statistically significant difference in DFS for women assigned to triptorelin and those assigned to chemotherapy alone, although study power was limited.


N° 800 Topic: Azithromycin versus Doxycycline for Urogenital Chlamydia trachomatis Infection
William M. Geisler et al N Engl J Med 2015; 373:2512-2521December 24, 2015DOI: 10.1056/NEJMoa1502599

Urogenital Chlamydia trachomatis infection remains prevalent and causes substantial reproductive morbidity. Recent studies have raised concern about the efficacy of azithromycin for the treatment of chlamydia infection.

The authors conducted a RCT (n=567) using oral azithromycin vs doxycycline for the treatment of urogenital chlamydia infection among adolescents in youth correctional facilities, to evaluate the noninferiority of azithromycin (1 g in one dose) to doxycycline (100 mg twice daily for 7 days). The primary end point was treatment failure at 28 days after treatment initiation, with treatment failure determined on the basis of nucleic acid amplification testing, sexual history, and outer membrane protein A (OmpA) genotyping of C. trachomatis strains.

There were no treatment failures in the doxycycline group. In the azithromycin group, treatment failure occurred in 5 participants (3.2%; 95% CI, 0.4 - 7.4%). The observed difference in failure rates between the treatment groups was 3.2 % points, with an upper boundary of the 90%CI of 5.9 % points, which exceeded the prespecified absolute 5-%-point cutoff for establishing the noninferiority of azithromycin.

Conclusions
In the context of a closed population receiving directly observed treatment for urogenital chlamydia infection, the efficacy of azithromycin was 97%, and the efficacy of doxycycline was 100%. The noninferiority of azithromycin was not established in this setting.


N° 799 Topic: Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial
Prof Ian J Jacobs et al (Lancet Published Online: 17 December 2015) designed a trial (n=202 638) women to establish the effect of early detection by screening on ovarian cancer mortality. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The RCT randomly allocated participants to annual multimodal screening (MMS) (n=50 640; 25·0%) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS, n=50 639; 25·0%)), or no screening, (101 359 ; 50·0%). The primary outcome was death due to ovarian cancer.
they diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer.
The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0–14 of 15% (95% CI −3 to 30; p=0·10) with MMS and 11% (−7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (−20 to 31) in years 0–7 and 23% (1–46) in years 7–14, and in the USS group, of 2% (−27 to 26) in years 0–7 and 21% (−2 to 42) in years 7–14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (−2 to 40) and a reduction of 8% (−27 to 43) in years 0–7 and 28% (−3 to 49) in years 7–14 in favour of MMS.
Interpretation
Although the mortality reduction was not significant in the primary analysis, they noted a significant mortality reduction with MMS when prevalent cases were excluded. The authors noted encouraging evidence of a mortality reduction in years 7–14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening.


N° 798 Topic: Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial
Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). JF Forbes et al on behalf of the IBIS-II investigators (Lancet 14.12.15 DOI: http://dx.doi.org/10.1016/S0140-6736(15)01129-0) compared the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS using a double-blind, multicentre, RCT (n=2980 postmenopausal women. Median follow-up was 7·2 years (IQR 5·6–8·9), and 144 breast cancer recurrences were recorded. There were no statistically significant differences in overall recurrence, deaths, adverse events: the side-effect profiles of the two drugs differed, with more fractures, musculoskeletal events, hypercholesterolaemia, and strokes with anastrozole and more muscle spasm, gynaecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses with tamoxifen.

N° 797 Topic: A Randomized Trial of Progesterone in Women with Recurrent Miscarriages
Arri Coomarasamy et al N Engl J Med 2015; 373:2141-2148November 26, 2015DOI: 10.1056/NEJMoa1504927 conducted a RCT (n=836 women) to investigate whether treatment with progesterone (2 X daily vaginal suppositories 400 mg micronized progesterone vs placebo) would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage, starting from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation. In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (RR, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 %; 95% CI, −4.0 to 9.0). There were no significant between-group differences in the rate of adverse events.

N° 796 Topic: Breast Cancer
Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial (Lancet 4/11/15 http://dx.doi.org/10.1016/S0140-6736(15)00774-6)

Noriaki Ohuchi, et al for the J-START investigator groups investigated the efficacy of adjunctive ultrasonography with
mammography for breast cancer screening in 72 998 young women or women aged 40–49 years at 42 study sites in Japan. Eligible women had no history of any cancer in the previous 5 years and were expected to live for more than 5 years. Participants were randomly assigned in 1:1 ratio to undergo mammography and ultrasonography (intervention group) or mammography alone (control group) twice in 2 years. The primary outcome was sensitivity, specificity, cancer detection rate, and stage distribution at the first round of screening. Analysis was by intention to treat.

Sensitivity was significantly higher in the intervention group than in the control group (91·1%, 95% CI 87·2–95·0 vs 77·0%, 70·3–83·7; p=0·0004), whereas specificity was significantly lower (87·7%, 87·3–88·0 vs 91·4%, 91·1–91·7; p<0·0001). More cancers were detected in the intervention group than in the control group (184 [0·50%] vs 117 [0·32%], p=0·0003) and were more frequently stage 0 and I (144 [71·3%] vs 79 [52·0%], p=0·0194). 18 (0·05%) interval cancers were detected in the intervention group compared with 35 (0·10%) in the control group (p=0·034).

Interpretation
Adjunctive ultrasonography increases sensitivity and detection rate of early cancers.


N° 795 Topic: Breast Cancer
Prospective Validation of a 21-Gene Expression Assay in Breast Cancer
Joseph A. Sparano et al (NEJM September 28, 2015DOI: 10.1056/NEJMoa1510764) performed a prospective trial involving women with hormone-receptor–positive, human epidermal growth factor receptor type 2 (HER2)–negative, axillary node–negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase–polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-cancer recurrence; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10, indicating a very low risk of recurrence (on a scale of 0 to 100, with higher scores indicating a greater risk of recurrence).

Of the 10,253 eligible women enrolled, 1626 women (15.9%) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy. At 5 years, in this patient population, the rate of invasive disease–free survival was 93.8% (95% CI, 92.4 - 94.9), the rate of freedom from recurrence of breast cancer at a distant site was 99.3% (95% CI, 98.7 - 99.6), the rate of freedom from recurrence of breast cancer at a distant or local–regional site was 98.7% (95% CI, 97.9 - 99.2), and the rate of overall survival was 98.0% (95% CI, 97.1 - 98.6).
Conclusions

Among patients with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features, those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone.


N° 794 Topic: Cancer and obstetrics
Frédéric Amant for the International Network on Cancer, Infertility, and Pregnancy (INCIP)( NEJM September 28, 2015DOI: 10.1056/NEJMoa1508913) reported the “Pediatric Outcome after Maternal Cancer Diagnosed during Pregnancy”, a multicenter case–control study, comparing children whose mothers received a diagnosis of cancer during the pregnancy with matched children of women without a cancer diagnosis with a follow up at 18 months, 36 months, or both and a cardiac assessment at 36 months. A total of 129 children (median age, 22 months; range, 12 to 42) whose mother had cancer were compared to the control group. During pregnancy, 96 children (74.4%) were exposed to chemotherapy (alone or in combination with other treatments), 11 (8.5%) to radiotherapy (alone or in combination), 13 (10.1%) to surgery alone, 2 (1.6%) to other drug treatments, and 14 (10.9%) to no treatment. Birth weight was below the 10th percentile in 28 of 127 children (22.0%) in the prenatal-exposure group and in 19 of 125 children (15.2%) in the control group (P=0.16). There was no significant between-group difference in cognitive development on the basis of the Bayley score (P=0.08) or in subgroup analyses. The gestational age at birth was correlated with the cognitive outcome in the two study groups. Cardiologic evaluation among 47 children at 36 months of age showed normal cardiac findings.

The authors concluded that Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood. Prematurity was correlated with a worse cognitive outcome, but this effect was independent of cancer treatment.


N° 793 Topic: Breast cancer
Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer. Poortmans PM et al (N Engl J Med. 2015 Jul 23;373(4):317-27. doi: 10.1056/NEJMoa1415369.)

The authors randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer.

A total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P=0.06).

The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P=0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P=0.02). Acute side effects of regional nodal irradiation were modest.
CONCLUSIONS:

In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced.

N° 792 Topic: Oncology and fertility
Protecting Ovaries During Chemotherapy Through Gonad Suppression: A Systematic Review and Meta-analysis

Elgindy, et al (Obstetrics and Gynecology July 2015)

estimated whether gonadotropin-releasing hormone (GnRH) analog administration during chemotherapy can protect against development of ovarian toxicity.

Gonadotropin-releasing hormone analog co treatment did not significantly increase ovarian function resumption. No protective effect existed after subgroup analyses (type of malignancy [P=.31], age [P=.14], and GnRH analog type [P=.44]). Gonadotropin-releasing hormone analogs did not protect any of ovarian reserve parameters, whether follicle-stimulating hormone (mean difference −2.63, 95% CI −7.33 to 2.07), antral follicle count (mean difference 1.66, 95% CI −0.69 to 4.01), or anti-Müllerian hormone (mean difference 0.31, 95% CI −0.41 to 1.03). Spontaneous pregnancy was also comparable (risk ratio 1.63, 95% CI 0.94–2.82).

CONCLUSION: Gonadotropin-releasing hormone analog administration during chemotherapy does not appear to protect the ovaries from gonadal toxicity. It is not a reliable method for fertility preservation.

N° 791 Topic: ovarian cancer
Whole–genome characterization of chemoresistant ovarian cancer

Ann-Marie Patch et al Nature 521,489–494 (28 May 2015) doi:10.1038/nature14410

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, the authors used whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. They observed that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. They observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.


N° 790 Topic: incontinence, women’s’ health
Comparative Effectiveness of Anticholinergic Therapy for Overactive Bladder in Women: A Systematic Review and Meta-analysis
Reynolds, W. Stuart et al Obstetrics & Gynecology. 125(6):1423-1432, June 2015.
summarized evidence about reduction in voiding and resolution of urine loss in overactive bladder
Evidence from more than 27,000 women participating in randomized controlled trials suggests that improvement in symptoms with anticholinergic management of overactive bladder is modest and rarely fully resolves symptom

N° 789 Topic: Osteoporosis
Comparative Effectiveness of Anticholinergic Therapy for Overactive Bladder in Women: A Systematic Review and Meta-analysis
Reynolds, W. Stuart et al Obstetrics & Gynecology. 125(6):1423-1432, June 2015.
summarized evidence about reduction in voiding and resolution of urine loss in overactive bladder
EvideSubclinical Thyroid Dysfunction and Fracture RiskA Meta-analysis

Manuel R. Blum et al (; for the Thyroid Studies Collaboration JAMA. 2015;313(20):2055-2065. doi:10.1001/jama.2015.5161) assed the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures using a Meta-analysis. Individual participant data were obtained from 13 prospective cohorts.
Among 70 298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762 401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies).

In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64); for any fracture, HR was 1.28 (95% CI, 1.06-1.53); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45).

Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15); for any fracture, HR was 1.98 (95% CI, 1.41-2.7); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78).

Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk.

Conclusions and Relevance Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

N° 788 Topic: Breast cancer

Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer
Growth of hormone-receptor–positive breast cancer is dependent on cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), which promote progression from the G1 phase to the S phase of the cell cycle.
Nicholas C. Turner, et al ( NEJM 1.6.15) reported the efficacy of palbociclib (an inhibitor of CDK4 and CDK6) and fulvestrant in advanced breast cancer during a phase 3 study (n=521 patients with advanced hormone-receptor–positive, human epidermal growth factor receptor 2–negative breast cancer) that had relapsed or progressed during prior endocrine therapy.
Patients were treated in a 2:1 ratio with palbociclib and fulvestrant or placebo and fulvestrant. Premenopausal or perimenopausal women also received goserelin.
The median progression-free survival was 9.2 months (95% [CI], 7.5 to not estimable) with palbociclib–fulvestrant and 3.8 months (95% CI, 3.5 to 5.5) with placebo–fulvestrant (HR for disease progression or death, 0.42; 95% CI, 0.32 to 0.56; P 0.42; 95% CI, 0.32 to 0.56).
The most common grade 3 or 4 adverse events in the palbociclib–fulvestrant group were neutropenia (62.0%, vs. 0.6% in the placebo–fulvestrant group), leukopenia (25.2% vs. 0.6%), anemia (2.6% vs. 1.7%), thrombocytopenia (2.3% vs. 0%), and fatigue (2.0% vs. 1.2%). Febrile neutropenia was reported in 0.6% of palbociclib-treated patients and 0.6% of placebo-treated patients. The rate of discontinuation due to adverse events was 2.6% with palbociclib and 1.7% with placebo. CONCLUSIONS Among patients with hormone-receptor–positive metastatic breast cancer who had progression of disease during prior endocrine therapy, palbociclib combined with fulvestrant resulted in longer progression-free survival than fulvestrant alone.

787 Topic: Surgery
Bowel Injury in Gynecologic Laparoscopy: A Systematic Review
Obstetrics & Gynecology:
June 2015 - Volume 125 - Issue 6 - p 1407–1417
doi: 10.1097/AOG.0000000000000855

Llarena, Natalia C. et al Obstetrics & Gynecology:
June 2015 - Volume 125 - Issue 6 - p 1407–1417 evaluated the incidence of bowel injury in gynecologic laparoscopy and determined the presentation, mortality, cause, and location of injury within the gastrointestinal tract using a systematic review.
Ninety studies published between 1972 and 2014 met eligibility criteria, representing 474,063 gynecologic laparoscopies. Six hundred four bowel injuries were reported for an incidence of 1 in 769 (0.13%, 95% [CI] 0.12–0.14%). The rate of bowel injury varied by procedure, ranging from 1 in 3,333 (0.03%, 95% CI 0.01–0.03%) for sterilization to 1 in 256 (0.39%, 95% CI 0.34–0.45%) for hysterectomy. The small intestine was the most frequently damaged region of the gastrointestinal tract, representing 166 of 354 (47%) injuries. The majority of bowel injuries occurred during abdominal access and insufflation obtained using a Veress needle or trocar placement (201/366, 55% of injuries). Although most bowel injuries were recognized intraoperatively, diagnosis was delayed by more than 1 day in 154 of 375 cases (41%, 95% CI 36–46%). Bowel injuries were managed primarily by laparotomy (80%). Mortality occurred after bowel injury in 5 of 604, or 1 of 125 (0.8%, 95% CI 0.36–1.9%) cases. All deaths occurred as a result of delayed recognition of bowel injury (n=154), making the mortality rate for unrecognized bowel injury 5 in 154 or 1 in 31 (3.2%, 95% CI 1–7%). There were no deaths associated with intraoperatively diagnosed bowel injury.



N° 784 Topic: Surgery
Innovative Technique for Enclosed Morcellation Using a Surgical Glove

Akdemir, Ali et al (Obstetrics and Gynecology May 2015)

described an innovative approach for enclosed morcellation using a surgical glove in multiport laparoscopic surgery.

METHODS: Power morcellation was performed within an insufflated surgical glove in a completely enclosed manner between January and May 2014. The specimen was placed into the glove within the abdomen. The glove opening and thumb were exteriorized through the umbilical and left lower abdominal trocar incisions, respectively. The optical trocar and optic were inserted into the glove, which was then insufflated. The thumb tip was cut, and a power morcellator was inserted through this finger. The morcellation was accomplished within the completely enclosed glove. The thumb tip was closed, and the glove, containing residual specimens and bloody fluid, was removed from the abdomen through the umbilical incision. Thus, the risks of bag piercing and leakage during contained power morcellation were eliminated. Demographic and operative data were collected and analyzed for all cases.

RESULTS: Thirty multiport laparoscopic myomectomy and morcellation procedures were performed during the study period. The median operative time was 85 minutes (range 60–140 minutes). The median morcellation preparation time, total morcellation time, and withdrawal time were 6 (range 4.5–14), 32 (range 15–55), and 1.2 (range 1–1.5) minutes, respectively. No intraoperative complications or bag ruptures were recorded.



N° 782 Topic: Menopausal hormone use and ovarian cancer risk
Menopausal hormone use and ovarian cancer risk: individual
participant meta-analysis of 52 epidemiological studies
A Collaborative Group on Epidemiological Studies of Ovarian Cancer*published in the Lancet Published Online
February 13, 2015 http://dx.doi.org/10.1016/ S0140-6736(14)61687-1) assessed the effects of hormone therapy on ovarian cancer risk using Individual participant datasets from 52 epidemiological studies. During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone
therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 yearsof use (RR 1·43, 95% CI 1·31–1·56; p<0·0001). Combining current-or-recent use (any duration, but stopped<5 years before diagnosis) resulted in an RR of 1·37 (95% CI 1·29–1·46; p<0·0001);
Women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users.


N° 781 Topic: Menopause
Duration of Menopausal Vasomotor Symptoms Over the Menopause Transition ONLINE FIRST
Nancy E. Avis, et al ; for the Study of Women’s Health Across the Nation (SWAN) (JAMA Intern Med. Published online February 16, 2015. doi:10.1001/jamainternmed.2014.8063 ) determined total duration of frequent menopausal vasomotor symptoms (VMS) (≥6 days in the previous 2 weeks) (hereafter total VMS duration) during the menopausal transition, to quantify how long frequent VMS persist after the final menstrual period (FMP) (hereafter post-FMP persistence), and to identify risk factors for longer total VMS duration and longer post-FMP persistence. They used the The Study of Women’s Health Across the Nation (SWAN), a multiracial/multiethnic observational study of the menopausal transition among 3302 women enrolled (from February 1996 -April 2013). Analyses included 1449 women with frequent VMS.
The median total VMS duration was 7.4 years. Among 881 women who experienced an observable FMP, the median post-FMP persistence was 4.5 years. Women who were premenopausal or early perimenopausal when they first reported frequent VMS had the longest total VMS duration (median, >11.8 years) and post-FMP persistence (median, 9.4 years). Women who were postmenopausal at the onset of VMS had the shortest total VMS duration (median, 3.4 years). Compared with women of other racial/ethnic groups, African American women reported the longest total VMS duration (median, 10.1 years). Additional factors related to longer duration of VMS (total VMS duration or post-FMP persistence) were younger age, lower educational level, greater perceived stress and symptom sensitivity, and higher depressive symptoms and anxiety at first report of VMS.
Conclusions and Relevance Frequent VMS lasted more than 7 years during the menopausal transition for more than half of the women and persisted for 4.5 years after the FMP. Individual characteristics (eg, being premenopausal and having greater negative affective factors when first experiencing VMS) were related to longer-lasting VMS. Health care professionals should counsel women to expect that frequent VMS could last more than 7 years, and they may last longer for African American women.

N° 781 Topic: Menopause
Duration of Menopausal Vasomotor Symptoms Over the Menopause Transition ONLINE FIRST
Nancy E. Avis, et al ; for the Study of Women’s Health Across the Nation (SWAN) (JAMA Intern Med. Published online February 16, 2015. doi:10.1001/jamainternmed.2014.8063 ) determined total duration of frequent menopausal vasomotor symptoms (VMS) (≥6 days in the previous 2 weeks) (hereafter total VMS duration) during the menopausal transition, to quantify how long frequent VMS persist after the final menstrual period (FMP) (hereafter post-FMP persistence), and to identify risk factors for longer total VMS duration and longer post-FMP persistence. They used the The Study of Women’s Health Across the Nation (SWAN), a multiracial/multiethnic observational study of the menopausal transition among 3302 women enrolled (from February 1996 -April 2013). Analyses included 1449 women with frequent VMS.
The median total VMS duration was 7.4 years. Among 881 women who experienced an observable FMP, the median post-FMP persistence was 4.5 years. Women who were premenopausal or early perimenopausal when they first reported frequent VMS had the longest total VMS duration (median, >11.8 years) and post-FMP persistence (median, 9.4 years). Women who were postmenopausal at the onset of VMS had the shortest total VMS duration (median, 3.4 years). Compared with women of other racial/ethnic groups, African American women reported the longest total VMS duration (median, 10.1 years). Additional factors related to longer duration of VMS (total VMS duration or post-FMP persistence) were younger age, lower educational level, greater perceived stress and symptom sensitivity, and higher depressive symptoms and anxiety at first report of VMS.
Conclusions and Relevance Frequent VMS lasted more than 7 years during the menopausal transition for more than half of the women and persisted for 4.5 years after the FMP. Individual characteristics (eg, being premenopausal and having greater negative affective factors when first experiencing VMS) were related to longer-lasting VMS. Health care professionals should counsel women to expect that frequent VMS could last more than 7 years, and they may last longer for African American women.


N° 780 Topic: cardiovascular disease
Association Between Sauna Bathing and Fatal Cardiovascular and All-Cause Mortality Events ONLINE FIRST
Tanjaniina Laukkanen, et al (JAMA Intern Med. Published online February 23, 2015. doi:10.1001/jamainternmed.2014.8187 ) investigated the association of frequency and duration of sauna bathing with the risk of sudden cardiac death (SCD), fatal coronary heart disease (CHD), fatal cardiovascular disease (CVD), and all-cause mortality using a prospective cohort study (Finnish Kuopio Ischemic Heart Disease Risk Factor Study) of a population-based sample of 2315 middle-aged (age range, 42-60 years) men from Eastern Finland. Baseline examinations were conducted from March 1, 1984, through December 31, 1989.
During a median follow-up of 20.7 years, 190 SCDs, 281 fatal CHDs, 407 fatal CVDs, and 929 all-cause mortality events occurred. A total of 601, 1513, and 201 participants reported having a sauna bathing session 1 time per week, 2 to 3 times per week, and 4 to 7 times per week, respectively. After adjustment for CVD risk factors, compared with men with 1 sauna bathing session per week, the hazard ratio of SCD was 0.78 (95% CI, 0.57-1.07) for 2 to 3 sauna bathing sessions per week and 0.37 (95% CI, 0.18-0.75) for 4- 7 sauna bathing sessions per week (P for trend = .005). Similar associations were found with CHD, CVD, and all-cause mortality (P for trend ≤.005). Compared with men having a sauna bathing session of less than 11 minutes, the adjusted hazard ratio for SCD was 0.93 (95% CI, 0.67-1.28) for sauna bathing sessions of 11 to 19 minutes and 0.48 (95% CI, 0.31-0.75) for sessions lasting more than 19 minutes (P for trend = .002); significant inverse associations were also observed for fatal CHDs and fatal CVDs (P for trend ≤.03) but not for all-cause mortality events.
Conclusions and Relevance Increased frequency of sauna bathing is associated with a reduced risk of SCD, CHD, CVD, and all-cause mortality. Further studies are warranted to establish the potential mechanism that links sauna bathing and cardiovascular health.
Comment : Is this also the case in women?


N° 779 Topic: cardiovascular disease and menopause
G Protein-coupled Estrogen Receptor Protects from Atherosclerosis
Matthias R. Meyer et al (Scientific Reports 4, Article number: 7564 doi:10.1038/srep07564)

Coronary atherosclerosis and myocardial infarction in postmenopausal women have been linked to inflammation and reduced nitric oxide (NO) formation. Natural estrogen exerts protective effects on both processes, yet also displays uterotrophic activity. Here, we used genetic and pharmacologic approaches to investigate the role of the G protein-coupled estrogen receptor (GPER) in atherosclerosis. In ovary-intact mice, deletion of gper increased atherosclerosis progression, total and LDL cholesterol levels and inflammation while reducing vascular NO bioactivity, effects that were in some cases aggravated by surgical menopause. In human endothelial cells, GPER was expressed on intracellular membranes and mediated eNOS activation and NO formation, partially accounting for estrogen-mediated effects. Chronic treatment with G-1, a synthetic, highly selective small molecule agonist of GPER, reduced postmenopausal atherosclerosis and inflammation without uterotrophic effects. In summary, this study reveals an atheroprotective function of GPER and introduces selective GPER activation as a novel therapeutic approach to inhibit postmenopausal atherosclerosis and inflammation in the absence of uterotrophic activity.


N° 778 Topic: Progesterone

A Clinical Trial of Progesterone for Severe Traumatic Brain Injury
Brett E. Skolnick, et al. for the SYNAPSE Trial Investigators (NEJM December 10, 2014DOI: 10.1056/NEJMoa1411090)

Progesterone has been associated with positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized, controlled trials. The authors investigated the efficacy and safety of progesterone in a large, prospective, phase 3 randomized clinical trial.
Proportional-odds analysis with covariate adjustment showed no treatment effect of progesterone as compared with placebo (odds ratio, 0.96; confidence interval, 0.77 to 1.18). The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between progesterone and placebo.


N° 777 Topic: Breast Cancer
Adjuvant Ovarian Suppression in Premenopausal Breast Cancer
Prudence A. Francis, for the SOFT Investigators and the International Breast Cancer Study Group (NEJM December 11, 2014DOI: 10.1056/NEJMoa1412379) randomly assigned 3066 premenopausal women, stratified according to prior receipt or nonreceipt of chemotherapy, to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The primary analysis tested the hypothesis that tamoxifen plus ovarian suppression would improve disease-free survival, as compared with tamoxifen alone. In the primary analysis, 46.7% of the patients had not received chemotherapy previously, and 53.3% had received chemotherapy and remained premenopausal. After a median follow-up of 67 months, the estimated disease-free survival rate at 5 years was 86.6% in the tamoxifen–ovarian suppression group and 84.7% in the tamoxifen group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.83; 95% confidence interval [CI], 0.66 to 1.04; P=0.10). Multivariable allowance for prognostic factors suggested a greater treatment effect with tamoxifen plus ovarian suppression than with tamoxifen alone (hazard ratio, 0.78; 95% CI, 0.62 to 0.98). Most recurrences occurred in patients who had received prior chemotherapy, among whom the rate of freedom from breast cancer at 5 years was 82.5% in the tamoxifen–ovarian suppression group and 78.0% in the tamoxifen group (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02). At 5 years, the rate of freedom from breast cancer was 85.7% in the exemestane–ovarian suppression group (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87).

Conclusions
Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes. Further improvement was seen with the use of exemestane plus ovarian suppression.

N° 776 Topic: Statin Therapy and Risk of Fracture: Results From the JUPITER Randomized Clinical Trial
Jessica M. Peña, et al
JAMA Intern Med. Published online December 01, 2014. doi:10.1001/jamainternmed.2014.6388
determined whether statin therapy reduces the risk of fracture and, in a secondary analysis, whether baseline levels of the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) are associated with the risk of fracture.The JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial was an international, randomized, double-blind, placebo-controlled study enrolling 17 802 men older than 50 years and women older than 60 years with hs-CRP level of at least 2 mg/L. Participants were screened from 2003 to 2006 and observed prospectively for up to 5 years (median follow-up, 1.9 years) and treated with Rosuvastatin calcium, 20 mg daily, or placebo.

During the study, 431 incident fractures were reported and confirmed. Among participants allocated to rosuvastatin, 221 fractures were confirmed, compared with 210 among those allocated to placebo, such that the incidence of fracture in the rosuvastatin and placebo groups was 1.20 and 1.14 per 100 person-years, respectively (adjusted HR, 1.06 [95% CI, 0.88-1.28]; P = .53). Overall, increasing baseline hs-CRP level was not associated with an increased risk of fractures (adjusted HR for each unit increase in hs-CRP tertile, 1.06 [95% CI, 0.94-1.20]; P for trend, .34).

Conclusions and Relevance Among men and women with elevated hs-CRP level enrolled in a large trial of rosuvastatin therapy for cardiovascular disease, statin therapy did not reduce the risk of fracture. Higher baseline hs-CRP level was not associated with an increased risk of incident fracture.

N° 775 Topic: fertility and cardiovascular
Lipid profiles and ovarian reserve status: a longitudinal study
Fahimeh Ramezani Tehrani et al Hum. Reprod. (2014)
doi: 10.1093/humrep/deu249) analysed the relation between ovarian reserve status and lipid profile changes. A longitudinal study was conducted on 1015 participants of Tehran Lipid and Glucose Study, an ongoing population based cohort study with 12 years follow-up. The ovarian reserve status of 1015 women aged 20-50, was identified according to their age-specific AMH levels, calculated using the exponential–normal 3-parameter model. Total cholesterol (TC) net changes per year were incremental in the first AMH quartile but not in the fourth quartile (P < 0.001). According to the generalized estimating equation (GEE), after adjustment for age, BMI, time interaction and menopause status, the changes across time in TC, LDL and HDL were varied according to the age-specific AMH status.

The authors suggest that women with lower ovarian reserve might be susceptible to developing cardiovascular risk factors, particularly lipid disturbances, even during their reproductive life span.

N° 773 Topic: Obesity and Age at Diagnosis of Endometrial Cancer
Nevadunsky, et al (Obstetrics & Gynecology. 124(2, PART 1):300-306, August 2014.) reported using a retrospective chart review of all cases of endometrial cancer diagnosed from 1999 to 2009 at a large medical center in New York City that the mean age at endometrial cancer diagnosis was 67.1 years (±11.9 SD) in women with a normal BMI, whereas it was 56.3 years (±10.3 SD) in women with a BMI greater than 50. Age at diagnosis of endometrioid-type cancer decreased linearly with increasing BMI. This association persisted after multivariable adjustment (R2=0.181, P<.02). A linear association between BMI and age of nonendometrioid cancers was not found. There were no differences in overall survival by BMI category.

N° 772 Topic: Biphosphonates and breast cancer
Results From the Randomized Clinical Trials of Alendronate and Zoledronic Acid

Trisha F. Hue et al (JAMA Intern Med. Published online August 11, 2014. doi:10.1001/jamainternmed.2014.3634 ) assessed the relationship of postmenopausal breast cancer incidence and bisphosphonate use , using data from 2 randomized (1:1), double-blind, placebo-controlled trials assessing Alendronate vs placebo (FIT) or zoledronic acid vs placebo (HORIZON-PFT). They found no significant difference in the rate of breast cancer in FIT: 1.5% in the placebo group and 1.8% in the alendronate group (hazard ratio [HR], 1.24 [95% CI, 0.84-1.83] nor in HORIZON-PFT, (0.8% ) in the placebo group and 0.9% in the zoledronic acid group (HR, 1.15 [95% CI, 0.70-1.89]). There was also no significant difference when the data from were pooled (HR, 1.20 [95% CI, 0.89-1.63]).

N° 771 Topic: Menopause and Cardiovascular Risks
Arterial Imaging Outcomes and Cardiovascular Risk Factors in Recently Menopausal Women: A Randomized Trial Cardiovascular Disease and Menopausal Hormone Therapy

SM Harman, et al (Ann Intern Med. Published online 29 July 2014 doi:10.7326/M14-0353 ) assessed atherosclerosis progression and CVD risk factors after MHT initiated in early menopause using an RCT. Healthy menopausal women aged 42 to 58 years between 6 and 36 months from last menses without prior CVD events who had a coronary artery calcium (CAC) score less than 50 Agatston units and had not received estrogen or lipid-lowering therapy for at least 90 days were treated with oral conjugated equine estrogens (o-CEE), 0.45 mg/d, or transdermal 17β-estradiol (t-E2), 50 mcg/d, each with 200 mg of oral progesterone for 12 days per month, or placebo for 48 months.
Primary end point was annual change in carotid artery intima–media thickness (CIMT). Secondary end points included changes in markers of CVD risk.
Results: Of 727 randomly assigned women, 89.3% had at least 1 follow-up CIMT and 79.8% had CIMT at 48 months. Mean CIMT increases of 0.007 mm/y were similar across groups. The percentages of participants in whom CAC score increased did not differ significantly across groups. No changes in blood pressure were observed with o-CEE or t-E2. Low- and high-density lipoprotein cholesterol levels improved and levels of C-reactive protein and sex hormone–binding globulin but not interleukin-6 increased with o-CEE. Insulin resistance decreased with t-E2. Serious adverse events did not differ by treatment.
Although the power to compare clinical events was insufficient, the authors concluded that 4 years of early MHT did not affect progression of atherosclerosis despite improving some markers of CVD risk.

N° 770 Topic: Breast Cancer : Risk in Families with Mutations in PALM2
AC. Antoniou, et al (N Engl J Med 2014; 371:497-506August 7, 2014DOI: 10.1056/NEJMoa1400382) analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The age-specific breast-cancer risk for mutation carriers was estimated with the use of a modified segregation-analysis approach that allowed for the effects of PALB2 genotype and residual familial aggregation.

The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI], 9 to 20) by 50 years of age and 35% (95% CI, 26 to 46) by 70 years of age. Breast-cancer risk was also significantly influenced by birth cohort (P<0.001) and by other familial factors (P=0.04). The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age.

Conclusions

The authors concluded that loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. They suggest that the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers.

N° 769 Topic: Global causes of maternal death
Global causes of maternal death: a WHO systematic analysis
Lale Say et al (Lancet Glob Health 2014; 2: e323–33 Published Online May 6, 2014 http://dx.doi.org/10.1016/) developed and analysed global, regional, and subregional estimates of the causes of maternal death during 2003–09, updating the previous WHO systematic review. They identified 23 eligible studies including 417 datasets from 115 countries and comprising 60 799 deaths in the analysis. About 73% of all maternal deaths were due to direct obstetric causes and deaths due to indirect causes accounted for 27·5% of all deaths. Haemorrhage accounted for 27·1%, hypertensive disorders 14·0% , and sepsis 10·7% of maternal deaths. The rest of deaths were due to abortion (7·9%), embolism (3·2%), and all other direct causes of death (9·6%, ). Regional estimates varied substantially.
Interpretation Between 2003 and 2009, haemorrhage, hypertensive disorders, and sepsis were responsible for more than half of maternal deaths worldwide. More than a quarter of deaths were attributable to indirect causes.

N° 768 Topic: Breast Cancer
In January 2013, the Swiss Medical Board, an independent health technology assessment initiative under the auspices of the Conference of Health Ministers of the Swiss Cantons, the Swiss Medical Association, and the Swiss Academy of Medical Sciences, was mandated to prepare a review of mammography screening.
In February, 2014 (www.medical-board.ch), the board recommended that no new systematic mammography screening programs be introduced and that a time limit be placed on existing programs. In addition, it stipulated that the quality of all forms of mammography screening should be evaluated and that clear and balanced information should be provided to women regarding the benefits and harms of screening.
Two of the participants of that board express their view in a commentary in the latest NEJM issue (Nikola Biller-Andorno, M.D., Ph.D., and Peter Jüni, M.D. N Engl J Med 2014; 370:1965-1967May 22, 2014DOI: 10.1056/NEJMp1401875) (http://www.nejm.org/d oi/pdf/10.1056/NEJMp1401875)

SHARING-OBGYN is a service that I intend to share with you. The idea is to send one short email message a day concerning an article that appeared recently and might be of interest to you.
The selection of the articles is arbitrary, but there are no commercial interests involved and no conflict of interest.
If you want to be removed from the list of persons to whom these emails are sent please let me know.
If you want to bring comments or add email addresses of friends or colleagues, please feel free to do so.

N° 767 Topic: Premature menopause
Impact of a premature menopause on cognitive function in later life. Ryan et al (JBJOG. 2014 May 7. doi: 10.1111/1471-0528.12828. ) These authors observed that menopause at or before the age of 40 years, both premature bilateral ovariectomy and premature ovarian failure (non-surgical loss of ovarian function), was associated with worse verbal fluency (OR 1.56, 95%CI 1.12-1.87, P = 0.004) and visual memory (OR 1.39, 95%CI 1.09-1.77, P = 0.007) in later life. HT at the time of premature menopause appeared beneficial for later-life visual memory but increased the risk of poor verbal fluency. Type of menopause was not significantly associated with cognitive function. Premature menopause was associated with a 30% increased risk of decline in psychomotor speed and global cognitive function over 7 years.


N° 766 Topic: Menopause
The FDA decided, despite a negative vote from an advisory committee, to approve Brisdelle for Menopausal Hot Flushes

First nonhormonal option to women who cannot or do not want to use hormonal medications to treat their menopausal vasomotor symptoms. Brisdelle contains 7.5 mg of paroxetine, a selective serotonin-reuptake inhibitor, and is taken at bedtime. The efficacy of Brisdelle was established in two RCT but shows a modest effect, but clinical relevant, over placebo.

It has a known interaction with tamoxifen use, and it can decrease plasma concentrations of endoxifen. There have been also concerns about suicidal ideation with this class of medication. Read more in the comment of RJ. Orleans et al N Engl J Med 2014; 370:1777-1779 May 8, 2014DOI: 10.1056/NEJMp1402080 (http://www.nejm.org/d oi/f ull/10.1056/NEJMp1402080)


SHARING-OBGYN is a service that I intend to share with you. The idea is to send one short email message a day concerning an article that appeared recently and might be of interest to you.
The selection of the articles is arbitrary, but there are no commercial interests involved and no conflict of interest.
If you want to be removed from the list of persons to whom these emails are sent please let me know.
If you want to bring comments or add email addresses of friends or colleagues, please feel free to do so.

N° 764 Topic: Osteoporosis
McClung, et al (NEJM January 1, 2014DOI: 10.1056/NEJMoa1305224) reported the effect of Romosozumab in Postmenopausal Women with Low Bone Mineral Density. Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation. They conducted a phase 2, multicenter, international, RCT over a 12-month period in 419 postmenopausal women, 55 to 85 years of age, who had low bone mineral density. Participants were randomly assigned to receive subcutaneous romosozumab monthly (at a dose of 70 mg, 140 mg, or 210 mg) or every 3 months (140 mg or 210 mg), subcutaneous placebo, or an open-label active comparator — oral alendronate (70 mg weekly) or subcutaneous teriparatide (20 μg daily). The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Secondary end points included percentage changes in bone mineral density at other sites and in markers of bone turnover. All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in bone mineral density at the total hip and femoral neck, as well as transitory increases in bone-formation markers and sustained decreases in a bone-resorption marker. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups.

N° 763 Topic: Being Happy!
Research Christmas 2013: Research Being right or being happy: pilot study by Bruce Arroll, Felicity Goodyear-Smith, Simon Moyes, Timothy Kenealy, BMJ 2013; 347 doi: http://dx.doi.org/10.1136/bmj.f7398 (Published 17 December 2013) Cite this as: BMJ 2013;347:f7398
Introduction
Three of the authors are general practitioners who see many patients and couples who lead unnecessarily stressful lives by wanting to be right rather than happy. Mathieu encourages her psychotherapy clients “to try to live in the gray. There are a million shades of gray” (although a recent erotic novel suggests there are only 50) “on the spectrum of white to black, and each provides a much richer telling of a story that is hardly ever as clear as this or that. So, when we looked a bit more closely, we saw that ‘right versus happy’ was not so much about getting crowned the winner or loser, a genius or fool; it was more about flawed thinking and a desire to want to feel being in control.”1 This might be the first study to systematically assess whether it is better to be right than happy; a Medline search in May 2013 found no similar articles. Our null hypothesis was that it is better to be right than happy.
Participants, setting, and design
To be eligible participants had to be part of a couple and willing to take part in the study. We carried out a parallel trial with one man and one woman in their own home. It was decided without consultation that the female participant would prefer to be right and the male, being somewhat passive, would prefer to be happy.
The male was informed of the intervention while the female participant was not (this form of pre-randomisation is known as the Zelen method2). The female participant was blind to the hypothesis being tested, other than being asked to record her quality of life.
Intervention
The intervention was for the male to agree with his wife’s every opinion and request without complaint. Even if he believed the female participant was wrong, the male was to bow and scrape.
Main outcome measure
We measured quality of life with a Likert score of 1 to 10 (10 being the best possible quality of life). Although our tool was unvalidated, it was thought to have face validity. It was justified on the grounds that brevity was essential, given that the intervention was administered in a potentially complex domestic environment.
Results
Two participants were eligible and both (100%) were randomised. All participants received the treatment and were analysed for the primary outcome with an intention to treat analysis. Several baseline characteristics differed between the subjects (see appendix).
The data safety monitoring committee stopped the study because of severe adverse outcomes after 12 days. By then the male participant found the female participant to be increasingly critical of everything he did. The situation had become intolerable by day 12. He sat on the end of their bed, made her a cup of tea, and said as much; explained the trial and then contacted the Data Safety Monitoring committee who terminated the trial immediately.
There were three data points in the intervention group and two in the control group (the control participant had become hostile to recording her quality of life).
The man’s quality of life score had fallen from 7 out of 10 at baseline to 3 at 12 days; the women’s had increased slightly from 8 to 8.5 at six days. The difference between the two participants’ QOL scores over time is significantly different (P=0.004, calculated with a repeated measures generalised linear model). We should treat the results cautiously because we cannot discount causes other than treatment reducing the male participant’s score. It seems that being right, however, is a cause of happiness, and agreeing with what one disagrees with is a cause of unhappiness. We cannot discount that the difference in results might be caused by differences between the two treatment groups, which unfortunately we were unable to match by possible confounders such as sex.
View larger version:
Quality of life by duration of intervention
The harms were estimated as 100% as all participants who received the intervention reported a serious adverse event.
Discussion
The results of this trial show that the availability of unbridled power adversely affects the quality of life of those on the receiving end.
Strengths and weaknesses
The study has some limitations. There was no trial registration, no ethics committee approval, no informed consent, no proper randomisation, no validated test instrument, and questionable statistical assessment. We used the eyeball technique for single patient trials which, as Sackett says, “more closely matches the way we think as clinicians.”3
Generalisability
Many people in the world live as couples, and we believe that it could be harmful for one partner to always have to agree with the other. However, more research is needed to see whether our results hold if it is the male who is always right.
References

Mathieu I. Emotional sobriety. Psychology Today2011.

Friedman ML, Fruberg CD, DeMets DL. Fundamentals of clinical trials. Springer-Science, 1998.

Sackett DL. Clinical trialist round 4. Why not do an N-of-1 RCT. Clin Trials2011;8:350-2.

N° 762 Topic: Women’s health, vitamin D
Vitamin D status and ill health: a systematic review
Low serum concentrations of 25-hydroxyvitamin D (25[OH]D) have been associated with many non-skeletal disorders. However, whether low 25(OH)D is the cause or result of ill health is not known. Philippe Autier et al (The Lancet Diabetes & Endocrinology, Volume 2, Issue 1, Pages 76 - 89, January 2014 ) conducted a systematic search of prospective and intervention studies that assessed the effect of 25(OH)D concentrations on non-skeletal health outcomes in individuals aged 18 years or older. They identified 290 prospective cohort studies (279 on disease occurrence or mortality, and 11 on cancer characteristics or survival), and 172 randomised trials of major health outcomes and of physiological parameters related to disease risk or inflammatory status. Investigators of most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality. High 25(OH)D concentrations were not associated with a lower risk of cancer, except colorectal cancer.
Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer. In 34 intervention studies including 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 μg per day or more did not show better results. Supplementation in elderly people (mainly women) with 20 μg vitamin D per day seemed to slightly reduce all-cause mortality.
The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin D status is reported in a wide range of disorders.
In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.

N° 761 Topic: Breast cancer, women’s health
Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial
Jack Cuzick, et al on behalf of the IBIS-II investigators (Lancet December 12, 2013) assessed the efficacy and safety of the aromatase inhibitor anastrozole for the prevention of breast cancer in postmenopausal women who are at high risk of the disease, using a double-blind, randomised placebo-controlled trial. 1920 women were randomly assigned to receive anastrozole and 1944 to placebo. After a median follow-up of
5·0 years (IQR 3·0–7·1), 40 women in the anastrozole group (2%) and 85 in the placebo group (4%) had developed breast cancer (HR 0·47, 95% CI 0·32–0·68, p<0·0001). The predicted cumulative incidence of all breast cancers after 7 years was 5·6% in the placebo group and 2·8% in the anastrozole group. 18 deaths were reported in the anastrozole group and 17 in the placebo group, and no specific causes were more common in one group than the other (p=0·836).
Interpretation Anastrozole effectively reduces incidence of breast cancer in high-risk postmenopausal women. This finding, along with the fact that most of the side-effects associated with oestrogen deprivation were not attributable to treatment, provides support for the use of anastrozole in postmenopausal women at high risk of breast cancer.


N° 760 Topic: Cervical cancer screening
cervical cancer screening (The Lancet, Early Online Publication, 3 November 2013 doi:10.1016/S0140-6736(13)62218-7)
Guglielmo Ronco et al for the International HPV screening working group analysed Efficacy of HPV-based screening for prevention of invasive cervical cancer using a follow-up of four European randomised controlled trials. The studies involved 176 464 women aged 20—64 years, randomly assigned to HPV-based (experimental arm) or cytology-based (control arm) screening in Sweden (Swedescreen), the Netherlands (POBASCAM), England (ARTISTIC), and Italy (NTCC). The median followed up was 6·5 years (1 214 415 person-years). 107 invasive cervical carcinomas were identified by linkage with screening, pathology, and cancer registries, by masked review of histological specimens, or from reports. Cumulative and study-adjusted rate ratios (experimental vs control) were calculated for incidence of invasive cervical carcinoma. They found that HPV-based screening provides 60—70% greater protection against invasive cervical carcinomas compared with cytology. Data of large-scale randomised trials support initiation of HPV-based screening from age 30 years and extension of screening intervals to at least 5 years.

SHARING-OBGYN is a service that I intend to share with you. The idea is to send one short email message a day concerning an article that appeared recently and might be of interest to you.
The selection of the articles is arbitrary, but there are no commercial interests involved and no conflict of interest.
If you want to be removed from the list of persons to whom these emails are sent please let me know.
If you want to bring comments or add email addresses of friends or colleagues, please feel free to do so.

N° 759 Topic: Surgery
Richard P G ten Broek et al (The Lancet, Early Online Publication, 27 September 2013
doi:10.1016/S0140-6736(13)61687-6Cite or Link Using DOI) evaluated the benefits and harms of four adhesion barriers that have been approved for clinical use.

Benefits and harms of adhesion barriers for abdominal surgery: a systematic review and meta-analysis
Formation of adhesions after peritoneal surgery results in high morbidity. Barriers to prevent adhesion are seldom applied, despite their ability to reduce the severity of adhesion formation.
Findings
This search returned 1840 results, from which 28 trials (5191 patients) were included in the meta-analysis. The risks of systematic and random errors were low. No trials reported data for the effect of oxidised regenerated cellulose or polyethylene glycol on reoperations for adhesive small bowel obstruction. Oxidised regenerated cellulose reduced the incidence of adhesions (relative risk [RR] 0·51, 95% CI 0·31—0·86). Some evidence suggests that hyaluronate carboxymethylcellulose reduces the incidence of reoperations for adhesive small bowel obstruction (RR 0·49, 95% CI 0·28—0·88). For icodextrin, reoperation for adhesive small bowel obstruction did not differ significantly between groups (RR 0·33, 95% CI 0·03—3·11). No barriers were associated with an increase in serious adverse events.
Interpretation
Oxidised regenerated cellulose and hyaluronate carboxymethylcellulose can safely reduce clinically relevant consequences of adhesions.
Funding
None.


N° 758 Topic: Osteoporosis
Fleur S. van Dijk, et al (NEJM October 2, 2013DOI: 10.1056/NEJMoa1308223) brief report:
PLS3 Mutations in X-Linked Osteoporosis with Fractures
Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, appears to be important in human bone health, on the basis of pathogenic variants in PLS3 in five families with X-linked osteoporosis and osteoporotic fractures that we report here. The bone-regulatory properties of PLS3 were supported by in vivo analyses in zebrafish. Furthermore, in an additional five families (described in less detail) referred for diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant (rs140121121) in PLS3 was found. This variant was also associated with a risk of fracture among elderly heterozygous women that was two times as high as that among noncarriers, which indicates that genetic variation in PLS3 is a novel etiologic factor involved in common, multifactorial osteoporosis.

N° 757 Topic: Obstetric
Nilsson, Ulrika et al (Nilsson, Ulrika W.; Johns, Terrance G.; Wilmann, Tania; Kaitu’u-Lino, Tu’uhevaha; Whitehead, Clare; Dimitriadis, Eva; Menkhorst, Ellen; Saglam, Burcu; Gao, Yane; Greenall, Sameer A.; Horne, Andrew W.; Tong, Stephen Less
Obstetrics & Gynecology. 122(4):737-744, October 2013) report Effects of Gefitinib, an Epidermal Growth Factor Receptor Inhibitor, on Human Placental Cell Growth. Placenta has the highest expression of epidermal growth factor (EGF) receptor of all tissues, a cell signaling pathway promoting survival and growth. Therefore, EGF receptor inhibition could potentially treat ectopic pregnancy. These authors examined whether gefitinib (orally available EGF receptor inhibitor) with or without methotrexate inhibits placental cell growth. Gefitinib and methotrexate were added to placental cells and their ability inhibit cell growth, block EGF receptor signaling, and induce apoptosis (programmed cell death) was examined. They were also administered to two animal mouse models to examine their effects on placental tissue in vivo. Epidermal growth factor receptor was highly expressed in placental tissue from ectopic pregnancies. Combining gefitinib with methotrexate potently inhibited growth of placental cells, including placental cell lines (JEG3, BeWo cells) and cells isolated from first-trimester placenta. These drugs were additive in blocking EGF receptor signaling and inducing apoptosis. Gefitinib and methotrexate administered together were more potent in decreasing the volume of human placental cells xenografted subcutaneously onto mice compared with either alone. Combining gefitinib with methotrexate potently inhibits placental cell growth in vitro and in mouse models. The combination may have potential in treating ectopic pregnancies.
Skubisz, Monika et al (Obstetrics & Gynecology. 122(4):745-751, October 2013) evaluated Combination Gefitinib and Methotrexate Compared With Methotrexate Alone to Treat Ectopic Pregnancy in a a phase I, single-arm (nonrandomized), open-label study in 12 women with ectopic pregnancies (methotrexate (50 mg/m2,IM) and 250 mg PO gefitinib in a dose-escalation protocol: one dose (day 1) n=3; three doses (days 1–3) n=3; seven doses (days 1–7) n=6. Efficacy was examined by comparing human chorionic gonadotrophin (hCG) decline and time to resolution with historic controls administered methotrexate only. Common side effects were transient acneiform rash in 67% (8/12) and diarrhea in 42% (5/12) of participants. There was no clinical or biochemical evidence of serious pulmonary, renal, hepatic, or hematologic toxicity. Of six participants with a pretreatment serum hCG level between 1,000 and 3,000 international units/L, hCG levels declined significantly faster than in the control group. Median serum hCG levels by day 7 after treatment were less than one fifth of levels observed among 71 historic controls treated with methotrexate alone (median [interquartile range] hCG in participants 261 [55–1,445] international units/L compared with controls 1,426 [940–2,573]; P=.008). Median time for the ectopic pregnancies to resolve with combination therapy was 34% shorter compared with methotrexate alone (21 days compared with 32 days; P=.018). Combination gefitinib and methotrexate has potential as a treatment for ectopic pregnancy but is commonly associated with minor side effects such as transient rash and diarrhea. The treatment requires validation of safety and efficacy in a larger trial.

N° 756 Topic: Women’s health
Leclair, Catherine et al (Obstetrics & Gynecology. 122(4):787-793, October 2013) assessed whether premenopausal and postmenopausal vestibulodynia have different histologic features. They conducted a retrospective analysis of vestibulectomy specimens from 21 women with postmenopausal vestibulodynia and compared them with 88 premenopausal patients (42 primary, 46 secondary).
Seventy-one percent (15/21) of postmenopausal women reported vestibular dyspareunia related to a drop in estrogen either with menopause (13/21) or previously, postpartum (2/21). Eighty-six percent (18/21) of postmenopausal patients were using local or systemic estrogen but pain persisted. Compared with premenopausal primary and secondary vestibular biopsies, postmenopausal tissues had more lymphocytes (unadjusted odds ratio [OR] 9.0, 95% confidence interval [CI] 2.8–33.3; adjusted OR for parity and duration of symptoms 9.1, 95% CI 2.6–31.9; unadjusted OR 6.2, 95% CI 1.9–20.0; adjusted OR 6.6, 95% CI 2.0–21.9, respectively) and mast cells (mean 36 compared with 28 and 36 compared with 26, respectively). There was significantly less neural hyperplasia and progesterone receptor expression in postmenopausal biopsies compared with primary cases but less progesterone receptor and similar neural hyperplasia compared with premenopausal secondary cases. Estrogen receptor α did not vary among groups.
CONCLUSION: Premenopausal and postmenopausal vestibulodynia share histologic features of neurogenic inflammation but differ strikingly in degree. When estrogen supplement does not alleviate symptoms of postmenopausal dyspareunia, vestibulodynia should be considered.


N° 755 Topic: Breast Cancer
Ju-Sheng Zheng, et al (BMJ 2013;346:f3706 ) investigated the association between intake of fish and n-3 polyunsaturated fatty acids (n-3 PUFA) and the risk of breast cancer using a meta-analysis and systematic review of prospective cohort studies.
Marine n-3 PUFA was associated with 14% reduction of risk of breast cancer (RR for highest v lowest category 0.86 (95% CI 0.78-0.94), I2=54), risk was more evident in studies that did not adjust for body mass index (BMI) (0.74, 0.64- 0.86, I2=0). Dose-response analysis indicated that risk of breast cancer was reduced by 5% per 0.1g/day (0.95, 0.90 to 1.00, I2=52%) or 0.1% energy/day (0.95, 0.90 to 1.00, I2=79%) increment of dietary marine n-3 PUFA intake. No significant association was observed for fish intake or exposure to alpha linolenic acid.
Higher consumption of dietary marine n-3 PUFA is associated with a lower risk of breast cancer. The associations of fish and alpha linolenic acid intake with risk warrant further investigation of prospective cohort studies. These findings could have public health implications with regard to prevention of breast cancer through dietary and lifestyle interventions.

SHARING-OBGYN is a service that I intend to share with you. The idea is to send one short email message a day concerning an article that appeared recently and might be of interest to you.
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N° 754 Topic: Breast Cancer
Selective Estrogen Receptor Modulators and Pharmacogenomic Variation in ZNF423 Regulation of BRCA1 Expression: Individualized Breast Cancer Prevention

The selective estrogen receptor modulators (SERM) tamoxifen and raloxifene can
reduce the occurrence of breast cancer in high-risk women by 50%, but this prevention therapy is not often used.

James N. Ingle, et al. (June 13, 2013. Cancer Discovery ) attempted to identify genetic factors that contribute to variation in SERM breast cancer prevention, using DNA from the NSABP P-1 and P-2 breast cancer prevention trials.


An initial discovery genome-wide association study identified common single nucleotide polymorphisms (SNP) in or near the ZNF423 and CTSO genes that
were associated with breast cancer risk during SERM therapy. The authors then showed that both ZNF423 and CTSO participated in the estrogen-dependent induction of BRCA1 expression, in both cases with SNP-dependent variation in induction. ZNF423 appeared to be an estrogen-inducible BRCA1 transcription
factor. The OR for differences in breast cancer risk during SERM therapy for subjects homozygous for both protective or both risk alleles for ZNF423 and CTSO was 5.71.

SIGNIFICANCE:
This study identified novel, functionally polymorphic genes involved in the estrogen-
dependent regulation of BRCA1 expression, as well as a novel mechanism for genetic variation in SERM therapeutic effect. These observations, and definition of their underlying mechanisms, represent steps toward pharmacogenomically individualized SERM breast cancer prevention.

N° 753 Topic: Obstetrics
Thorsten Kuehn et al (The Lancet Oncology, Volume 14, Issue 7, Pages 609 - 618, June 2013 doi:10.1016/S1470-2045(13)70166-9) reported Sven Cnattingius et al (JAMA. 2013;309(22):2362-2370. doi:10.1001/jama.2013.6295.) studied the associations between early pregnancy body mass index (BMI) and risk of preterm delivery by gestational age and by precursors of preterm delivery using a population-based cohort of women with live singleton births in Sweden from 1992 through 2010. Among 1 599 551 deliveries with information on early pregnancy BMI, 3082 were extremely preterm, 6893 were very preterm, and 67 059 were moderately preterm.

Risks of extremely, very, and moderately preterm deliveries increased with BMI and the overweight and obesity-related risks were highest for extremely preterm delivery. Among normal-weight women (BMI 18.5-<25), the rate of extremely preterm delivery was 0.17%. As compared with normal-weight women, rates (%) and adjusted odds ratios (ORs [95% CIs]) of extremely preterm delivery were as follows: BMI 25 to less than 30 (0.21%; OR, 1.26; 95% CI, 1.15-1.37), BMI 30 to less than 35 (0.27%; OR, 1.58; 95% CI, 1.39-1.79), BMI 35 to less than 40 (0.35%; OR, 2.01; 95% CI, 1.66-2.45), and BMI of 40 or greater (0.52%; OR, 2.99; 95% CI, 2.28-3.92). Risk of spontaneous extremely preterm delivery increased with BMI among obese women (BMI≥30). Risks of medically indicated preterm deliveries increased with BMI among overweight and obese women.

Conclusions and Relevance In Sweden, maternal overweight and obesity during pregnancy were associated with increased risks of preterm delivery, especially extremely preterm delivery. These associations should be assessed in other populations.

N° 752 Topic: Breast Cancer
Thorsten Kuehn et al (The Lancet Oncology, Volume 14, Issue 7, Pages 609 - 618, June 2013 doi:10.1016/S1470-2045(13)70166-9) reported results of the prospective, multicentre cohort study :"Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA)", which was designed to evaluate a specific algorithm for timing of a standardised sentinel-lymph-node biopsy procedure in patients who undergo neoadjuvant chemotherapy.

SENTINA is a four-arm, prospective, multicentre cohort study (103 institutions in Germany and Austria, 1737 breast cancer patients scheduled for neoadjuvant chemotherapy). clinically node-negative disease (cN0) Patients underwent sentinel-lymph-node biopsy before neoadjuvant chemotherapy (arm A). If the sentinel node was positive (pN1), a second sentinel-lymph-node biopsy procedure was done after neoadjuvant chemotherapy (arm B). Women with clinically node-positive disease (cN+) received neoadjuvant chemotherapy. Those who converted to clinically node-negative disease after chemotherapy (ycN0; arm C) were treated with sentinel-lymph-node biopsy and axillary dissection. Only patients whose clinical nodal status remained positive (ycN1) underwent axillary dissection without sentinel-lymph-node biopsy (arm D). The primary endpoint was accuracy (false-negative rate) of sentinel-lymph-node biopsy after neoadjuvant chemotherapy for patients who converted from cN1 to ycN0 disease during neoadjuvant chemotherapy (arm C). Secondary endpoints included comparison of the detection rate of sentinel-lymph-node biopsy before and after neoadjuvant chemotherapy, and also the false-negative rate and detection rate of sentinel-lymph-node biopsy after removal of the sentinel lymph node. Analyses were done according to treatment received (per protocol).

Findings
Of 1737 patients who received treatment, 1022 women underwent sentinel-lymph-node biopsy before neoadjuvant chemotherapy (arms A and B), with a detection rate of 99·1% (95% CI 98·3—99·6; 1013 of 1022). In patients who converted after neoadjuvant chemotherapy from cN+ to ycN0 (arm C), the detection rate was 80·1% (95% CI 76·6—83·2; 474 of 592) and false-negative rate was 14·2% (95% CI 9·9—19·4; 32 of 226). The false-negative rate was 24·3% (17 of 70) for women who had one node removed and 18·5% (10 of 54) for those who had two sentinel nodes removed (arm C). In patients who had a second sentinel-lymph-node biopsy procedure after neoadjuvant chemotherapy (arm B), the detection rate was 60·8% (95% CI 55·6—65·9; 219 of 360) and the false-negative rate was 51·6% (95% CI 38·7—64·2; 33 of 64).

Interpretation
Sentinel-lymph-node biopsy is a reliable diagnostic method before neoadjuvant chemotherapy. After systemic treatment or early sentinel-lymph-node biopsy, the procedure has a lower detection rate and a higher false-negative rate compared with sentinel-lymph-node biopsy done before neoadjuvant chemotherapy. These limitations should be considered if biopsy is planned after neoadjuvant chemotherapy.



N° 751 Topic: Women’s health
Prediction of Regression and Relapse of Endometrial Hyperplasia With Conservative Therapy

Gallos et al (Obstetrics & Gynecology. 121(6):1165-1171, June 2013. doi: 10.1097/AOG.0b013e31828cb563) identified predictors for regression and relapse of endometrial hyperplasia treated with levonorgestrel-releasing intrauterine system or oral progestogens using a cohort study of women treated with levonorgestrel-releasing intrauterine system or oral progestogens for complex hyperplasia or atypical complex hyperplasia.

Regression was evaluated in 344 women over a 12-year period, with a median follow-up of 58.8 months for levonorgestrel-releasing intrauterine system compared with 95.1 months for oral progestogens. In women treated with levonorgestrel-releasing intrauterine system for complex hyperplasia, 221 women regressed (96.5%, 221/229) and BMI 35 or higher was associated with 5 fold higher failure to regress. Relapse was evaluated in 219 women over a 9-year period, with median follow-up of 67 months for levonorgestrel-releasing intrauterine system and 96.8 months for oral progestogens. In women treated with levonorgestrel-releasing intrauterine system for complex hyperplasia, 18 women experienced relapse (12.7%, 18/142) and BMI 35 or higher was found to be a strong independent predictor of relapsed endometrial hyperplasia (HR 18.93, 95% CI 3.93–91.15; P<.001). Only 3.3% of women with complex hyperplasia treated with levonorgestrel-releasing intrauterine system and with BMI less than 35 experienced relapse during long-term follow-up compared with 32.6% of women with BMI 35 or higher.

CONCLUSION: Body mass index 35 or higher is strongly associated with failure to regress and relapse of complex hyperplasia treated with levonorgestrel-releasing intrauterine system.

LEVEL OF EVIDENCE: II

N° 750 Topic: Women’s health
DiBonaventura et al (Int J Womens Health. 2013 May 24;5:261-9. doi: 10.2147/IJWH.S39027. Print 2013.) examined the burden of vasomotor symptoms (VMS) in women aged 40–75 years from France, Germany, Italy, Spain, and the UK. The conducted an Industry sponsored Internet-based survey using the Menopausal Rating Scale. Over half (50.3%) of postmenopausal women experienced either mild (24.6%), moderate (17.6%), or severe (8.1%) VMS. The authors concluded that these symptoms are also associated with both humanistic and economic outcomes. Improved management of VMS may be able to increase the health status and ability to work productively as well as reduce societal direct costs.

N° 749 Topic: Women’s health
(Rosner, et al The Journal of Clinical Endocrinology & Metabolism April 1, 2013 vol. 98 no. 4 1376-1387 )
Challenges to the Measurement of Estradiol: An Endocrine Society Position Statement concluded that The measurement of estradiol in biological fluids is important in human biology from cradle to grave. In addition to its centrality in sexual development, it has significant effects on skin, blood vessels, bone, muscle, coagulation, hepatic cells, adipose tissue, the kidney, the gastrointestinal tract, brain, lung, and pancreas. Alterations in its plasma concentration have been implicated in coronary artery disease, stroke, and breast cancer. Although modern immunoassays and liquid chromatography/tandem mass spectrometry-based methods for estradiol are reasonably well suited to the diagnosis and management of infertility (nonetheless, imprecision and method-to-method differences remain problematic), the very low concentrations that appear to be crucial in nonreproductive tissues are a separate and more difficult issue. Such levels of estradiol are too low to be routinely measured accurately or precisely, and further evolution of analytical methods and the way in which estradiol is standardized is needed.

N° 748 Topic: Women’s health, Vitamin D, pregnancy, Bone Mineral Content
Debbie A Lawlor et al (The Lancet, Early Online Publication, 19 March 2013
doi:10.1016/S0140-6736(12)62203) studied the association of maternal vitamin D status during pregnancy with bone-mineral content in offspring using a prospective cohort study with a follow up of 9—10 years in 3960 mother-and-offspring pairs, mainly of white European origin. They found no relevant association between maternal vitamin D status in pregnancy and offspring BMC in late childhood.

N° 747 Topic: Menopause, women’s health
Parker et al (Obstetrics & Gynecology. 121(4):709-716, April 2013. doi: 10.1097/AOG.0b013e3182864350) reported long-term mortality after oophorectomy or ovarian conservation at the time of hysterectomy in subgroups of women based on age at the time of surgery, use of estrogen therapy, presence of risk factors for coronary heart disease, and length of follow-up using the prospective cohort study of 30,117
Nurses’ Health Study participants. Bilateral oophorectomy was associated with increased mortality in women aged younger than 50 years who never used estrogen therapy; at no age was oophorectomy associated with increased survival.

The article is momentarily freely available on http://journals.lww.c om/greenjournal/pages/default.aspx

N° 746 Topic: Women’s health
Effects of Promoting Longer-term and Exclusive Breastfeeding on child obesity
Richard M. Martin et al (JAMA. 2013;309(10):1005-1013. doi:10.1001/jama.2013.167.) investigated effects of an intervention to promote increased duration and exclusivity of breastfeeding on child adiposity and circulating insulin-like growth factor (IGF)-I, which regulates growth, since some studies suggested that that longer-term and exclusive breastfeeding may reduce child obesity .
They conducted a Cluster-randomized controlled trial in 31 Belarusian maternity hospitals and their affiliated clinics, randomized into 1 of 2 groups: breastfeeding promotion intervention (n = 16) or usual practices (n = 15). Participants were 17 046 breastfeeding mother-infant pairs enrolled in 1996 and 1997, of whom 13 879 (81.4%) were followed up between January 2008 and December 2010 at a median age of 11.5 years. The intervention was the Breastfeeding promotion intervention modeled on the WHO/UNICEF Baby-Friendly Hospital Initiative (World Health Organization/United Nations Children's Fund).
The experimental intervention substantially increased breastfeeding duration and exclusivity when compared with the control (43% vs 6% exclusively breastfed at 3 months and 7.9% vs 0.6% at 6 months) but did not prevent overweight or obesity, nor did it affect IGF-I levels at age 11.5 years.
Breastfeeding may have many advantages but population strategies to increase the duration and exclusivity of breastfeeding are unlikely to curb the obesity epidemic.

N° 745 Topic: Breast cancer
Circulating Tumor DNA to Monitor Metastatic Breast Cancer
Sarah-Jane Dawson et al (N Engl J Med 2013. DOI: 10.1056/NEJMoa1213261) analysed the use of Circulating Tumor DNA to Monitor Metastatic Breast Cancer. They compared the radiographic imaging of tumors with the assay of circulating tumor DNA, CA 15-3, and circulating tumor cells in 30 women with metastatic breast cancer who were receiving systemic therapy. They used targeted or whole-genome sequencing to identify somatic genomic alterations and designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens. CA 15-3 levels and numbers of circulating tumor cells were measured at identical time points. Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%).


N° 744 Topic: Women’s health, cardiovascular breast cancer
Risk of Ischemic Heart Disease in Women after Radiotherapy for Breast Cancer
Sarah C. Darby, et al N Engl J Med 2013; 368:987-998March 14, 2013 conducted a population-based case–control study of major coronary events (i.e., myocardial infarction, coronary revascularization, or death from ischemic heart disease) in 2168 women who underwent radiotherapy for breast cancer between 1958 and 2001 in Sweden and Denmark; the study included 963 women with major coronary events and 1205 controls. For each woman, the mean radiation doses to the whole heart and to the left anterior descending coronary artery were estimated from her radiotherapy chart. The overall average of the mean doses to the whole heart was 4.9 Gy (range, 0.03 to 27.72). Rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per gray (95%CI, 2.9- 14.5; P<0.001), with no apparent threshold. The increase started within the first 5 years after radiotherapy and continued into the third decade after radiotherapy. The proportional increase in the rate of major coronary events per gray was similar in women with and women without cardiac risk factors at the time of radiotherapy.

N° 743 Topic: Women’s health, obstetrics
Cox et al (BMJ 2013;346:f441 ) studied in Flanders the cohort of live born singleton births delivered at 24–44 weeks of gestation (n=606 877, with n=448 520 spontaneous deliveries). They found reductions in the risk of preterm birth after the introduction of each phase of the smoking ban. A step change in the risk of spontaneous preterm delivery of −3.13% (95% CI −4.37% to −1.87%; P<0.01) occurred on 1 January 2007 (ban on smoking in restaurants), and an annual slope change of −2.65% (−5.11% to −0.13%; P=0.04) after 1 January 2010 (ban on smoking in bars serving food). The analysis for all births gave similar results: a step change of −3.18% (−5.38% to −0.94%; P<0.01) on 1 January 2007, and an annual slope change of −3.50% (−6.35% to −0.57%; P=0.02) after 1 January 2010. These changes could not be explained by personal factors (infant sex, maternal age, parity, socioeconomic status, national origin, level of urbanisation); time related factors (underlying trends, month of the year, day of the week); or population related factors (public holidays, influenza epidemics, and short term changes in apparent temperature and particulate air pollution).
This study shows a consistent pattern of reduction in the risk of preterm delivery with successive population interventions to restrict smoking.


N° 742 Topic: Women’s health
Work stress and risk of cancer: meta-analysis of 5700 incident cancer events in 116 000 European men and women (BMJ 2013;346:f165)
Katriina Heikkilä et al investigated whether work related stress, measured and defined as job strain, is associated with the overall risk of cancer and the risk of colorectal, lung, breast, or prostate cancers.
They conducted a Meta-analysis of pooled prospective individual participant data from 12 European cohort studies including 116 056 men and women aged 17-70 who were free from cancer at study baseline and were followed-up for a median of 12 years. Work stress was measured and defined as job strain, which was self reported at baseline. Incident cancers (all n=5765, colorectal cancer n=522, lung cancer n=374, breast cancer n=1010, prostate cancer n=865) were ascertained from cancer, hospital admission, and death registers. Data were analysed in each study with Cox regression and the study specific estimates pooled in meta-analyses. Models were adjusted for age, sex, socioeconomic position, body mass index (BMI), smoking, and alcohol intake There was no clear evidence for an association between the categories of job strain and the risk of cancer.


N° 741 Topic: Osteoporosis, Cancer

Exposure to bisphosphonates and risk of gastrointestinal cancers: series of nested case-control studies with QResearch and CPRD data
Vinogradova et al (BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f114 (Published 16 January 2013) Cite this as: BMJ 2013;346:f114 ) investigated the association between use of bisphosphonates estimated from prescription information and risk of gastrointestinal cancers using a series of nested case-control studies based on general practices in the United Kingdom contributing to the QResearch primary care database (660) and the Clinical Practice Research Datalink (CPRD) (643).
Patients aged ≥50 with a diagnosis of a primary gastrointestinal cancer in 1997-2011 were each matched with up to five controls by age, sex, practice, and calendar year.
Odds ratios for incident gastrointestinal cancers (colorectal, oesophageal, gastric) and use of bisphosphonates were calculated, adjusted for smoking status, ethnicity, comorbidities, and use of other drugs.
20 106 and 19 035 cases of colorectal cancer cases, 5364 and 5135 cases of oesophageal cancer cases, and 3155 and 3157 cases of gastric cancer were identified from QResearch and CPRD, respectively. Overall bisphosphonate use (at least one prescription) was not associated with risk of colorectal, oesophageal, or gastric cancers in either database. Adjusted OR (95%CI) for QResearch and CPRD were 0.97 (0.79- 1.18) and 1.18 (0.97 - 1.43) for oesophageal cancer; 1.12 (0.87 - 1.44) and 0.79 (0.62 -1.01) for gastric cancer; and 1.03 (0.94 - 1.14) and 1.10 (1.00 - 1.22) for colorectal cancer. Additional analyses showed no difference between types of bisphosphonate for risk of oesophageal and colorectal cancers. For gastric cancer, alendronate use was associated with an increased risk (1.47, 1.11- 1.95; P=0.008), but only in data from the QResearch database and without any association with duration and with no definitive confirmation from sensitivity analysis.
Conclusions In this series of population based case-control studies in two large primary care databases, exposure to bisphosphonates was not associated with an increased risk of common gastrointestinal cancers.


N° 740 Topic: Women’s health, Fertility

Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study
Henriksson et al ( BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.e8632 (Published 15 January 2013) Cite this as: BMJ 2013;346:e8632) estimated the risk of pulmonary embolism and venous thromboembolism in pregnant women after in vitro fertilization using a cross sectional study in Sweden. 23 498 women who had given birth after in vitro fertilisation between 1990 and 2008 were matched to 116 960 individually women with natural pregnancies. Venous thromboembolism occurred in 4.2/1000 women (n=99) after in vitro fertilisation compared with 2.5/1000 (n=291) in women with natural pregnancies (HR 1.77, 95% CI 1.41 - 2.23). The risk of venous thromboembolism was increased during the whole pregnancy (P<0.001) and differed between the trimesters (P=0.002). The risk was particularly increased during the first trimester, at 1.5/1000 after in vitro fertilisation versus 0.3/1000 (HR 4.22, 2.46- 7.26). The proportion of women experiencing pulmonary embolism during the first trimester was 3.0/10 000 after in vitro fertilisation versus 0.4/10 000 (HR 6.97, 2.21- 21.96).


N° 739 Topic: Women’s health

Levonorgestrel Intrauterine System versus Medical Therapy for Menorrhagia
Janesh Gupta et al (N Engl J Med 2013; 368:128-137January 10, 2013DOI: 10.1056/NEJMoa1204724) randomly assigned 571 women with menorrhagia to treatment with levonorgestrel-IUS or usual medical treatment (tranexamic acid, mefenamic acid, combined estrogenâprogestogen, or progesterone alone). The primary outcome was the patient-reported score on the Menorrhagia Multi-Attribute Scale (MMAS) (ranging from 0 to 100, with lower scores indicating greater severity), assessed over a 2-year period. Secondary outcomes included general quality-of-life and sexual-activity scores and surgical intervention.
MMAS scores improved from baseline to 6 months in both the levonorgestrel-IUS group and the usual-treatment group (mean increase, 32.7 and 21.4 points, respectively; P<0.001 for both comparisons). The improvements were maintained over a 2-year period but were significantly greater in the levonorgestrel-IUS group than in the usual-treatment group (mean between-group difference, 13.4 points; 95% confidence interval, 9.9 to 16.9; P<0.001). Improvements in all MMAS domains (practical difficulties, social life, family life, work and daily routine, psychological well-being, and physical health) were significantly greater in the levonorgestrel-IUS group than in the usual-treatment group, and this was also true for seven of the eight quality-of-life domains. At 2 years, more of the women were still using the levonorgestrel-IUS than were undergoing the usual medical treatment (64% vs. 38%, P<0.001). There were no significant between-group differences in the rates of surgical intervention or sexual-activity scores. There were no significant differences in serious adverse events between groups.
The authors concluded that in women with menorrhagia who presented to primary care providers, the levonorgestrel-IUS was more effective than usual medical treatment in reducing the effect of heavy menstrual bleeding on quality of life.


N° 738 Topic: Premature menopause, oncology
Gonadatrophin Suppression to Prevent Chemotherapy-Induced Ovarian Damage: A Randomized Controlled Trial
Elgindy, et al (Obstetrics & Gynecology: January 2013 - Volume 121 - Issue 1 - p 78–86
doi: http://10.1097/AOG.0b013e31827374e2) estimated the effectiveness of gonadotropin-releasing hormone (GnRH) analogues cotreatment in preventing chemotherapy-induced amenorrhea in young breast cancer patients undergoing cyclophosphamide-based chemotherapy in 100 hormone-insensitive breast cancer participants (aged 18-40 years) in Egypt. Fifty women ready for early chemotherapy were randomized to receive either chemotherapy alone (arm I) or chemotherapy after downregulation (estradiol less than 50 pg/mL) by GnRH antagonist and agonist (arm II). Then, GnRH antagonist was discontinued and agonist was continued until the end of chemotherapy. When chemotherapy was to start later than 10 days after study inclusion, 50 women were randomized to receive either chemotherapy alone (arm III) or chemotherapy after downregulation with GnRH agonist (arm IV). Resumption of menstruation at 12 months after end of chemotherapy was the primary outcome. Postchemotherapy hormonal and ultrasound changes were secondary outcomes.
Twelve months after termination of chemotherapy, there were no differences in menstruation resumption rates between GnRH-treated patients and control group individuals in either early (80% in arms I and II, risk ratio 1, 95% confidence interval 0.7-.32; P=1.00) or delayed chemotherapy groups (80% and 84% in arms III and IV, risk ratio 0.95, 95% confidence interval 0.73-1.235; P=.71).
There were no differences in hormonal and ultrasound markers between GnRH analogue users and control group individuals. The use of GnRH analogue cotreatment did not predict independently the odds of menstruating at 12 months.


N° 737 Topic: Women’s health, cancer
Risk-Reducing Salpingo-oophorectomy (RRSO) and Ovarian Cancer Screening in 1077 Women After BRCA Testing
Gabriel N. Mannis, et al (Arch Intern Med. 2012;():1-8. doi:10.1001/2013.jamainternmed.962. ) surveyed a large cohort of women after BRCA testing to identify the prevalence and posttest predictors of risk-reducing and screening interventions, a median of 3.7 years after BRCA testing, in 1447 women who received genetic counseling and BRCA testing. Among the respondents (77.6% response rate), 201 women (18.7%) received positive test results for a deleterious mutation, 103 women (9.6%) received true-negative results, and 773 women (71.8%) received uninformative results. Overall, 19.1% of eligible women underwent RRSO and 39.6% used screening procedures. A positive BRCA result predicted RRSO (odds ratio [OR], 28.1; 95% CI, 16.2-48.6), TVUS (9.5 [4.3-21.0]), and serum CA-125 (13.0 [5.5-29.0]). Similarly, a true-negative BRCA result reduced the OR for RRSO (0.1 [0.0-0.6]), TVUS (0.2 [0.1-0.5]), and serum CA-125 (0.3 [0.1-0.7]). Of the 71.8% of women who received uninformative results after BRCA testing, 12.3% subsequently underwent RRSO, 33.8% reported ever having undergone screening serum CA-125 since BRCA testing, and 37.3% reported ever having undergone screening TVUS since BRCA testing.
Conclusions Results of BRCA testing strongly predict RRSO and ovarian cancer screening. Use of RRSO and ovarian screening was reported in a sizable percentage of non- BRCA carriers despite insufficient data to determine the effectiveness of these interventions.

N° 735 Topic: breast cancer
Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial
Davis et al (lancet h ttp://ww w.th elanc et.co m/po pup ? fileName=cite- using- doi) report that Interpretation
For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis.


N° 734 Topic: Domestic violence
Extracts from Intimate-Partner Violence (IPV) — What Physicians Can Do Jane M. Liebschutz, M.D., M.P.H., and Emily F. Rothman, Sc.D.
NEJM 2012

All health care providers should be alert to aspects of patients’ histories or symptoms that could suggest IPV and then should follow up with specific questions.
. …all primary care physicians should now be screening female patients 12 years of age or older for IPV. Specialty professional organizations recommend that obstetricians and pediatricians also consider performing regular IPV screening.
Numerous IPV screening instruments may be used to begin a dialogue with the patient; one of them (known as HITS) is shown in the table. Another question that may be used to start a discussion about safety at home is
simply, “Are you afraid of your partner or anyone else?”
There are several steps doctors should take when patients report potential IPV.
First, clinicians should acknowledge the patient’s admission of abuse: we advise thanking the patient for trusting the provider with the information and expressing concern about the patient’s safety.
Second, we suggest asking the patient if he or she would like to be connected to IPV advocacy services.
If patients do want legal assistance, counseling, shelter, or other services, local domestic violence agencies affiliated with the state coalition are likely to be the most reliable resources (see box).
Third, clinicians should offer the patient the National Domestic Violence hotline number (see box);
Fourth, clinicians should consider whether child protective services are required.
Fifth, they should screen the patient for coexisting depression, anxiety, and substance abuse.
Use caution when prescribing sedatives, since the sedating action may diminish patients’ physical or mental ability to defend themselves.
Even if a patient screen negative, we would encourage the provider to state that many patients do experience IPV at some point and that there are many resources to help people who feel unsafe in their relationships.


N° 733 TOPIC: Breast cancer, screening
Effect of Three Decades of Screening Mammography on Breast-Cancer Incidence
Archie Bleyer, et al (N Engl J Med 2012; 367:1998-2005November 22, 2012DOI: 10.1056/NEJMoa1206809) used Surveillance, Epidemiology, and End Results data to examine trends from 1976 through 2008 in the incidence of early-stage breast cancer (ductal carcinoma in situ and localized disease) and late-stage breast cancer (regional and distant disease) among women 40 years of age or older.
The introduction of screening mammography in the United States has been associated with a doubling in the number of cases of early-stage breast cancer that are detected each year, from 112 to 234 cases per 100,000 women — an absolute increase of 122 cases per 100,000 women. Concomitantly, the rate at which women present with late-stage cancer has decreased by 8%, from 102 to 94 cases per 100,000 women — an absolute decrease of 8 cases per 100,000 women. With the assumption of a constant underlying disease burden, only 8 of the 122 additional early-stage cancers diagnosed were expected to progress to advanced disease. After excluding the transient excess incidence associated with hormone-replacement therapy and adjusting for trends in the incidence of breast cancer among women younger than 40 years of age, they estimated that breast cancer was overdiagnosed (i.e., tumors were detected on screening that would never have led to clinical symptoms) in 1.3 million U.S. women in the past 30 years. The authors estimated that in 2008, breast cancer was overdiagnosed in more than 70,000 women; this accounted for 31% of all breast cancers diagnosed.
Conclusions:
Despite substantial increases in the number of cases of early-stage breast cancer detected, screening mammography has only marginally reduced the rate at which women present with advanced cancer. Although it is not certain which women have been affected, the imbalance suggests that there is substantial overdiagnosis, accounting for nearly a third of all newly diagnosed breast cancers, and that screening is having, at best, only a small effect on the rate of death from breast cancer.

N° 732 TOPIC: Women’s health, cancer Statin Use and Reduced Cancer-Related Mortality
Sune F. Nielsen, et al (N Engl J Med 2012; 367:1792-1802November 8, 2012DOI: 10.1056/NEJMoa1201735) tested the hypothesis that statin use begun before a cancer diagnosis is associated with reduced cancer-related mortality using mortality among patients from the entire Danish population who had received a diagnosis of cancer between 1995 and 2007, with follow-up until December 31, 2009. Among patients 40 years of age or older, 18,721 had used statins regularly before the cancer diagnosis and 277,204 had never used statins. Multivariable-adjusted HR for statin users, as compared with patients who had never used statins, were 0.85 (95% CI, 0.83 to 0.87) for death from any cause and 0.85 (95% CI, 0.82 to 0.87) for death from cancer. The reduced cancer-related mortality among statin users as compared with those who had never used statins was observed for each of 13 cancer types.

N° 731 TOPIC: Fracture Risk and Zoledronic Acid Therapy in Men with Osteoporosis
Steven Boonen, M.D., Ph.D., Jean-Yves Reginster, M.D., Ph.D., Jean-Marc Kaufman, M.D., et al (N Engl J Med 2012; 367:1714-1723November 1, 2012DOI: 10.1056/NEJMoa1204061) studied the effect of zoledronic acid or blacebo ( + calcium and vitamin D) in 1199 men with primary or hypogonadism-associated osteoporosis who were 50 to 85 years of age. The rate of any new morphometric vertebral fracture was 1.6% in the zoledronic acid group and 4.9% in the placebo group over the 24-month period, representing a 67% risk reduction with zoledronic acid (RR, 0.33; 95% CI, 0.16- 0.70; P=0.002). As compared with men who received placebo, men who received zoledronic acid had fewer moderate-to-severe vertebral fractures (P=0.03) and less height loss (P=0.002). Fewer participants who received zoledronic acid had clinical vertebral or nonvertebral fractures, although this difference did not reach significance because of the small number of fractures. Bone mineral density was higher and bone-turnover markers were lower in the men who received zoledronic acid (P<0.05 for both comparisons). Results were similar in men with low serum levels of total testosterone. The zoledronic acid and placebo groups did not differ significantly with respect to the incidence of death (2.6% and 2.9%, respectively) or serious adverse events (25.3% and 25.2%).


N° 730 TOPIC: BREAST CANCER
Rita S. Mehta, et al (N Engl J Med 2012; 367:435-444August 2, 2012) tested whether the Combination of Anastrozole and Fulvestrant would be more effective than anastrozole alone in patients with hormone-receptor (HR)–positive metastatic breast cancer
Postmenopausal women with previously untreated metastatic disease were randomly assigned, in a 1:1 ratio, to receive either 1 mg of anastrozole orally every day (group 1), with crossover to fulvestrant alone strongly encouraged if the disease progressed, or anastrozole and fulvestrant in combination (group 2). Patients were stratified according to prior or no prior receipt of adjuvant tamoxifen therapy. Fulvestrant was administered intramuscularly at a dose of 500 mg on day 1 and 250 mg on days 14 and 28 and monthly thereafter. The primary end point was progression-free survival, with overall survival designated as a prespecified secondary outcome. The median progression-free survival was 13.5 months in group 1 and 15.0 months in group 2 (HR for progression or death with combination therapy, 0.80; 95% [CI], 0.68 to 0.94; P=0.007 by the log-rank test). The combination therapy was generally more effective than anastrozole alone in all subgroups, with no significant interactions. Overall survival was also longer with combination therapy (median, 41.3 months in group 1 and 47.7 months in group 2; HR for death, 0.81; 95% CI, 0.65 to 1.00; P=0.05 by the log-rank test), despite the fact that 41% of the patients in group 1 crossed over to fulvestrant after progression. Three deaths that were possibly associated with treatment occurred in group 2. The rates of grade 3 to 5 toxic effects did not differ significantly between the two groups.
Conclusions
The combination of anastrozole and fulvestrant was superior to anastrozole alone or sequential anastrozole and fulvestrant for the treatment of HR-positive metastatic breast cancer, despite the use of a dose of fulvestrant that was below the current standard. (Funded by the National Cancer Institute and AstraZeneca; SWOG ClinicalTrials.gov number, NCT00075764.)


N° 729 TOPIC: MENOPAUSE
A decade after the Women's Health Initiative—the experts do agree
Stuenkel et al Fertil & Steril 9.07.12 in press
Overview: ,Systemic hormone therapy is an acceptable option for relatively young (up to age 59 or within 10 years of menopause) and healthy women who are bothered by moderate to severe menopausal symptoms. Individualization is key in the decision to use hormone therapy. Consideration should be given to the woman's quality-of-life priorities as well as her personal risk factors such as age, time since menopause, and her risk of blood clots, heart disease, stroke, and breast cancer.
Symptom Relief Benefits
Systemic hormone therapy is the most effective treatment for most menopausal symptoms, including vasomotor symptoms and vaginal atrophy. Estrogen therapy as a single agent is sufficient in women who have undergone hysterectomy.
Progestogen therapy is required to prevent endometrial cancer when estrogen is used systemically in women with a uterus.
Local estrogen therapy is effective and preferred for women whose symptoms are limited to vaginal dryness or discomfort with intercourse; low-dose vaginal estrogen therapy is recommended in this setting.
Hormone therapy risks
Vascular Risks
Both estrogen therapy and estrogen with progestogen therapy increase the risk of venous thromboembolic events—deep vein thrombosis and pulmonary emboli. Although the risks of venous thromboembolic events and ischemic stroke increase with either estrogen therapy or estrogen and progestogen therapy, the risk is rare in the 50- to 59-year-old age group.
Breast Cancer
An increased risk of breast cancer is seen with 5 years or more of continuous estrogen with progestogen therapy, possibly earlier with continuous use since menopause. The risk is real but not great, and the risk decreases after hormone therapy is discontinued. Use of estrogen alone for a mean of 7 years in the Women's Health Initiative did not increase the risk of breast cancer.
Duration of therapy
The lowest dose of hormone therapy should be used for the shortest amount of time to manage menopausal symptoms. Although fewer than 5 years is recommended for estrogen with progestogen therapy, duration should be individualized.
For estrogen therapy alone, more flexibility in duration of therapy may be possible. There are reports of increased risk of breast cancer after 10 to 15 years of use in large observational studies with estrogen alone.
Additional information
In observational studies, both transdermal estrogen therapy and low-dose oral estrogen therapy have been associated with lower risks of venous thromboembolic events and stroke than standard doses of oral estrogen, but comparison randomized clinical trials are not yet available.
Many options for Food and Drug Administration–approved bioidentical hormone therapy (estradiol and progesterone) are available. Evidence is lacking that custom compounded bioidentical hormone therapy is safe or effective. Many medical organizations and societies agree in recommending against the use of custom compounded hormone therapy for menopause management, particularly given concerns regarding content, purity, and labeling. There is a lack of safety data supporting the use of estrogen or estrogen with progestogen therapy in breast cancer survivors. Nonhormonal therapies should be the first approach in managing menopausal symptoms in breast cancer survivors.
Conclusion
Leading medical societies devoted to the care of menopausal women agree that the decision to initiate hormone therapy should be for the indication of treatment of menopause-related symptoms. Although research is ongoing and these recommendations may be modified over time, there is no question that hormone therapy has an important role in managing symptoms for women during the menopausal transition and in early menopause.


N° 728 TOPIC: BREAST CANCER AND OSTEOPOROSIS
I to K, Blinde r VS, Elkin EB (J Clin Oncol. 2012 May 1;30(13):1468-75. Epub 2012 Feb 27.)
Evaluated the "Cost effectiveness of fracture prevention in postmenopausal women who receive aromatase inhibitors for early breast cancer, using a Markov state transition model to simulate clinical practice and outcomes in a hypothetical cohort of women age 60 years with HR-positive EBC starting a 5-year course of AI therapy after primary surgery for breast cancer. Outcomes were quality-adjusted life-years (QALYs), lifetime cost, and incremental cost-effectiveness ratio (ICER). They compared the following strategies: no intervention; one-time bone mineral density (BMD) screening and selective bisphosphonate therapy in women with osteoporosis or osteopenia; annual BMD screening and selective bisphosphonate therapy in women with osteoporosis or osteopenia; and universal bisphosphonate therapy.
RESULTS:
ICERs for annual BMD screening followed by oral bisphosphonates for those with osteoporosis, annual BMD screening followed by oral bisphosphonates for those with osteopenia, and universal treatment with oral bisphosphonates were $87,300, $129,300, and $283,600 per QALY gained, respectively. One-time BMD screening followed by oral bisphosphonates for those with osteoporosis or osteopenia was dominated. These results were sensitive to age at the initiation of AI therapy, type of bisphosphonates, post-treatment residual effect of bisphosphonates, and a potential adjuvant benefit of intravenous bisphosphonates.
CONCLUSION:
In postmenopausal women receiving adjuvant AIs for HR-positive EBC, a policy of baseline and annual BMD screening followed by selective treatment with oral bisphosphonates for those diagnosed with osteoporosis is a cost-effective use of societal resources.



N° 726 TOPIC: WOMEN'S HEALTH, ENDOMETRIAL CANCER
Ha oula< /a> et al (Hum. Reprod. (2012) 27(5)) performed a systematic review of the literature to determine the exact strength of the association between polycystic ovary syndrome (PCOS) and endometrial cancer (EC). The non-comparative and comparative data suggested that women with PCOS were more likely to develop EC. A meta-analyses of five comparative studies showed an increased risk of EC in women with an odds ratio of 2.89 with a 95% confidence interval of 1.52–5.48. This translates into a 9% lifetime risk of EC in Caucasian women with PCOS compared with 3% in women without it.

N° 725 TOPIC: BREAST CANCER
The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups
C hri stina Curtis et al (Nature (2012) doi:10.1038/nature10983) presented an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up.
They identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network.
These results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.
A more simple explanation is provided in the BMJ 2012;344:e2829
“Before this study breast cancer was basically classified into four types according to whether the tumour was positive for receptors for oestrogen (Er+), human epidermal growth factor receptor 2 (Her2+), and progesterone (Pr+). Er+ tumours may respond to tamoxifen or aromatase inhibitors, whereas Her2+ tumours may respond to trastuzumab (Herceptin). Tumours that are negative for all these receptors are known as triple negative: they are very aggressive, the only treatment is chemotherapy, and there is no targeted therapy.
Seventy per cent of women have breast cancer that is Er+ and Her2−, and the researchers have now subdivided this group into seven subtypes. The likelihood that a woman with a high proliferation Er+ and Her2− tumour would be alive after 10 years is 75%, but when these tumours are subdivided into the seven new types the researchers found that survival varied from less than 40% to more than 80% after 15 years.
Of the other three new subtypes, one “robustly identifies” the Her2+ tumours, Caldas said. “All previous molecular tests have failed to do that properly.” The second contains most of the triple negative tumours, which have a very poor prognosis.
The third and final subtype contains a subset of Er+ tumours, a subset of Er− tumours, and a subset of triple negative tumours. What this group have in common is significant infiltration of inflammatory cells and lymphocytes. “This subset of breast cancer is a very important one for us to have recognised,” said Caldas, “because it looks like in this subset the immune system is playing a very active role in improving the prognosis of these women.”
Subsequent studies will try to understand why in this group the immune system seems to be particularly engaged and fighting against the tumour, giving the woman a better prognosis, Caldas predicted. “The fact that we know that breast cancer is not one disease but 10 different types of disease will allow us to go forward and look within these groups and see if we can detect differential responses.””

N° 724 TOPIC: URINARY INCONTINENCE
Tat yan a Shamliyan, et al (Annals of Internal Medicine April 3, 2012, 156 (7)) report a systematic Review on Benefits and Harms of Pharmacologic Treatment for Urinary Incontinence in Women. 94 RCTs were eligible. Pooled analyses showed that among drugs for urgency UI, per 1000 treated, continence was achieved in 130 with fesoterodine (CI, 58- 202), 85 with tolterodine (CI, 40-129), 114 with oxybutynin (CI, 64-163), 107 with solifenacin (CI, 58- 156), and 114 with trospium (CI, 83- 144). Rates of treatment discontinuation due to adverse effects were 31 per 1000 treated with fesoterodine (CI, 10- 56), 63 with oxybutynin (CI, 12- 127), 18 with trospium (CI, 4- 33), and 13 with solifenacin (CI, 1- 26). The studies' inconsistent definitions of improvement in UI and quality of life hampered synthesis of evidence.
Conclusion: Overall, drugs for urgency UI showed similar small benefit. Therapeutic choices should consider the harms profile. Evidence for long-term adherence and safety of treatments is lacking.

N° 723 TOPIC: BREAST CANCER
Anderson et al (WHI study) reported in the Lancet Oncol. 2012 Mar 6. [Epub ahead of print]) that after a median follow-up of 11·8 years (IQR 9·1-12·9), the use of oestrogen for a median of 5·9 years (2·5-7·3) was associated with lower incidence of invasive breast cancer (151 cases, 0·27% per year) compared with placebo (199 cases, 0·35% per year; HR 0·77, 95% CI 0·62-0·95; p=0·02) with no difference (p=0·76) between intervention phase (0·79, 0·61-1·02) and post-intervention phase effects (0·75, 0·51-1·09). In subgroup analyses, they noted that the breast cancer risk reduction with oestrogen use was concentrated in women without benign breast disease (p=0·01) or a family history of breast cancer (p=0·02). In the oestrogen group, fewer women died from breast cancer (six deaths, 0·009% per year) compared with controls (16 deaths, 0·024% per year; HR 0·37, 95% CI 0·13-0·91; p=0·03). Fewer women in the oestrogen group died from any cause after a breast cancer diagnosis (30 deaths, 0·046% per year) than did controls (50 deaths, 0·076%; HR 0·62, 95% CI 0·39-0·97; p=0·04).
The authors noted that these findings provide reassurance for women with hysterectomy seeking relief of climacteric symptoms in terms of the effects of oestrogen use for about 5 years on breast cancer incidence and mortality. However, their data do not support use of oestrogen for breast cancer risk reduction because any noted benefit probably does not apply to populations at increased risk of such cancer.

N° 722 TOPIC: MENOPAUSE
Mishra GD Kuh D (BMJ. 2012 Feb 8;344:e402. doi: 10.1136/bmj.e402) reported Health symptoms during midlife in relation to menopausal transition in a British prospective cohort study of 695 women followed-up since birth in 1946 and annually from age 47 to 54 who experienced natural menopause and reported on 20 common health symptoms. A small proportion of women (10%, n=63) had a severe psychological symptom profile that peaked at or in the year after menopause. For vasomotor symptoms, 14% of women (n=83) had the early severe profile that also peaked around early postmenopause and then declined noticeably; 11% (n=67) had the late severe profile of bothersome symptoms that increased rapidly in perimenopause and remained high for four years or more after menopause. Women were less likely to have a profile for severe vasomotor symptoms if they were from a non-manual social class (odds ratio 0.79, 95%CI 0.57 to 1.01) or had degree level qualifications (0.37, 0.18 to 0.77). The 14% of women (n=85) who had the late severe profile for sexual discomfort showed a similar increase in symptoms until menopause, with symptoms persisting after menopause. Married women were more likely to have the late severe or late moderate profile than women of other marital status (2.40, 1.30 to 4.41). Four profiles each were identified for somatic symptoms (mild, moderate, severe, and very severe), although these did not vary by chronological age or age at menopause.

N° 721 TOPIC: TVT, WOMEN’S HEALTH
The efficacy of tension-free vaginal tape (TVT) to transobturator tape in the treatment of women with stress urinary incontinence (SUI) and intrinsic sphincter deficiency at 3-year follow-up was studied in 164 women who were randomized to either treatment after diagnosis of urodynamic stress incontinence and intrinsic sphincter deficiency. Concomitant pelvic organ prolapse surgery was not an exclusion criterion. The primary outcome assessed at 3-year follow-up was symptomatic stress incontinence requiring repeat surgery. Secondary outcomes were quality-of-life parameters assessed by validated questionnaires and numerical success score.
At 3 years, 15 of the 75 (20%) women in the transobturator tape group underwent repeat surgery to correct SUI compared with one of the 72 (1.4%) in the TVT group. In other words, if TVT had been used exclusively, repeat surgery would have been avoided in one in six patients. The risk ratio of repeat surgery was 15 (95% CI: 2–113; P<.001) times greater in the transobturator tape group. In the transobturator tape group, the median time to repeat surgery was 15.6 months compared with 43.7 months for TVT (P<.001). The quality-of-life outcomes did show an improvement in both groups before and after surgery but no difference between the two slings in the Urogenital Distress Inventory short form, the Incontinence Impact Questionnaire short form, and a patient-rated numerical success score.
CONCLUSION: The long-term cure rates for retropubic TVT are significantly greater than for transobturator tape in women with urodynamic stress incontinence and intrinsic sphincter deficiency. Urethral functions tests such as urethral closure pressure and Valsalva leak point pressures are of value in determining what surgery to perform.

N° 716 TOPIC: BONE-DENSITY TESTING INTERVAL, WOMEN’S HEALTH
Bone-Density Testing Interval and Transition to Osteoporosis in Older Women
Gourlay et al (N Engl J Med 2012; 366:225-233January 19, 2012) studied 4957 women, 67 years of age or older, with normal BMD (T score at the femoral neck and total hip, −1.00 or higher) or osteopenia (T score, −1.01 to −2.49) and with no history of hip or clinical vertebral fracture or of treatment for osteoporosis, and followed prospectively for up to 15 years. The BMD testing interval was defined as the estimated time for 10% of women to make the transition to osteoporosis before having a hip or clinical vertebral fracture, with adjustment for estrogen use and clinical risk factors. Transitions from normal BMD and from three subgroups of osteopenia (mild, moderate, and advanced) were analyzed with the use of parametric cumulative incidence models. Incident hip and clinical vertebral fractures and initiation of treatment with bisphosphonates, calcitonin, or raloxifene were treated as competing risks.
The estimated BMD testing interval was 16.8 years (95% CI, 11.5- 24.6) for women with normal BMD, 17.3 years (95% CI, 13.9 to 21.5) for women with mild osteopenia, 4.7 years (95% CI, 4.2 to 5.2) for women with moderate osteopenia, and 1.1 years (95% CI, 1.0 to 1.3) for women with advanced osteopenia.
The authors concluded that osteoporosis would develop in less than 10% of older, postmenopausal women during rescreening intervals of approximately 15 years for women with normal bone density or mild osteopenia, 5 years for women with moderate osteopenia, and 1 year for women with advanced osteopenia.

N° 714 TOPIC: WOMEN’S HEALTH
Association between bisphosphonate use and implant survival after primary total arthroplasty of the knee or hip: population based retrospective cohort study
Daniel Prieto-Alhambra, et al (BMJ 2011; 343 doi: 10.1136/bmj.d7222 (Published 6 December 2011)
Cite this as: BMJ 2011;343:d7222 ) tested whether bisphosphonate use is related to improved implant survival after total arthroplasty of the knee or hip using a Population based retrospective cohort study involving all patients undergoing primary total arthroplasty of the knee (n=18 726) or hip (n=23 269) in 1986-2006 within the United Kingdom’s General Practice Research Database, after excluding patients with a history of hip fracture before surgery or rheumatoid arthritis, and individuals younger than 40 years at surgery. Of 41 995 patients undergoing primary hip or knee arthroplasty, they identified 1912 bisphosphonate users, who had a lower rate of revision at five years than non-users (0.93% (95% CI 0.52% to 1.68%) v 1.96% (1.80% to 2.14%)). Implant survival was significantly longer in bisphosphonate users than in non-users in propensity adjusted models (hazard ratio 0.54 (0.29 to 0.99); P=0.047) and had an almost twofold increase in time to revision after hip or knee arthroplasty (time ratio 1.96 (1.01 to 3.82)). Assuming 2% failure over five years, we estimated that the number to treat to avoid one revision was 107 for oral bisphosphonates. In patients undergoing lower limb arthroplasty, bisphosphonate use was associated with an almost twofold increase in implant survival time. These findings require replication and testing in experimental studies for confirmation.

N° 713 TOPIC: WOMEN’S HEALTH
Association of Antenatal Corticosteroids With Mortality and Neurodevelopmental Outcomes Among Infants Born at 22 to 25 Weeks' Gestation
W alde mar A. Carlo, et al (JAMA. 2011;306(21):2348-2358. doi: 10.1001/jama.2011.1752 ) determined if use of antenatal corticosteroids is associated with improvement in major outcomes for infants born at 22 and 23 weeks' gestation They analysed data collected prospectively on inborn infants with a birth weight between 401 g and 1000 g (N = 10 541) born at 22 to 25 weeks' gestation between I/ 1993, and XII/ 2009, at 23 academic perinatal centers in the United States. Certified examiners unaware of exposure to antenatal corticosteroids performed follow-up examinations on 4924 (86.5%) of the infants born between 1993 and 2008 who survived to 18 to 22 months. Death or neurodevelopmental impairment at 18 to 22 months was significantly lower for infants who had been exposed to antenatal corticosteroids and were born at 23 weeks' gestation (83.4% with exposure to antenatal corticosteroids vs 90.5% without exposure; AOR, 0.58 [95% CI, 0.42-0.80]), at 24 weeks' gestation (68.4% with exposure to antenatal corticosteroids vs 80.3% without exposure; AOR, 0.62 [95% CI, 0.49-0.78]), and at 25 weeks' gestation (52.7% with exposure to antenatal corticosteroids vs 67.9% without exposure; AOR, 0.61 [95% CI, 0.50-0.74]) but not in those infants born at 22 weeks' gestation (90.2% with exposure to antenatal corticosteroids vs 93.1% without exposure; AOR, 0.80 [95% CI, 0.29-2.21]). If the mothers had received antenatal corticosteroids, the following events occurred significantly less in infants born at 23, 24, and 25 weeks' gestation: death by 18 to 22 months; hospital death; death, intraventricular hemorrhage, or periventricular leukomalacia; and death or necrotizing enterocolitis. For infants born at 22 weeks' gestation, the only outcome that occurred significantly less was death or necrotizing enterocolitis (73.5% with exposure to antenatal corticosteroids vs 84.5% without exposure; AOR, 0.54 [95% CI, 0.30-0.97]).
Conclusion Among infants born at 23 to 25 weeks' gestation, antenatal exposure to corticosteroids compared with nonexposure was associated with a lower rate of death or neurodevelopmental impairment at 18 to 22 months.

N° 712 TOPIC: WOMEN’S HEALTH
Bilateral oophorectomy is not associated with increased mortality: the California Teachers Study.
Duan et al (Fertil Steril. 2011 Nov 14. [Epub ahead of print] investigated the effect of surgical menopause due to bilateral oophorectomy on mortality, in the "California Teachers Study (CTS)", a prospective cohort study of 133,479 women initiated in 1995-1996 through a mailed, self-administered questionnaire. Among participants aged <45 years at menopause, multivariable relative risks were 0.86 (95% CI, 0.74-1.00), 0.85 (95% CI, 0.66-1.11), and 0.91 (95% CI, 0.67-1.23) for all-cause mortality, cardiovascular mortality, and cancer mortality, respectively. Among participants with an age at menopause of ≥45 years, multivariable relative risks were 0.87 (95% CI, 0.80-0.94), 0.83 (95% CI, 0.71-0.96), and 0.84 (95% CI, 0.72-0.98) for all-cause, cardiovascular, and cancer mortality, respectively. The association between bilateral oophorectomy and mortality did not differ by baseline status of hormone therapy use.

N° 711 TOPIC: BREAST CANCER, WOMEN’S HEALTH
Statin prescriptions and breast cancer recurrence risk: a danish nationwide prospective cohort study.
Ahern TP, et al (J Natl Cancer Inst. 2011 Oct 5;103(19):1461-8. Epub 2011 Aug 2) conducted a nationwide, population-based prospective cohort study of all female residents in Denmark diagnosed with stage I-III invasive breast carcinoma who were reported to the Danish Breast Cancer Cooperative Group registry between 1996 and 2003 (n = 18 769). Women were followed for a median of 6.8 years after diagnosis. Prescriptions for lipophilic and hydrophilic statins were ascertained from the national electronic pharmacy database. Associations between statin prescriptions and breast cancer recurrence were estimated with generalized linear models and Cox proportional hazards regression with adjustment for age and menopausal status at diagnosis; histological grade; estrogen receptor status; receipt of adjuvant therapy; type of primary surgery received; pre-diagnosis hormone replacement therapy; and co-prescriptions of aspirin, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or anticoagulants. Most prescriptions for lipophilic statins in the study population were for simvastatin. Exclusive simvastatin users experienced approximately 10 fewer breast cancer recurrences per 100 women after 10 years of follow-up (adjusted 10-year risk difference = -0.10, 95% confidence interval = -0.11 to -0.08), compared with women who were not prescribed a statin. Exclusive hydrophilic statin users had approximately the same risk of breast cancer recurrence as women not prescribed a statin over follow-up (adjusted 10-year risk difference = 0.05, 95% confidence interval = -0.01 to 0.11). Conclusions Simvastatin, a highly lipophilic statin, was associated with a reduced risk of breast cancer recurrence among Danish women diagnosed with stage I-III breast carcinoma, whereas no association between hydrophilic statin use and breast cancer recurrence was observed.

N° 710 TOPIC: MENOPAUSE, SYMPTOMS
Aedo S, et al (Climacteric. 2011 Aug 24. [Epub ahead of print]) evaluated the efficacy of sertraline (50 mg/day) versus placebo in the management of somatic and psychological complaints of the climacteric syndrome using a RCT involving 44 women with moderate to severe complaints. A reduction of 50% or more in the score was considered as a successful response Thirty-three patients finished the trial showing an odds ratio of 7.94 (95% confidence interval 1.3-57.3), p = 0.0038 for the sertraline group, in spite of the prominent effect of placebo.

N° 709 TOPIC: BREAST CANCER
Effect of the Gonadotropin-Releasing Hormone Analogue Triptorelin on the Occurrence of Chemotherapy-Induced Early Menopause in Premenopausal Women With Breast Cancer : a RCT.
Luci a Del Mastro, et al (JAMA. 2011;306(3):269-276. doi: 10.1001/jama.2011.991 determined the effect of the temporary ovarian suppression obtained by administering the gonadotropin-releasing hormone analogue triptorelin during chemotherapy on the incidence of early menopause in young patients with breast cancer undergoing adjuvant or neoadjuvant chemotherapy. They enrolled 281 premenopausal women with stage I through III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy. Twelve months after the last cycle of chemotherapy, the rate of early menopause was 25.9% in the chemotherapy-alone group and 8.9% in the chemotherapy plus triptorelin group, an absolute difference of −17% (95% confidence interval, −26% to −7.9%; P < .001). The odds ratio for treatment-related early menopause was 0.28 (95% confidence interval, 0.14 to 0.59; P < .001).

N° 708 TOPIC: WOMEN'S HEALTH
Adherence to a Low-Risk, Healthy Lifestyle and Risk of Sudden Cardiac Death (SCD) Among Women...
Chiuve, et al (JAMA. 2011;306(1):62-69. doi: 10.1001/jama.2011.907) estimated the degree to which adherence to a healthy lifestyle may lower the risk of SCD among women using a prospective cohort study of 81 722 US women in the Nurses' Health Study from June 1984 to June 2010. Lifestyle factors were assessed via questionnaires every 2 to 4 years. A low-risk lifestyle was defined as not smoking, body mass index of less than 25, exercise duration of 30 minutes/day or longer, and top 40% of the alternate Mediterranean diet score, which emphasizes high intake of vegetables, fruits, nuts, legumes, whole grains, and fish and moderate intake of alcohol. There were 321 cases of SCD (defined as death occurring within 1 hour after symptom onset without evidence of circulatory collapse) during 26 years of follow-up. Women were a mean age of 72 years at the time of the SCD event. Compared with women with 0 low-risk factors, the multivariable relative risk of SCD was 0.54 (95% CI, 0.34-0.86) for women with 1 low-risk factor, 0.41 (95% CI, 0.25-0.65) for 2 low-risk factors, 0.33 (95% CI, 0.20-0.54) for 3 low-risk factors, and 0.08 (95% CI, 0.03-0.23) for 4 low-risk factors. The proportion of SCD attributable to smoking, inactivity, overweight, and poor diet was 81% (95% CI, 52%-93%). Among women without clinically diagnosed coronary heart disease, the percentage of population attributable risk was 79% (95% CI, 40%-93%).

N° 707 TOPIC: BREAST CANCER
Goss et al (N Engl J Med. 2011 Jun 4. [Epub ahead of print]) conducted a randomized, placebo-controlled, double-blind trial of exemestane designed to detect a 65% relative reduction in invasive breast cancer, in postmenopausal women at increased breast cancer risk. A total of 4560 women (median age 62.5 years, median Gail risk score was 2.3%) were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; HR, 0.35; 95% [CI], 0.18 to 0.70; P=0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (HR, 0.47; 95% CI, 0.27 to 0.79; P=0.004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P=0.003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatment-related deaths. Minimal quality-of-life differences were observed.
Conclusions: Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer.

N° 706 TOPIC: MENOPAUSE, WOMEN’S HEALTH, QUALITY OF LIFE
Duration of Menopausal Hot Flushes and Associated Risk Factors
Freeman, et al (Obstetrics & Gynecology. 117(5):1095-1104, May 2011. doi: 10.1097/AOG.0b013e318214f0de)
Freeman, et al. estimated the duration of moderate-to-severe menopausal hot flushes and identified potential risk factors for hot flush duration using “The Penn Ovarian Aging Study cohort”, which was monitored for 13 years. Hot flushes were evaluated at 9-month to 12-month intervals through in-person interviews. The primary outcome was the duration of moderate-to-severe hot flushes estimated by survival analysis (n=259). Potential risk factors included menopausal stage, age, race, reproductive hormone levels, body mass index (BMI), and current smoking. A secondary analysis included women who reported any hot flushes (n=349). The median duration of moderate-to-severe hot flushes was 10.2 years and was strongly associated with menopausal stage at onset. Hot flushes that started near entry into the menopause transition had a median duration greater than 11.57 years; onset in the early transition stage had a median duration of 7.35 years (95% CI 4.94–8.89; P<.001); and onset in the late transition to postmenopausal stages had a median duration of 3.84 years (95% CI 1.77–5.52; P<.001). The most common ages at onset of moderate-to-severe hot flushes were 45–49 years (median duration, 8.1 years; 95% CI 5.12–9.28). African American women had a longer duration of hot flushes than white women in adjusted analysis. They concluded that median duration of hot flushes considerably exceeded the timeframe that is generally accepted in clinical practice. The identified risk factors, particularly menopausal stage, race, and BMI, are important to consider in individualizing treatment and evaluating the risk-to-benefit ratio of hormones and other therapies.

N° 705 TOPIC: WOMEN’S HEALTH, PROLAPSE, INCONTINENCE
Anterior Colporrhaphy versus Transvaginal Mesh for Pelvic-Organ Prolapse
Daniel Altman, et al for the Nordic Transvaginal Mesh Group (N Engl J Med 2011; 364:1826-1836May 12, 2011)
Daniel Altman, et al. conducted a multicenter, parallel-group, randomized, controlled trial, comparing the use of a trocar-guided, transvaginal polypropylene-mesh repair kit with traditional colporrhaphy in women with prolapse of the anterior vaginal wall (cystocele). The primary outcome was a composite of the objective anatomical designation of stage 0 (no prolapse) or 1 (position of the anterior vaginal wall more than 1 cm above the hymen), according to the Pelvic Organ Prolapse Quantification system, and the subjective absence of symptoms of vaginal bulging 12 months after the surgery. Of 389 women who were randomly assigned to a study treatment, 200 underwent prolapse repair with the transvaginal mesh kit and 189 underwent traditional colporrhaphy. At 1 year, the primary outcome was significantly more common in the women treated with transvaginal mesh repair (60.8%) than in those who underwent colporrhaphy (34.5%) (absolute difference, 26.3 percentage points; 95% confidence interval, 15.6 to 37.0). The surgery lasted longer and the rates of intraoperative hemorrhage were higher in the mesh-repair group than in the colporrhaphy group (P<0.001 for both comparisons). Rates of bladder perforation were 3.5% in the mesh-repair group and 0.5% in the colporrhaphy group (P=0.07), and the respective rates of new stress urinary incontinence after surgery were 12.3% and 6.3% (P=0.05). Surgical reintervention to correct mesh exposure during follow-up occurred in 3.2% of 186 patients in the mesh-repair group. As compared with anterior colporrhaphy, use of a standardized, trocar-guided mesh kit for cystocele repair resulted in higher short-term rates of successful treatment but also in higher rates of surgical complications and postoperative adverse events.

N° 704 TOPIC: OSTEOPOROSIS
Bisphosphonate Use and Atypical Fractures of the Femoral Shaft
Jörg Schilcher, et al (N Engl J Med 2011; 364:1728-1737May 5, 2011)
Jörg Schilcher, et al reviewed radiographs of 1234 of the 1271 women who had a subtrochanteric or shaft fracture and identified 59 patients with atypical fractures. Data on medications and coexisting conditions were obtained from national registries. The relative and absolute risk of atypical fractures associated with bisphosphonate use was estimated by means of a nationwide cohort analysis. The 59 case patients were also compared with 263 control patients who had ordinary subtrochanteric or shaft fractures The age-adjusted relative risk of atypical fracture was 47.3 (95% CI, 25.6 to 87.3) in the cohort analysis. The increase in absolute risk was 5 cases per 10,000 patient-years (95% CI, 4 to 7). A total of 78% of the case patients and 10% of the controls had received bisphosphonates, corresponding to a multivariable-adjusted odds ratio of 33.3 (95% CI, 14.3 to 77.8). The risk was independent of coexisting conditions and of concurrent use of other drugs with known effects on bone. The duration of use influenced the risk (odds ratio per 100 daily doses, 1.3; 95% CI, 1.1 to 1.6). After drug withdrawal, the risk diminished by 70% per year since the last use (odds ratio, 0.28; 95% CI, 0.21 to 0.38). The authors concluded that these population-based nationwide analyses may be reassuring for patients who receive bisphosphonates. Although there was a high prevalence of current bisphosphonate use among patients with atypical fractures, the absolute risk was small. (Funded by the Swedish Research Council.)

N° 703 TOPIC: MENOPAUSE, WHI AND BREAST CANCER
Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy
(LaCroix et al. April 6, 2011 JAMA. 2011;305(13):1305-1314. doi: 10.1001/jama.2011.382)
WHI Investigators published a recent update of the RCT in (hysterectomied women) treated with conjugated equine estrogens after a mean of 10.7 years of follow-up through August 2009. The postintervention risk (annualized rate) for coronary hearth disease (CHD) among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (HR, 0.97; 95%CI, 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00; 95% CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27; 95% CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95). Health outcomes were more favorable for younger compared with older women for CHD (P = .05 for interaction), total myocardial infarction (P = .007 for interaction), colorectal cancer (P = .04 for interaction), total mortality (P = .04 for interaction), and global index of chronic diseases (P = .009 for interaction).
Conclusions: Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted.

N° 702 TOPIC: BREAST CANCER
Preventive therapy for breast cancer: a consensus statement (Jack Cuzick et al The Lancet Oncology, Early Online Publication, 28 March 2011 doi:10.1016/S1470-2045(11)70030-4)(doi:10.1016/S0140-6736(08)61345-8)
A group of breast cancer experts met to develop a consensus statement on breast cancer prevention. They agreed that the term chemoprevention is inappropriate and suggested that the term preventive therapy better represents this feature of management. Two selective oestrogen-receptor modulators—tamoxifen and raloxifene—are so far the only medical options approved by the US Food and Drug Administration for preventive therapy. Of these tamoxifen has greater efficacy and can be used in premenopausal women, but raloxifene has fewer side-effects. Two newer drugs in this class, lasofoxifene and arzoxifene, also show efficacy and possibly a better overall risk-benefit profile, but need further assessment. Aromatase inhibitors might be more efficacious, and results of prevention trials are eagerly awaited. Newer agents, notably bisphosphonates and metformin, have shown promise in observational studies and need to be assessed in randomised prevention trials. Other agents, such as aspirin, other non-steroidal anti-inflammatory drugs, COX-2 inhibitors, retinoids, rexinoids, and dietary components have limited effects or are in the early phases of investigation. New contralateral tumours in women with breast cancer might be generally useful as a model for prevention, as has been seen for tamoxifen. If valid such a model would facilitate the design of simpler, cheaper, and better-focused trials for assessing new agents.

N° 701 TOPIC: VITAMIN D AND WOMEN’S HEALTH
Vitamin D and Prevention of Cancer — Ready for Prime Time? (JE. Manson, ST. Mayne, SK. Clinton. March 23, 2011 (10.1056/NEJMp1102022)
Despite biologic plausibility and widespread enthusiasm, the American Institute of Medicine (IOM) committee found that the evidence that vitamin D reduces cancer incidence and related mortality was inconsistent and inconclusive as to causality. Indeed, for instance 3 vitamin D trials, including one trial comparing a combination of vitamin D with calcium to calcium alone, have assessed the occurrence of newly diagnosed cancers or cancer mortality as secondary outcomes, but the results were null. New trials assessing moderate-to-high-dose vitamin D supplementation for cancer prevention are in progress and should provide additional information within 5 to 6 years. Although future research may demonstrate clear benefits of vitamin D related to cancer and other nonskeletal health outcomes, and possibly support higher intake requirements, the existing evidence falls short.

N° 700 TOPIC: WOMEN’S HEALTH, BREAST CANCER, SMOKING
Cigarette Smoking and the Incidence of Breast Cancer
Fei Xue, et al ( Arch Intern Med. 2011;171(2):125-133. doi:10.1001/archinternmed.2010.503) evaluated the effect of smoking on breast cancer (BC) incidence in the prospective cohort study of 111 140 participants of the Nurses' Health Study from 1976 to 2006 for active smoking and 36 017 women from 1982 to 2006 for passive smoking. During 3 005 863 person-years of follow-up, 8772 incident cases of invasive BC were reported. After adjustment for potential confounders, the HR of BC was 1.06% (95%CI, 1.01%-1.10%) for ever smokers relative to never smokers. Breast cancer incidence was associated with a higher quantity of current (P for trend = .02) and past (P for trend = .003) smoking, younger age at smoking initiation (P for trend = .01), longer duration of smoking (P for trend = .01), and more pack-years of smoking (P for trend = .005). Premenopausal smoking was associated with a slightly higher incidence of BC (HR, 1.11; 95% CI, 1.07-1.15 for every increase of 20 pack-years), especially smoking before first birth (1.18; 1.10-1.27 for every increase of 20 pack-years). Conversely, the direction of the association between postmenopausal smoking and BC was inverse (0.93; 0.85-1.02 for every increase of 20 pack-years). Passive smoking in childhood or adulthood was not associated with BC risk.
Conclusion Active smoking, especially smoking before the first birth, may be associated with a modest increase in the risk of BC.

N° 699 TOPIC: BREAST CANCER
Axillary Dissection vs No Axillary Dissection in Women With Invasive Breast Cancer and Sentinel Node Metastasis: A Randomized Clinical Trial
Giuliano, et al (JAMA. 2011;305(6):569-575. doi: 10.1001/jama.2011.90) determined the effects of complete axillary lymph node dissection (ALND) on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer in a phase 3 noninferiority multicenter involving women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section. All patients underwent lumpectomy and tangential whole-breast irradiation. Those with SLN metastases identified by SLND were randomized to undergo ALND or no further axillary treatment. Those randomized to ALND underwent dissection of 10 or more nodes. Clinical and tumor characteristics were similar between 445 patients randomized to ALND and 446 randomized to SLND alone. However, the median number of nodes removed was 17 with ALND and 2 with SLND alone. At a median follow-up of 6.3 years (last follow-up, March 4, 2010), 5-year overall survival was 91.8% (95% CI, 89.1%-94.5%) with ALND and 92.5% (95% CI, 90.0%-95.1%) with SLND alone; 5-year disease-free survival was 82.2% (95% CI, 78.3%-86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. The hazard ratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) without adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy.
The authors concluded that among patients with limited SLN metastatic breast cancer treated with breast conservation and systemic therapy, the use of SLND alone compared with ALND did not result in inferior survival.

N° 697 TOPIC: BREAST CANCER
Gulisa Turashvili et al (Modern Pathology (2011) 24, 64–81; doi:10.1038/modpathol.2010.189; published online 17 September 2010) http://www.nature.com/modpathol/journal/v24/n1/full/modpathol2010189a.html reported an analysis of P-cadherin expression as a prognostic biomarker in a 3992 case tissue microarray series of breast cancer. P-cadherin expression was evaluated using immunohistochemistry. Median follow-up was 12.5 years. P-cadherin was expressed in 34.8% of cases. P-cadherin staining was strongly associated with HER2+ and basal carcinoma subtypes (P<0.0005). P-cadherin-positive patients showed significantly poorer short-term (0–10 years) overall survival, disease-specific survival, distant relapse-free interval, and locoregional relapse-free interval in univariable models (P<0.05). In multivariable Cox models containing standard clinical covariates and cancer subtypes, P-cadherin did not show independent prognostic value. P-cadherin expression was positively associated with histological grade, chemotherapy, Ki-67, EGFR, CK5/6, p53, YB-1, and HER2 expression (P<0.002), and negatively associated with age at diagnosis, ER, PR, and Bcl-2 expression (P<0.0005). This study shows the value of P-cadherin as a marker of poor prognosis. The large sample size of this series clarifies contradictory findings of many smaller studies. P-cadherin positivity is associated with high-grade tumor subtypes and well-established markers of poor prognosis, and may represent a promising antibody therapeutic target.

N° 696 TOPIC: ENDOMETRIAL CANCER, SCREENING, POSTMENOPAUSAL BLEEDING
Sensitivity of transvaginal ultrasound screening for endometrial cancer in postmenopausal women: a case-control study within the UKCTOCS cohort
In this paper, Ian Jacobs et al from United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) (The Lancet Oncology, Early Online Publication, 13 December 2010 doi:10.1016/S1470-2045(10)70268-0) analysed whether Transvaginal ultrasound (TVS) is a possible screening test for endometrial cancer. They did a nested case-control study of postmenopausal women who underwent (TVS) between April 17, 2001, and Sept 29, 2005. Endometrial thickness and endometrial abnormalities were recorded, and follow-up, through national registries and a postal questionnaire, documented the diagnosis of endometrial cancer. The primary outcome measure was endometrial cancer and atypical endometrial hyperplasia (AEH). Performance characteristics of endometrial thickness and abnormalities for detection of endometrial cancer within 1 year of TVS were calculated. Epidemiological variables were used to develop a logistic regression model and assess a screening strategy for women at higher risk. 48 230 women underwent TVS in the UKCTOCS prevalence screen. 9078 women were ineligible because they had undergone a hysterectomy and 2271 because their endometrial thickness had not been recorded; however, 157 of these women had an endometrial abnormality on TVS and were included in the analysis. Median follow-up was 5•11 years (IQR 4•05—5•95). 136 women with endometrial cancer or AEH within 1 year of TVS were included in the primary analysis. The optimum endometrial thickness cutoff for endometrial cancer or AEH was 5•15 mm, with sensitivity of 80•5% (95% CI 72•7—86•8) and specificity of 86•2% (85•8—86•6). Sensitivity and specificity at a 5 mm or greater cutoff were 80•5% (72•7—86•8) and 85•7% (85•4—86•2); for women with a 5 mm or greater cutoff plus endometrial abnormalities, the sensitivity and specificity were 85•3% (78•2—90•8) and 80•4% (80•0—80•8), respectively. For a cutoff of 10 mm or greater, sensitivity and specificity were 54•1% (45•3—62•8) and 97•2% (97•0—97•4). When our analysis was restricted to the 96 women with endometrial cancer or AEH who reported no symptoms of postmenopausal bleeding at the UKCTOCS scan before diagnosis and had an endometrial thickness measurement available, a cutoff of 5 mm achieved a sensitivity of 77•1% (67•8—84•3) and specificity of 85•8% (85•7—85•9). The logistic regression model identified 25% of the population as at high risk and 39•5% of endometrial cancer or AEH cases were identified within this high risk group. In this high-risk population, a cutoff at 6•75 mm achieved sensitivity of 84•3% (71•4—93•0) and specificity of 89•9% (89•3—90•5).
Interpretation
These findings show that TVS screening for endometrial cancer has good sensitivity in postmenopausal women. The burden of diagnostic procedures and false-positive results can be reduced by limiting screening to a higher-risk group. The role of population screening for endometrial cancer remains uncertain, but these findings are of immediate value in the management of increased endometrial thickness in postmenopausal women undergoing pelvic scans for reasons other than vaginal bleeding.

N° 695 TOPIC: CANCER, WOMEN’S HEALTH
Detection of lung, breast, colorectal, and prostate cancers from exhaled breath using a single array of nanosensors
G Peng et al (British Journal of Cancer (2010) 103, 542–551. doi:10.1038/sj.bjc.6605810 www.bjcancer.com) investigated the ability of a nanosensor array to discriminate between the emission of volatile organic compounds (VOCs) (breath VOCs) that characterise healthy states and the most widespread cancer states in the developed world: lung, breast, colorectal, and prostate cancers. Exhaled alveolar breath was collected from 177 volunteers aged 20–75 years (patients with lung, colon, breast, and prostate cancers and healthy controls). The healthy population was healthy according to subjective patient's data. The breath of volunteers was examined by a tailor-made array of cross-reactive nanosensors based on organically functionalised gold nanoparticles and gas chromatography linked to the mass spectrometry technique (GC-MS). The results showed that the nanosensor array could differentiate between ‘healthy’ and ‘cancerous’ breath, and, furthermore, between the breath of patients having different cancer types. Moreover, the nanosensor array could distinguish between the breath patterns of different cancers in the same statistical analysis, irrespective of age, gender, lifestyle, and other confounding factors. The GC-MS results showed that each cancer could have a unique pattern of VOCs, when compared with healthy states, but not when compared with other cancer types.

N° 694 TOPIC: WOMEN'S HEALTH
Baer et al Am J Epidemiol. 2010 Dec 6. [Epub ahead of print] examined associations of lifestyle and dietary factors with all-cause and cause-specific mortality among 50,112 participants in the Nurses' Health Study. There were 4,893 deaths between 1986 and 2004: 1,026 from cardiovascular disease, 931 from smoking-related cancers, 1,430 from cancers not related to smoking, and 1,506 from all other causes. Age, body mass index at age 18 years, weight change, height, current smoking and pack-years of smoking, glycemic load, cholesterol intake, systolic blood pressure and use of blood pressure medications, diabetes, parental myocardial infarction before age 60 years, and time since menopause were directly related to all-cause mortality, whereas there were inverse associations for physical activity and intakes of nuts, polyunsaturated fat, and cereal fiber. Moderate alcohol consumption was associated with decreased mortality. A model that incorporated differences in the associations of some risk factors with specific causes of death had a significantly better fit compared with a model in which all risk factors had common associations across all causes. In the future, this new model may be used to identify individuals at increased risk of mortality.

N° 693 TOPIC: OSTEOPOROSIS AND BREAST CANCER
Two studies published today in Nature show how progestin can cause breast cancer in mice by activating the protein RANKL. The studies highlight a potential role for RANKL inhibition in the management of proliferative breast disease.
Daniel Schramek et al (Nature 468, 98-102, 4 November 2010) observed that the in vivo administration of MPA triggers massive induction of the key osteoclast differentiation factor RANKL (receptor activator of NF-κB ligand) in mammary-gland epithelial cells. Genetic inactivation of the RANKL receptor RANK in mammary-gland epithelial cells prevents MPA-induced epithelial proliferation, impairs expansion of the CD49fhi stem-cell-enriched population, and sensitizes these cells to DNA-damage-induced cell death. Deletion of RANK from the mammary epithelium results in a markedly decreased incidence and delayed onset of MPA-driven mammary cancer. These data show that the RANKL/RANK system controls the incidence and onset of progestin-driven breast cancer.
Eva Gonzalez-Suarez (Nature 468, 103-107 (4 November 2010) | doi:10.1038/nature09495) showed that RANK and RANKL are expressed within normal, pre-malignant and neoplastic mammary epithelium, and using complementary gain-of-function (mouse mammary tumour virus (MMTV)-RANK transgenic mice) and loss-of function (pharmacological inhibition of RANKL) approaches, define a direct contribution of this pathway in mammary tumorigenesis. Accelerated pre-neoplasias and increased mammary tumour formation were observed in MMTV-RANK transgenic mice after multiparity or treatment with carcinogen and hormone (progesterone). Reciprocally, selective pharmacological inhibition of RANKL attenuated mammary tumour development not only in hormone- and carcinogen-treated MMTV-RANK and wild-type mice, but also in the MMTV-neu transgenic spontaneous tumour model. The reduction in tumorigenesis upon RANKL inhibition was preceded by a reduction in pre-neoplasias as well as rapid and sustained reductions in hormone- and carcinogen-induced mammary epithelial proliferation and cyclin D1 levels. Collectively, these results indicate that RANKL inhibition is acting directly on hormone-induced mammary epithelium at early stages in tumorigenesis, and the permissive contribution of progesterone to increased mammary cancer incidence is due to RANKL-dependent proliferative changes in the mammary epithelium.

N° 692 TOPIC: OSTEOPOROSIS
Effect of Music-Based Multitask Training on Gait, Balance, and Fall Risk in Elderly People
Andrea Trombetti, et al (Arch Intern Med. Published online November 22, 2010. doi:10.1001/archinternmed.2010.446) conducted a 12-month RCT involving 134 community-dwelling individuals older than 65 years, who are at increased risk of falling. They were randomly assigned to an intervention group (n = 66) or a delayed intervention control group scheduled to start the program 6 months later (n = 68). The intervention was a 6-month multitask exercise program performed to the rhythm of piano music. Change in gait variability under dual-task condition from baseline to 6 months was the primary end point. Secondary outcomes included changes in balance, functional performances, and fall risk.
At 6 months, Balance and functional tests improved compared with the control group. And there were fewer falls in the intervention group (incidence rate ratio, 0.46; 95%CI, 0.27-0.79) and a lower risk of falling (RR, 0.61; 95% CI, 0.39-0.96). Similar changes occurred in the delayed intervention control group during the second 6-month period with intervention. The benefit of the intervention on gait variability persisted 6 months later.

N° 691 TOPIC: BREAST CANCER
Cuzick et al (The Lancet Oncology, Early Online Publication, 17 November 2010
doi:10.1016/S1470-2045(10)70257-6) report the long-term outcomes after a median follow-up of 120 months of the The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial comparing the efficacy and safety of anastrozole (1 mg) with tamoxifen (20 mg), both given orally every day for 5 years, as adjuvant treatment for postmenopausal women with early-stage breast cancer.
The primary endpoints were the disease-free survival, and the secondary endpoints: time to recurrence, time to distant recurrence, incidence of new contralateral breast cancer, overall survival, and death with or without recurrence in all randomised patients (anastrozole n=3125, tamoxifen n=3116) and hormone-receptor-positive patients (anastrozole n=2618, tamoxifen n=2598). After treatment completion, they continued to collect data on fractures and serious adverse events in a masked fashion (safety population: anastrozole n=3092, tamoxifen n=3094).
There were 24 522 woman-years of follow-up in the anastrozole group and 23 950 woman-years in the tamoxifen group. In the full study population, there were significant improvements in the anastrozole group compared with the tamoxifen group for disease-free survival (HR] 0•91, 95% CI 0•83—0•99; p=0•04), time to recurrence (0•84, 0•75—0•93; p=0•001), and time to distant recurrence (0•87, 0•77—0•99; p=0•03). For hormone-receptor-positive patients, the results were also significantly in favour of the anastrozole group for disease-free survival (HR 0•86, 95% CI 0•78—0•95; p=0•003), time to recurrence (0•79, 0•70—0•89; p=0•0002), and time to distant recurrence (0•85, 0•73—0•98; p=0•02). In hormone-receptor-positive patients, absolute differences in time to recurrence between anastrozole and tamoxifen increased over time (2•7% at 5 years and 4•3% at 10 years) and recurrence rates remained significantly lower on anastrozole than tamoxifen after treatment completion (HR 0•81, 95% CI 0•67—0•98; p=0•03), although the carryover benefit was smaller after 8 years. There was weak evidence of fewer deaths after recurrence with anastrozole compared with tamoxifen treatment in the hormone-receptor-positive subgroup (HR 0•87, 95% CI 0•74—1•02; p=0•09), but there was little difference in overall mortality (0•95, 95% CI 0•84—1•06; p=0•4).
Fractures were more frequent during active treatment in patients receiving anastrozole than those receiving tamoxifen (451 vs 351; OR 1•33, 95% CI 1•15—1•55; p<0•0001), but were similar in the post-treatment follow-up period (110 vs 112; OR 0•98, 95% CI 0•74—1•30; p=0•9). Treatment-related serious adverse events were less common in the anastrozole group than the tamoxifen group (223 anastrozole vs 369 tamoxifen; OR 0•57, 95% CI 0•48—0•69; p<0•0001), but were similar after treatment completion (66 vs 78; OR 0•84, 95% CI 0•60—1•19; p=0•3). No differences in non-breast cancer causes of death were apparent and the incidence of other cancers was similar between groups (425 vs 431) and continue to be higher with anastrozole for colorectal (66 vs 44) and lung cancer (51 vs 34), and lower for endometrial cancer (six vs 24), melanoma (eight vs 19), and ovarian cancer (17 vs 28). No new safety concerns were reported.

Interpretation
These data confirm the long-term superior efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer.

N° 690 TOPIC: OSTEOPOROSIS, BREAST CANCER
Chlebowski et al (J Clin Oncol. 2010 Aug 1;28(22):3582-90. Epub 2010 Jun 21) evaluated the association between oral bisphosphonate use and invasive breast cancer was in postmenopausal women enrolled onto the WHI. Of the 154,768 participants, 2,816 were oral bisphosphonate users at entry (90% alendronate, 10% etidronate). As calculated hip fracture risk score was significantly associated with both BMD (regression line = 0.79 to 0.0478 log predicted fracture; P < .001; r = 0.43) and breast cancer incidence (P = .03), this variable was incorporated into regression analyses to adjust for BMD difference between users and nonusers of bisphopshonate. After 7.8 mean years of follow-up (standard deviation, 1.7), invasive breast cancer incidence was lower in bisphosphonate users (hazard ratio [HR], 0.68; 95% CI, 0.52 to 0.88; P < .01) as was incidence of estrogen receptor (ER) -positive invasive cancers (HR, 0.70; 95% CI, 0.52 to 0.94, P = .02). A similar but not significant trend was seen for ER-negative invasive cancers. The incidence of ductal carcinoma in situ was higher in bisphosphonate users (HR, 1.58; 95% CI, 1.08 to 2.31; P = .02).

N° 689 TOPIC: OSTEOPOROSIS
Leslie, et al (Ann Intern Med November 2, 2010 vol. 153 no. 9 580-586) assessed the changes in physician prescribing behavior after introduction of absolute 10-year fracture risk reporting in Manitoba, Canada. Absolute fracture risk reporting reclassified more women (32.7%) into lower-risk categories than into higher-risk categories (10%). This effect was more prominent in women younger than 65 years. Fewer women per physician were prescribed osteoporosis drugs after introduction of absolute fracture risk reporting. The absolute fracture risk reporting system was associated with an overall reduction in osteoporosis medications dispensed (adjusted absolute reduction, 9.0 percentage points [95% CI, 3.9 to 14.2 percentage points]; relative reduction, 21.3% [CI, 9.2% to 33.5%]; P < 0.001). The reduction was attributed to fewer drugs dispensed to women at low and moderate risk for fracture.

N° 688 TOPIC: POI
Schmidt et al J Clin Endocrinol Metab.2010 Nov 3. [Epub ahead of print] characterized the prevalence of psychiatric disorders and the timing of onset of clinically significant depression relative to both the diagnosis of primary ovarian insufficiency (POI) and the onset of menstrual irregularity in women with POI. They conducted a cross-sectional clinic-based study: A total of 174 women with spontaneous 46, XX POI and 100 women with Turner syndrome participated in the study. Lifetime histories of depression in POI exceeded rates of depression reported in women with Turner syndrome and community-based samples of women (P < 0.001). The onset of depression frequently preceded the diagnosis of POI but occurred after the onset of menstrual irregularity. Analyses standardizing the periods of risk for depression showed that similar numbers of depressions occurred before and after these events. The authors concluded that POI is associated with an increased lifetime risk for major depression. Attention to the presence of depression in POI should become an important part of the care for these women. The onset of depression frequently occurs after signs of altered ovarian function but before the diagnosis of POI. Thus, in some women the association between POI and depression suggests an overlapping pathophysiology rather than a causal relationship.

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