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: 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.
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.
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

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.

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.
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.

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).
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
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).
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
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
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
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

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:
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

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.

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
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
et al (Lancet Respiratory medicine DOI:

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;
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
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
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
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
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,

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

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

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

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”
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.
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:
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:

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
Quadrivalent HPV vaccination during pregnancy was not associated with a
significantly higher risk of adverse pregnancy outcomes than no such

N° 829
Topic: A clinical model for identifying the short-term risk of breast
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.

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
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

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

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
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.

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
Poorthuis and al. Female- and Male-Specific Risk Factors for Stroke: A
Systematic Review and Meta-analysis. (JAMA Neurol. 2016 Nov 14. doi:
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

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).
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.
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

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)
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.
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.
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.
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.
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

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.
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.
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.
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:
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).
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
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%.
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

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.
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).


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:

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

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.

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.
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
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

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
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

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

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).

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
Cancer and obstetrics
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
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.

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
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)

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

N° 790
incontinence, women’s’ health
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
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

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:

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
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

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

N° 782
Topic: Menopausal
hormone use and ovarian cancer risk
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.

781 Topic: Menopause
of Menopausal Vasomotor Symptoms Over the Menopause Transition ONLINE
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
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

781 Topic: Menopause
of Menopausal Vasomotor Symptoms Over the Menopause Transition ONLINE
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

N° 780 Topic:
cardiovascular disease
Between Sauna Bathing and Fatal Cardiovascular and All-Cause Mortality
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
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:
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).

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.
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.


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

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

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
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

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
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!
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
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.
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.
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.
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
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.

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

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
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

N° 760 Topic: Cervical
cancer screening
cancer screening (The Lancet, Early Online Publication, 3 November 2013
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

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
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.
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.
Oxidised regenerated cellulose and hyaluronate carboxymethylcellulose
can safely reduce clinically relevant consequences of adhesions.

N° 758
Topic: Osteoporosis
Fleur S.
van Dijk, et al (NEJM October 2, 2013DOI: 10.1056/NEJMoa1308223) brief
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
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
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
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.
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° 754
Topic: Breast Cancer
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.

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
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
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).

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).

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
of Regression and Relapse of Endometrial Hyperplasia With Conservative

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

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.


N° 750
Topic: Women’s health
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.

749 Topic: Women’s health
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.

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.

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

N° 746 Topic: Women’s
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
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%).

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.

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
Women’s health
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

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
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

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

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
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
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

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.
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

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%).


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
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.)


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
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
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
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.
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.


, Blinde
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.
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
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.


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.


The genomic and transcriptomic
architecture of 2,000 breast tumours reveals novel subgroups

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
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.””


, 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.


Anderson et al (WHI study) reported in the Lancet Oncol.
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:

Mishra GD Kuh D (BMJ.

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

N° 721 TOPIC: TVT,

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


Bone-Density Testing Interval and Transition to Osteoporosis in Older
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.


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.


Association of Antenatal Corticosteroids With Mortality and
Neurodevelopmental Outcomes Among Infants Born at 22 to 25 Weeks’

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.


Bilateral oophorectomy is not associated with increased mortality: the
California Teachers Study.
Duan et al (Fertil
. 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.


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.


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.


Effect of the Gonadotropin-Releasing Hormone Analogue Triptorelin on
the Occurrence of Chemotherapy-Induced Early Menopause in Premenopausal
Women With Breast Cancer : a RCT.

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).


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%).


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.


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.


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.


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.)


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:
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.


Preventive therapy for breast cancer: a consensus statement (Jack
Cuzick et al The Lancet Oncology, Early Online Publication, 28 March
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.


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.


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.


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


Gulisa Turashvili et al (Modern Pathology (2011) 24, 64–81;
doi:10.1038/modpathol.2010.189; published online 17 September 2010)
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.


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).
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.


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.


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.


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
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.


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.


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.

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:

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).


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.

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.