Mammographic Density and Estimation of Breast Cancer Risk in Intermediate Risk Population.
ABSTRACT It is not clear to what extent mammographic density represents a risk factor for breast cancer among women with moderate risk for disease. We conducted a population-based study to estimate the independent effect of breast density on breast cancer risk and to evaluate the potential of breast density as a marker of risk in an intermediate risk population. From November 2006 to April 2009, data that included American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) breast density categories and risk information were collected on 52,752 women aged 50-69 years without previously diagnosed breast cancer who underwent screening mammography examination. A total of 257 screen-detected breast cancers were identified. Logistic regression was used to assess the effect of breast density on breast carcinoma risk and to control for other risk factors. The risk increased with density and the odds ratio for breast cancer among women with dense breast (heterogeneously and extremely dense breast), was 1.9 (95% confidence interval, 1.3-2.8) compared with women with almost entirely fat breasts, after adjustment for age, body mass index, age at menarche, age at menopause, age at first childbirth, number of live births, use of oral contraceptive, family history of breast cancer, prior breast procedures, and hormone replacement therapy use that were all significantly related to breast density (p < 0.001). In multivariate model, breast cancer risk increased with age, body mass index, family history of breast cancer, prior breast procedure and breast density and decreased with number of live births. Our finding that mammographic density is an independent risk factor for breast cancer indicates the importance of breast density measurements for breast cancer risk assessment also in moderate risk populations.
- SourceAvailable from: Cristina Laguna Benetti-Pinto[Show abstract] [Hide abstract]
ABSTRACT: This study aims to compare breast density between two mammograms in women with premature ovarian failure (POF). A cohort study evaluated 56 women with POF. Two mammograms performed at least 2 years apart were analyzed. Mammogram films were digitalized, and images were assessed using a computer-assisted method; the percentage of breast image that is radiologically dense is referred to as the percentage of mammographic density (PMD). Age at menarche, age at onset of POF, length of POF, length of estrogen-progestin therapy (EPT), body mass index (BMI), pregnancy, and age at the time of each mammogram were evaluated. The mean (SD) age at POF diagnosis was 32.35 (5.95) years. In the first mammogram, the mean (SD) age, BMI, and length of POF were 37.58 (3.72) years, 26.79 (4.86) kg/m, and 5.25 (4.61) years, respectively. EPT had been used for a mean (SD) of 2.71 (3.12) years. In the second mammogram, the mean (SD) age, BMI, and length of POF were 43.23 (4.98) years, 27.6 (5.39) kg/m, and 10.5 (5.11) years, respectively. EPT had been used for a mean (SD) of 7.25 (4.6) years. The mean (SD) interval between mammograms was 5.25 (3) years, and the mean (SD) PMD decreased from 27.78% (21.04%) to 17.53% (15.71%) (P = 0.007). Comparing PMD between women taking EPT and those not taking EPT, we observed no significant differences. In both instances, multiparous women had lower PMD than nulliparous women (P < 0.05). BMI, length of POF, and pregnancy were negatively correlated with PMD. Breast density in young women with POF decreases across a period of 5 years, regardless of EPT use. Further studies may elucidate how this result will correlate with decision-making in clinical therapeutics and breast cancer risk in POF.Menopause (New York, N.Y.) 02/2014; · 3.08 Impact Factor
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ABSTRACT: Breast cancer, a major cause of female morbidity and mortality, is a global health problem; 2008 data show an incidence of ~450,000 new cases and 140,000 deaths (mean incidence rate 70.7 and mortality rate 16.7, world age-standardized rate per 100,000 women) in European Union Member States. Incidence rates in Western Europe are among the highest in the world. We review the situation of BC screening programmes in European Union. Up to date information on active BC screening programmes was obtained by reviewing the literature and searching national health ministries and cancer service websites. Although BC screening programmes are in place in nearly all European Union countries there are still considerable differences in target population coverage and age and in the techniques deployed. Screening is a mainstay of early BC detection whose main weakness is the rate of participation of the target population. National policies and healthcare planning should aim at maximizing participation in controlled organized screening programmes by identifying and lowering any barriers to adhesion, also with a view to reducing healthcare costs.International Journal of Oncology 09/2014; · 2.77 Impact Factor
Mammographic Density and Estimation of Breast
Cancer Risk in Intermediate Risk Population
Vanja Tesic, MD,* Branko Kolaric, MD, PhD,†,‡Ariana Znaor, MD, PhD,§,¶
Sanja Kusacic Kuna, MD, PhD,** and Boris Brkljacic, MD, PhD††
*Department of Epidemiology, Dr. Andrija Stampar Institute of Public Health, Zagreb, Croatia;
†School of Medicine, University of Rijeka, Rijeka, Croatia;‡Department of Public Health, Zagreb
County Institute of Public Health, Zagreb, Croatia;§Croatian National Cancer Registry, Croatian
National Institute of Public Health, Zagreb, Croatia;¶Andrija Stampar School of Public Health, Uni-
versity of Zagreb Medical School, Zagreb, Croatia; **Department of Nuclear Medicine and Radiation
Protection, Clinical Hospital Centre, Zagreb, Croatia;††Department of Diagnostic and Interventional
Radiology, University Hospital “Dubrava”, Medical School, University of Zagreb, Zagreb, Croatia
women with moderate risk for disease. We conducted a population-based study to estimate the independent effect of breast
density on breast cancer risk and to evaluate the potential of breast density as a marker of risk in an intermediate risk pop-
ulation. From November 2006 to April 2009, data that included American College of Radiology Breast Imaging Reporting
and Data System (BI-RADS) breast density categories and risk information were collected on 52,752 women aged 50–
69 years without previously diagnosed breast cancer who underwent screening mammography examination. A total of 257
screen-detected breast cancers were identified. Logistic regression was used to assess the effect of breast density on
breast carcinoma risk and to control for other risk factors. The risk increased with density and the odds ratio for breast can-
cer among women with dense breast (heterogeneously and extremely dense breast), was 1.9 (95% confidence interval, 1.3
–2.8) compared with women with almost entirely fat breasts, after adjustment for age, body mass index, age at menarche,
age at menopause, age at first childbirth, number of live births, use of oral contraceptive, family history of breast cancer,
prior breast procedures, and hormone replacement therapy use that were all significantly related to breast density
(p < 0.001). In multivariate model, breast cancer risk increased with age, body mass index, family history of breast cancer,
prior breast procedure and breast density and decreased with number of live births. Our finding that mammographic density
is an independent risk factor for breast cancer indicates the importance of breast density measurements for breast cancer
risk assessment also in moderate risk populations. n
Abstract: It is not clear to what extent mammographic density represents a risk factor for breast cancer among
Key Words: breast cancer risk, breast density, screening mammography
vary sixfold between developed regions of the world
and less developed countries (1). Since the first report
by Wolfe (2) in 1976, numerous studies have shown
amounts of stromal and epithelial tissue in the breast,
is an important marker of breast cancer in high risk
populations (3–6). Women with mammographically
dense breasts, with a large proportion of epithelial
he burden of breast cancer is unevenly distributed
by geographic location and the incidence rates
and connective tissue, have a higher risk of developing
breast cancer than women of similar age whose
breasts are radiologic lucent with a large proportion
of fatty tissue. The relative risk estimates ranged in
most studies between a twofold and a sixfold increase
in breast cancer risk, and the risk remains increased at
least 10 years after the determination of breast density
on a mammogram (7–11).
Breast density varies geographically, as well as
between different ethnic groups and correlations of
country-specific mammographic densities with breast
cancer incidence rates suggests that mammographic
density may underlie international differences (12,13).
It is not clear to what extent mammographic den-
sity represents a risk factor for breast cancer among
women with moderate risk for disease. It is also not
Address correspondence and reprint requests to: Vanja Tesic, MD,
Department of Epidemiology, Dr. Andrija Stampar Institute of Public Health,
Mirogojska 16, 10 000 Zagreb, Croatia, or e-mail: email@example.com.
© 2012 Wiley Periodicals, Inc., 1075-122X/13
The Breast Journal, Volume 19 Number 1, 2013 71–78
certain whether the association is modified by other
risk factors as the extent of breast density can be
modified by age, body mass index (BMI), family
history of breast cancer, age of menarche, age at first
birth, parity, age of menopause and postmenopausal
hormone replacement therapy use (11–30).
Most studies to date have been carried out in
western populations with high prevalence of dense
breast and the highest incidence rates of breast cancer.
However, less attention has been paid to the associa-
tion of mammographic density to risk of breast
cancer, or to the factors that influence this association
in populations at lower risk of the disease. We investi-
gated associations in the European population with
intermediate breast cancer incidence, such as the
Croatian population (ASR-W 64.0/100 000) (1). It is
essential to determine whether or not mammographic
density represents a risk factor in intermediate risk
population if it is to be used as a surrogate end point
for breast cancer in interventions studies.
The aim of our study was to estimate the effect of
breast density on breast cancer risk after adjustment
for other risk factors using data routinely collected in
Zagreb Breast Cancer Surveillance and to evaluate the
potential of breast density as a biomarker of breast
cancer risk in an intermediate risk population.
This study used data from the Zagreb Mammogra-
phy Registry (ZMR), which is a population-based
registry formed as part of the Croatian Breast Screen-
ing Program and represents 22% of Croatian female
population aged 50–69 years. The Croatian Breast
Screening Program which started in November 2006
is a free population-based organized mammographic
screening program for women aged 50–69 years with
active invitation. Screening is biannual and consists of
two-view mammograms and double reading. The
ZMR includes 27 radiology facilities in Zagreb
County accredited by the Croatian Ministry of Health
and Welfare: six university hospital-based facilities, 19
mammography units. Since 2006, the ZMR has
collected information on all screening mammography
performedin Zagreb. The
demographic and health history information relevant
to breast carcinoma from women at the time of
mammography by using self-administered question-
naire, breast pathology data from all pathology facili-
ties in Zagreb and cancer information from the
Croatian Cancer Registry.
The study subjects were women aged 50–69 years,
who underwent first screening mammography exami-
nation in Zagreb County between November 2006
and April 2009. Women with history of breast cancer
were excluded. Women with breast augmentation
were also excluded because augmentation decreases
breast cancer detection by mammography (31). We
also restricted our analysis to postmenopausal women
because they make the majority of target population
in screening (participation of premenopausal women
was only 4.4%). There were 52,763 eligible screening
mammograms from postmenopausal women without
previously diagnosed breast cancer. Within 1 year of
diagnosed with breast cancer (257 screen-detected
cancers and 11 interval cancers). Women with interval
cancers (239 invasive breast cancers and 18 ductal
carcinoma in situ). Women were classified as screen-
detected patients if their breast cancers diagnosed after
a positive screening mammogram (BI-RADS code 0, 3,
4, 5). Breast cancer cases were identified through
linkage of mammography registry with the Croatian
National Cancer registry or pathology data. Both
invasive carcinoma and ductal carcinoma in situ were
included as breast cancer.
Screening Mammograms and Risk Factors
A standard screening examination consisted of two
views mammograms (craniocaudal and mediolateral
oblique view) of each breast. It is performed in
asymptomatic women and needs to be done at least
12 months after any preceding breast imaging to
ensure an accurate designation as a screening mammo-
mammography and signed the informed consent form.
Assessment of the mammograms was performed by
double blind readings by board-certified radiologists
using the Breast Imaging. Reporting and Data System
(BI-RADS) designed by the American College of
Radiology (ACR) (32).
72 • tesic ET AL.
Patient information was obtained from self-reported
questionnaire at the time of the screening mammogram.
Questions include information about birth date, height,
weight, age at menarche, age at menopause, age at the
birth of first child, number of live births, use of oral
contraceptive, family history of breast cancer, prior
breast procedures, and use of hormone replacement
therapy. Prior breast procedure included self-reported
breast biopsy, fine needle aspiration, cyst aspiration
and breast reconstruction, but women with previous
breast cancer in either breast were excluded. Women
with at least one-first-degree relative with breast cancer
were considered to have a family history of breast can-
cer. Women were considered to be postmenopausal if
they reported that their menstrual periods had stopped
permanently, or if they were older than 50 years and
using hormone replacement therapy.
In addition to self-reported data, breast density was
also recorded at the time of the mammogram and was
typically classified by use of the four categories of the
ACR density grading system: (a) almost entirely fat,
(b) scattered fibroglandular densities, (c) heteroge-
neously dense, and (d) extremely dense (32). Several
studies have shown that categorization of breast
density according to ACR has a good reproducibility
(33–35). Average intraobserver agreement was sub-
stantial (j = 0.71 on a four-grade scale, and even
higher (j = 0.81 on a two-grade scale (1–2/3–4)).
Average interobserver agreement
(j = 0.54 on a four-grade scale, and substantial
j = 0.71 on a two-grade scale) (34).
Frequency distributions of various risk factors, age,
body mass index, age at menarche, age at menopause,
age at the birth of first child, number of delivery, use
of oral contraceptive, family history of breast cancer,
prior breast procedures, and use of hormone therapy,
were determined for all women, as well as the
frequency distributions of
Because of the small numbers in some subgroups,
categories “heterogeneously dense” and “extremely
dense” were collapsed into a single category, which
we termed “dense breast”. Quantitative variables were
tested for the normality of the distribution with
We used Pearson’s chi-squared exact test and Krus-
kal-Wallis rank test for group comparisons. For risk
analysis, we used bivariate and multiple logistic
ACR density scores.
regression. Variables with a p < 0.20 in bivariate anal-
ysis were included in the multivariate model.
All statistical calculations were performed using
STATA/IC ver.11.1. (StataCorp. 2009. Stata Statistical
Software: Release 11. College Station, TX: StataCorp
LP). Results of two-sided statistical tests in which
p-values were less than 0.05 were considered to be
Among 52,752 postmenopausal women aged 50–
69 years who underwent screening mammography
examination, 257 breast cancers were detected, which
is the absolute rate of 4.9 breast cancers per 1,000
screening mammograms (95% CI = 4.3–5.5). A family
history of breast cancer in first-degree relative was
reported by 11% of women, and prior breast proce-
dure by 10% of women (Table 1). Almost three quar-
ters (71.1%) of the women had BMI values over 25.
For 9% of women age at menarche was less than 12.
Eleven percent of women were nulliparous and 9.3%
had their first child after the age of 30 years. Only
one quarter (26.3%) of the women had ever used oral
contraceptives in the past. Current use of hormone
replacement therapy was reported for only 5.8%
women. The distribution of ACR breast density assess-
ments favored less dense breast assessments, “entirely
fat” or “scattered fibroglandular densities” in 86.8%.
In addition, only 13.2% of women were assessed as
“heterogeneously and extremely dense breast”.
Women in the four breast density categories dif-
fered significantly with respect to age and all the other
potential risk factors examined in the study (Table 2).
BMI was inversely related to breast density with the
average BMI significantly decreasing from a median of
28.4 in women with entirely fat breasts to 23.8 in
women with extremely dense breasts. Women with a
family history of breast cancer, prior breast procedure,
later menarcheal age, later age at first birth, and low
parity had a tendency toward higher breast density.
High breast density was more common in women cur-
rently using hormone therapy, and in women who
used oral contraceptives compared to nonusers.
Factors that were not significantly associated with
breast cancer in bivariate logistic regression analysis
were BMI, age at menarche, age at menopause, age at
first childbirth, oral contraceptive use, and current use
of hormone therapy. The significant factors were age
(p < 0.001), familyhistoryofbreastcancer
Mammographic Density and Breast Cancer Risk • 73
(p < 0.001), prior breast procedure (p < 0.001), breast
density (p < 0.002, p = 0.013), and number of live
births (p = 0.006). After adjustment for age and other
covariates, BMI became significantly associated with
breast cancer risk (p = 0.008; Table 3).
When women with scattered fibroglandular densi-
ties were compared with women with almost entirely
fat breasts, the odds ratio for breast cancer was 1.7
(95% confidence interval [CI], 1.3–2.2). For women
with dense breast (heterogeneously and extremely
dense breast) the odds ratio was 1.9 (95% CI, 1.3–
In multivariate model, breast cancer risk increased
with age, BMI and breast density, and decreased with
number of live births. Other factors associated with
higher risk included family history of breast cancer
and prior breast procedure (Table 4).
To the best of our knowledge, this is the first study
of mammographic breast density and breast cancer
risk in a Central and South East European population
with a moderate risk for breast cancer. The incidence
rates for breast cancer (age-adjusted rates to the world
standard population per 100,000) in Croatia are 64.0
and they are in the middle when compared with high
incidence rates (>80) in developed regions of the
world (except Japan) and low (<40) in most of the
developing regions (1). Our results showed that after
adjustment for other risk factors, mammographic
density was significantly associated with an increased
risk of breast cancer. We also confirmed the effect of
most previously established independent breast cancer
A recent meta-analysis (36) illustrated high preva-
whether estimated by percentage density (26–32% of
women had 50% or more), parenchymal pattern (21–
55% of women had the P2 or DY pattern), or ACR
density (31–43% had ACR of 3 or 4). In our study
prevalence of woman with dense breast (ACR score 3
or 4) was only 13.2%, which was just slightly higher
than in the study from Japan (11.9%), which is
known as low risk population for breast cancer (37).
Although mammographic density is influenced by sev-
eral risk factors for breast cancer, it is not clear
whether populations at different risk for the disease
have different averagelevels
Differences in breast density patterns of the Croatian
screening population from that in other countries
could be partly explained by differences in the
prescription patterns of hormone replacement therapy,
because hormone replacement therapy use may signifi-
cantly increase breast density (38,39). The proportion
of current hormone replacement therapy users in our
study was rather low (5.8%) compared to, for exam-
ple, postmenopausal women who had undergone
screening mammography in the United States from
1996 to 2002 (48.4%) (40).
of breast density.
Table 1. Distribution of Risk Factors and Cancer
Rate per 1,000 Screening Mammograms*
Family history of breast cancer
Prior breast procedure
Age at menarche (years)
Age at menopause (years)
No of live birth
1 do 2
Age at first childbirth (years)
Postmenopausal hormone therapy
Never or formerly used
Breast density (BI-RADS)
1. Almost entirely fat
2. Scattered fibroglandular
3. Heterogeneously and
4.8 (4.2–5.4) 229
6,968 (13.2) 42 6.0 (4.2–7.8)
52,752 (100)2574.9 (4.3–5.5)
*CI = confidence interval; BMI = body mass index; BI-RADS = Breast imaging Reporting
and Data System.
†Rate is presented as number per 1000 screening mammograms.
74 • tesic ET AL.
Consistent with other studies, we found that mam-
mographic breast density, measured by ACR category,
was associated with breast cancer risk (8–10,40). In
our study, women with an ACR breast density cate-
gory of 2 and women with ACR category of 3 and 4
were at increased risk of breast cancer when com-
pared to women with ACR breast density of 1, the
most common density group. Boyd et al. (5), in an
extensive review, found that odds ratios ranged from
2.1 to 6.0 when women with a high percentage of
density were compared to women with no or low per-
centage density (5). Our overall age-adjusted relative
risk estimate of 1.9 (95% CI 1.3–2.7) for the dense
breast (ACR score 3 and 4) category is slightly lower.
Adjustment for BMI had little influence on the relative
risk associated with breast density, the largest effect
being an increase from 1.9 to 2.1 for women with
dense breasts. Further adjustments for other variables
associated with breast density and breast cancer risk
as family history of breast cancer, prior breast
procedure, age at menarche, age at menopause, nulli-
parity, age at first childbirth, oral contraceptive use,
and use of hormone replacement therapy did not sub-
stantially alter the relative risk estimates for breast
density, consistent with other studies (8–10).
The reverse effects of age and BMI on breast cancer
risk observed in this study are compatible with
epidemiologic evidences that older age and obesity
among postmenopausal women increases risk (6,9,40–
Previous studies showed that increased breast can-
cer risk was associated with combined hormone
replacement therapy (43–46). There is also evidence
that estrogen-only therapy significantly delays the
decline in breast density over time (18). In this study,
we did not find the significant association between
breast cancer and current postmenopausal hormone
replacement therapy use as many of few studies which
have included ACR density did (6,8,9,40). The sub-
group of women using hormone replacement therapy
Table 2. Association Between Breast Density and Other Risk Factors
Breast density category
Entirely fatScattered HeterogeneousExtremly
p value Median (range)Median (range) Median (range) Median (range)
Family history of breast cancer
Prior breast procedure
Age at menarche (years)
Age at menopause (years)
No. of live birth
Age at first childbirth (years)
Postmenopausal hormone therapy
Mammographic Density and Breast Cancer Risk • 75
was rather small (5.8%) with very low number of
cancers, limiting our ability to identify important asso-
ciations. We observed increase in breast cancer inci-
dence among women with earlier age at menarche,
but the associations were not statistically significant,
similar to results from model for breast cancer risk
prediction in a screening population developed by Tice
et al. (8). Unlike some previous studies which demon-
strated that age at menopause was significantly associ-
ated with the risk of breast cancer we did not confirm
that finding (47,48).
The independent effects of family history of breast
cancer and prior breast procedure, as estimated from
obtained from bivariate models which suggests that
their age-adjusted effects on breast cancer risk are not
primarily due to their joint associations with breast
density, other covariates and each other, but interrela-
tionships between risk factors are complex.
The magnitudes of the relative risks associated with
family history of breast cancer were consistent with
estimates from other studies that adjusted for breast
density measured by ACR categories (9,40,49).
Only a few studies estimated the relative risk for
breast cancer associated with prior breast procedure
(8,40,50). Our result (OR = 1.81) is higher than the
estimate from the Barlow breast cancer risk prediction
model for postmenopausal women (OR = 1.30) and
from model developed by Tice for women older than
50 (OR = 1.41) (8,40).
The various methods of classifying breast density,
differences in study population, study design as well
as differing of adjustments for the covariates led to
some discrepancies across studies in relative risk esti-
mates for breast density and other risk factors. Since
breast density correlated with several breast cancer
risk factors, the adjustments for them are necessary
for accurately estimating the breast cancer risk.
Although the strongest associations are seen with body
mass index and age, in many previous studies lack of
multivariate models,were similarto those
Table 4. Multivariate Model for Estimate Breast
Cancer Risk within 1 year in Postmenopausal
Risk factor CoefficientSE*p
Family history of breast cancer (yes)
Prior breast procedure (yes)
No of live birth
Breast density (BI-RADS)
Scattered fibroglandular densities
Heterogeneously and extremely dense
*SE = standard error.
Table 3. Odds Ratios (OR) and 95% Confidence Intervals (CI) for Risk of Breast Cancer Within 1 year
in Postmenopausal Women Who Have Undergone Screening Mammography
odds ratio 95% CIp
odds ratio* 95% CIp
Family history of breast cancer
Prior breast procedure
Age at menarche
Age at menopause
No of live birth
Age at first childbirth
Postmenopausal hormone therapy
Never or formerly used
Breast density (BI-RADS)
1. Almost entirely fat
2. Scattered fibroglandular densities
3. Heterogeneously and extremely dense
*Adjusted for all covariates in the table.†BMI = body mass index.
76 • tesic ET AL.
information was just regarding the body mass index
(51). Besides that, age at first live birth, age at menar-
che and age at menopause were the most often omit-
ted variables. Strengths of our study include a large
sample size with systematic collection of the most rele-
vant covariates for all participants. Furthermore, epi-
demiologic data were obtained during the time of the
mammographic visit, ensuring updated information.
One limitation of our study is the use of qualitative
rating of breast density assessed by numerous radiolo-
gists, although they had specific training. Based on
prior reports, the interrater agreement of the ACR-BI-
RADS breast density measure is moderate (33,34).
Therefore, misclassification of ACR categories may
have influenced our results, such that some of the dif-
ferences we observed could result in an under- or
overestimation of associations. Despite limitations, use
of ACR classification of breast density has some
advantages. It is routinely used by radiologists as part
of mammographic assessment, and therefore is readily
available for large number of women. Another limita-
tion of the study could be the small size of some
groups that changed ACR breast density category and
the low number of cancers in these groups, limiting
our ability to identify important associations. Our
estimate of breast cancer risk is really a short-term
estimate for diagnosis a recently developed breast can-
cer within a year of a scheduled screening examina-
tion. Despite that, the risk factors are similar to
studies which were based on a longer follow-up (6,9).
Our finding that breast density is an independent risk
factor confirms the importance of breast density measure-
ments for breast cancer risk assessment also in moderate
risk populations. The study suggests that breast density
should be taken into consideration when evaluating indi-
vidual risk in women to enable physicians to make deci-
sions regarding appropriate risk-reducing interventions
and strategies. At the population level estimate of breast
cancer risk with breast density could be important in cre-
ating future policy for screening women with higher den-
sity. The results of this study could help the development
of widely applicable models for assessing breast cancer
risk in individual women.
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