Research

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ONCOLOGY

Patients with cervical cancer: why did

screening not prevent these cases?
Roosmarie P. de Bie, MD; Henke C. Vergers-Spooren, MD; Leon F. A. G. Massuger, MD, PhD;
Albertus G. Siebers, PhD; Maria R. J. Salet-van der Pol; Judith E. M. Vedder; Willem J. G. Melchers,
PhD; Johan Bulten, MD, PhD; Ruud L. M. Bekkers, MD, PhD
OBJECTIVE: The objective of the study was to assess the screening

his- tory of women with cervical cancer and review normal cervical
smears 5 years preceding the diagnosis.
STUDY DESIGN: Cytological and histological results of 401 women

treated for invasive cervical cancer between 1991 and 2008 at the
Rad- boud University Nijmegen Medical Center were studied. Ninetyeight normal smears were reviewed.

third fell outside the target age of the NCSP. Seventeen percent never
responded to the invitation(s). Twenty-one percent had 1 or more normal smears within 5 years preceding the diagnosis. After review, only
39% of those smears were reviewed as a normal smear.
CONCLUSION: Half of the women with cervical cancer were never

RESULTS: Of the 401 women, 269 (67%) received at least 1 invitation

screened because of the limited target age range or nonattendance.

Twenty-one percent had a normal smear within 5 years preceding the
diagnosis, caused by interpretation and/or sampling errors.

for the national screening program for cervical cancer (NCSP). One-

Key words: cervical cancer, cervical smear, screening

Cite this article as: de Bie RP, Vergers-Spooren HC, Massuger LFAG, et al. Patients with cervical cancer: why did screening not prevent these cases? Am J Obstet
Gynecol 2011;205:64.e1-7.

national screening program for cervical cancer (NCSP) was introduced in The Netherlands in 1988.
Women between the ages of 35 and 53
years were invited for a cervical smear
every 3 years. The NCSP was
reorganized in 1996 to improve the
effectiveness and efficiency of the
screening. Therefore, the age range of
the target population was extended to
30-60 years, and the screening interval
increased from 3 to 5 years. From 1990
to 2006, the incidence

and mortality rate for cervical cancer in

The Netherlands decreased by 28% and
42%, respectively.1-3
Despite organized screening in The
Netherlands, around 600-700 women are
still diagnosed with cervical cancer annually.1 Factors influencing these numbers
are the target age range of the screening
program, the frequency of screening, and
nonattendance
to
the
screening
program.4
Important factors in women diagnosed
with cervical cancer despite adequate
screening are problems with sampling,

From the Departments of Obstetrics and

Gynecology (Drs de Bie, Vergers-Spooren,
Massuger, and Bekkers), Pathology (Dr
Siebers and Bulten, Ms Salet-van der Pol,
and Ms Vedder), and Medical Microbiology
(Dr Melchers), Radboud University
Nijmegen Medical Center, Nijmegen, The
Netherlands.

reserved. doi:
10.1016/j.ajog.2011.02.046

Received Nov. 12, 2010; revised Jan. 1, 2011;

accepted Feb. 14, 2011.
Reprints: Roosmarie P. de Bie, MD,
Radboud University Nijmegen Medical
Center, Department of Obstetrics and
Gynecology (internal mail 791), P.O. Box
9101, 6500 HB Nijmegen, The Netherlands.
r.debie@obgyn.umcn.nl.
0002-9378/$36.00
2011 Mosby, Inc. All rights

64.e1

American Journal of Obstetrics & Gynecology JULY 2011

progressive form of cervical cancer. A

study of WNL smears preceding
cervical cancer may show to what
extent improv- ing interventions might
be possible.9
The aim of this study was to
determine how many women diagnosed
with cervi- cal cancer in the Nijmegen
region had been screened according to
the national guidelines and, if screened
properly, why screening did not prevent
these cases?

M ATERIALS AND M ETHODS

Data collection
interpretation, and consistent clinical
follow-up.5 However, a small number of
rapidly developing cancers (interval cancers) cannot be ruled out.
The Papanicolaou smear has been a remarkably effective tool in cancer prevention. However, cytological smears have
been associated with a significant rate of
sampling and/or interpretation errors,
resulting in a sensitivity of approximately 60-70%.6-8 False-negative results
may have a great impact because cervical
abnormalities might be missed and
therefore left untreated. Smears within
normal limits (WNL) preceding cervical
cancer and confirmed by cytological re-

view may be either an indication for a

rapidly

Between 1991 and 2008, 421 women

were diagnosed with invasive cervical
cancer and treated at the Radboud
University Nijmegen Medical Center
(RUNMC),
Nijmegen,
The
Netherlands.
Data con- cerning
cervical cytology and histology were
retrieved from the Dutch nationwide
registry
of
histoand
sampling error or suggestive for a

cytopathology
(PALGA).10
This
database has national coverage from
1991 onward, enclosing all surgical
specimens and cervical smears ever
taken from each patient, both by the
general practitioner
and medical
specialists. Twenty patients who were
initially diagnosed in a foreign
country or had incomplete data were excluded, leaving 401 patients opting for
evaluation.

JULY 2011 American Journal of Obstetrics & Gynecology

64.e2

Research

Oncology

The cytological results were registered

according to the diagnostic categories of
Papanicolaou and/or CISOE-A (Composition, Inflammation, Squamous
epithelium, Other and endometrium,
Endocervical columnar epithelium, Adequacy of the smear), which is easily
translatable to the Bethesda 2001 (TBS
2001) classification.11 Only cytological
smears performed within the framework
of the screening program were registered. Diagnostic smears leading to the
diagnosis of cervical cancer, performed
as a consequence of symptoms, were
not included. Analysis has focused on
smears within the screening program,
prior to the diagnosis.
Patient and tumor characteristics (eg,
stage/type) were obtained from the hospital medical records. All histological
types were included in our analysis to
properly evaluate the current screening
program. According to the date of birth,
we assessed whether women had ever
been invited for the national screening
program. Women within the age category of the national screening program
constituted our target group for further
study. They had been invited at least
once.
Women who were younger or older
than the target cohorts were not further
analyzed with respect to their screening
history because the aim of the study
was to evaluate women who were
eligible for cervical cancer screening.
In the collected data, women were
scored as regularly screened, irregularly
screened, or never screened. A patient
was scored as regularly screened when
screened according to the guidelines of
the national screening program on
cervi- cal cancer (responded to all
invitations of the national screening
program, every 5 years from the age of
30 years until 60 years). A deviation in
screening interval of
10% was accepted. Patients were scored
as never screened if they never had a
smear taken (nonresponders). Otherwise,
the pa- tients were scored as irregularly
screened. This group responded to at
least 1 of the invitations of the screening
program but not to all, or the frequency
and/or timing was not adequate (interval
longer than 5 years).

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All normal cervical smears within 5
years before the diagnosis of cervical
can- cer were requested from pathology
labora- tories around the country. All
smears were made anonymous before
sending them to 2 expert
cytotechnologists (CTs) (M.R.J.S.v.d.P. and J.E.M.V.) for re- view. Both
CTs scrutinized the smears for
abnormal cells with full knowledge of
the study, using a review protocol, noting the CISOE-A classification, the
quantity and nature of the cells, and the
extent of certainty about their judgment.12 The aim was not to repeat a
nor- mal screening setting but to
scrutinize the smears for abnormal cells
to distin- guish interpretation errors
from sam- pling errors/progressive
forms of cancer. After an extensive
search for abnormal cells, all cervical
smears were provided with a new
diagnosis, according to the
2001 Bethesda System.11 In case the
judgments of the 2 CTs were
discordant, they reassessed the smear
together and came to concordance.

Statistical analysis
The Statistical Package for Social Sciences (SPSS version 16.0; SPSS,
Chicago, IL) was used to perform the
analyses. Pa- tient characteristics and
tumor charac- teristics were compared
using nonpara- metrical tests ( 2 and
Mann-Whitney). We considered P
.
05 as statistically significant.
The study was exempt from institutional review board approval because
data were gathered retrospectively and
subsequently made anonymous.

R ESULTS
Of the 401 eligible women, 269 (67%)
had been invited at least once for participation in the national screening program (target cohorts). A number of 87
women (22%) exceeded the age limit to
be invited for the NCSP (older than target cohorts), and 45 (11%) were
younger than the starting age of the
NCSP when diagnosed with cervical
cancer (younger than target cohorts)
(Figure 1).
The youngest group showed 36%
nonsquamous
cell
carcinomas
compared with

16% of the oldest group (P

.011). The
nonsquamous cell carcinomas in the
youngest group mainly consisted of ade-

Oncology

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nocarcinomas. They accounted for
26.7% of the total carcinomas in the
youngest group, compared with 19.7% in
the target cohort and 11.5% in the oldest
group. In the oldest group, 54% had
advanced stage (IIB or greater) disease,
compared with
18% in the youngest and 11% in the
target group (P
.001). Women of the
target co- hort who were regularly
screened had in
13.1% stage 1A disease vs 7.4% for
those who were irregularly screened. This
differ- ence was not statistically
significant (P
.123). Patient and tumor characteristics
are shown in Table 1.
Of the 269 women of the target cohorts, 107 (40%) were screened according to the guidelines of NCSP
(cytologi- cal smear every 5 years from
the age of 30 years to 60 years). Of the
remaining in- vited patients, 68 (25%)
were never screened (nonresponders)
and 94 (35%) were irregularly screened
(Figure 1). Of the 107 regularly
screened women, 36 were diagnosed
with cervical cancer when they
responded to their first invi- tation for
cervical screening.
Of the 201 women who ever participated in the NCSP, 85 (42%) had at
least
1 normal cervical smear within the 5
years before the diagnosis of cervical
cancer and therefore within the screening interval. Because some women had
more than 1 normal smear within the
in- terval, these 85 women had a total
of 136 normal smears preceding the
diagnosis. Of these smears, 105 (77%)
were re- trieved from 17 different
pathology laboratories. The other 31
smears were not retrieved because 1
pathology lab- oratory denied
collaboration because the smears
were older than the re- stricted
storage period of 10 years and
therefore destroyed, or they were not
traceable. Seven AutoCyte PREP smears
(BD Diagnostics/Tripath, Inc, Burlington, VT) were excluded because the selected CTs lacked experience with this
method and the selection of a third CT
would not contribute to the equality of
the study. Of the remaining 98 smears,
87 (89%) were conventional smears
and

11 (11%) were liquid-based smears

(Thin
Prep;
Hologic,
Inc,
Marlborough, MA). In total, 38
(39%) smears were considered to be
normal after review and

Research

23 (24%) were judged as unsatisfactory

for evaluation.
Reasons for unsatisfactory smears
were few epithelial cells, too many
leucocytes, and too much blood or a
combination of these. These smears
were initially incor- rectly classified as
WNL instead of repeated after 6 weeks.
In total, 18 smears (18%) were reviewed
as
atypical
squamous
cells
of
undetermined significance (ASC-US) or
low-grade
squamous
intraepithelial
lesion (LSIL). These women would
otherwise have been advised to have a
repeat smear in
6 months. Nineteen smears were
reviewed as high-grade squamous
intraepithelial le- sion (HSIL) or more
severe and should therefore have been
referred to
the
gyne- cologist
immediately. For the review reWhen the total 401 women with
cervi- cal cancer were considered, 33%
were di- agnosed outside the target age
range of the NCSP, and 17% never
responded to the invitation of the
NCSP. These women were never
screened. Another
17% were screened, but the last smear
before the diagnosis of cervical cancer
years. Thirteen percent were incorrectly
diagnosed with a normal smear within 5
years preceding the diagnosis of cervical
cancer. Eight percent had a normal
smear (confirmed by review), suggesting
a sam- pling error or a rapidly
progressive tumor.
The remaining 12% were either
diagnosed when they attended their
first screening
round (9%) or developed cervical cancer
despite follow-up of abnormal smears by
cytology and/or colposcopy (3%) (Figure
2). It was not possible to trace where
appropriate follow-up, evaluation (eg, colposcopy) or treatment (eg, loop electrosurgical excision procedure, cone biopsy,
or cryotherapy) went wrong. It was estimated that these follow-up smears were
ei- ther misinterpreted or the colposcopic
evaluation was insufficient.

C OMMENT

FIGURE 1

Women with invasive cervical cancer

421
Cervical cancer
20
Immigrants excluded

401
Cervical cancer

45 (11%)
Younger than target cohort

87 (22%)
Older than target cohort

269 (67%)
Target cohort

68 (25%)
Never screened

94 (35%)
Irregularly
screened

107 (40%)
Regularly
screened

85/269 (32%)

WNL smear < 5yrs

before diagnosis

Review:

Review:

Review:

Review:

24% unsatisfactory

39% WNL

18% ASCUS/LSIL

19% HSIL

Flow diagram of total 401 women with invasive cervical cancer at the RUNMC in the period 19912008, including reviews of the normal smears within 5 years before the diagnosis.
ASCUS, atypical squamous cells of undetermined significance; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade
squamous intraepithelial lesion; RUNMC, Radboud University Nijmegen Medical Center; WNL, within normal limits.
de Bie. Failures of cervical cancer prevention. Am J Obstet Gynecol 2011.

This relatively large study, from a

cen- trally organized program, with a
pathol- ogy database that has full
national cover- age makes these data
useful alongside other studies.13-15
This study shows that
33% of women with cervical cancer
are

diagnosed outside the target age range of

the NCSP. Additionally, 17% of the patients within the target age range never
responded to any of the invitations.
Therefore, half of the women were never
screened before the diagnosis of cervical
cancer. An additional 9% were diagnosed after responding to the invitation

of their first screening round. Seventeen

percent were screened at least once but
had their last smear longer than 5 years
before the diagnosis of cervical cancer.
Twenty-one percent had a normal smear
preceding the diagnosis of cervical can-

cer, suggesting an interpretation or

sam- pling error or a combination of
those.
Of the 401 women included in this
study, 45 (11%) and 87 (22%) women
were, respectively, younger or older
than the target cohorts to be invited
for cervi- cal cancer screening.
Another 9%, diag- nosed after their
first invitation, were due to too-late
initiation of screening. This is in
accordance with the study of Bos et
16
al, in which they describe that in The
Netherlands around 30% of the
women with cervical cancer never
had been invited for cervical cancer
screen-

TABLE 1

Patient and tumor characteristics of women with invasive

e
cervical cancer at the RUNMC in the period 1991-2008
Target cohorts (II) (%)
Characteristic

Younger than target

cohorts (I) (%) a

Median age, y (range)

29 (2135)

Regularly
screened
37 (3060)

P value

Irregularly
screened

Older than target

cohorts (III) (%) c

43 (3060) 72 (5484)

Total (%)

I vs III

I vs II

II vs III

42 (2184)

................................................................................................................................................................................................................................................................................................................................................................................

Histological type

.......................................................................................................................................................................................................................................................................................................................................................................

Squamous cell carcinoma

29 (64.4)

74 (69.2)

134 (82.7)

73 (83.9)

310 (77.3)

Nonsquamous cell carcinoma

16 (35.6)

33 (30.8)

28 (17.3)

14 (16.1)

91 (22.7)

Adenocarcinoma

.011

.063

.190

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................

12 (26.7)

28 (26.2)

25 (15.4)

10 (11.5)

75 (18.8)

Adenosquamous carcinoma

3 (6.7)

3 (2.8)

3 (1.9)

1 (1.1)

10 (2.5)

Other

1 (2.2)

2 (1.8)

3 (3.4)

6 (1.4)

.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

FIGO stage

.......................................................................................................................................................................................................................................................................................................................................................................

Stage IA

1 (2.2)

14 (13.1)

12 (7.4)

1 (1.1)

28 (7.0)

36 (80.0)

88 (82.2)

125 (77.2)

46 (52.9)

295 (73.5)

.001d

.624d

.001d

.......................................................................................................................................................................................................................................................................................................................................................................

Stage IB, IIA

.......................................................................................................................................................................................................................................................................................................................................................................

Advanced stage IIB or greater

8 (17.8)

5 (4.7)

25 (15.4)

40 (46.0)

78 (19.5)

................................................................................................................................................................................................................................................................................................................................................................................

Total

45 (11.2)

107 (26.7)

162 (40.4)

87 (21.7)

401 (100.0)

................................................................................................................................................................................................................................................................................................................................................................................

FIGO, Fdration Internationale de Gyncologie et dObsttrique; RUNMC, Radboud University Nijmegen Medical Center.
a

Younger than the age limit to be invited for the screening program; b Target age of the screening program, currently 30-60 years; c Older than the age limit to be invited for the screening program;
d
Stage IIA or less vs stage IIB or greater.

de Bie. Failures of cervical cancer prevention. Am J Obstet Gynecol 2011.

ing because of their age. However, the

proportion of women older than the target cohort will be reduced in the future
because this cohort will vanish in time.
In The Netherlands, the age range
(30 60 years) is rather limited as
com- pared with other countries in
which some screening programs start
inviting at the age of 20 years and
continue until the age of 65 years.17
Extending the age range may lead to
better prevention of cervical cancer and
to earlier diagnoses of earlier stage of
disease. However, de- spite extending
the age range, there is still

a risk of missing adenocarcinomas in

the youngest group because the
sensitivity of cervical cytology for the
detection
of adenocarcinomas is
significantly lower than that for
18-21
squamous carcinomas.
Despite the NCSP with 5 year invitations, 25% of the invited patients never
responded to any of the invitations before they were diagnosed with cervical
cancer. Another 35% of the women responded to at least 1 of the invitations
but not to all or not in time. This
stresses the fact that, in accordance with
previous studies,16,22-27 underscreening
is the

TABLE 2

Review of WNL cervical smears within 5 years

before the diagnosis of cervical cancer
Review

Conventional, n (%)

Total, n (%)

Unsatisfactory smear

Liquid based, n (%)

2 (18)

21 (24)

23 (24)

WNL smear

7 (64)

31 (36)

38 (39)

ASC-US/LSIL smear

2 (18)

16 (18)

18 (18)

HSIL smear or greater

19 (22)

19 (19)

87 (100)

98 (100)

..............................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................

Total

11 (100)

..............................................................................................................................................................................................................................................

ASC-US, atypical squamous cells of undetermined significance; HSIL, high-grade squamous intraepithelial lesion; LSIL,
low-grade squamous intraepithelial lesion; WNL, within normal limits.
de Bie. Failures of cervical cancer prevention. Am J Obstet Gynecol 2011.

most important modifiable risk factor

for cervical cancer. Nonattendance has
been reported previously as being due
to fear, embarrassment, a male doctor,
and having a too-busy schedule.28
Efforts should be undertaken
to
increase the coverage of screening.29
Consistent with previous studies, we
found a substantial number of women
with a WNL smear preceding the diagnosis cervical cancer.23,26 The fact that
cervical cancer can occur despite a history of regular screening suggests the
need for further studies of primary
screening tests.23 According to the reviews of the WNL smears in this study,
38% indicated interpretation errors.
Another 39% of the smears was confirmed
WNL by review and suggestive for sampling errors or a fast carcinogenesis
(rap- idly progressive cancer) after the
smear was taken.
Nonsquamous cancers might be those
rapidly progressive cancers and are
often located in the endocervix. These
non- squamous cancers are therefore
not eas- ily detected by cytological
screening.
The
percentage
of

nonsquamous cancers was slightly higher (34%) in the group of

TABLE 3

Unsatisfactory smears previously

diagnosed as WNL smears
Reasons for
unsatisfactory smears

FIGURE 2

Women with cervical cancer, subdivided into categories

Unsatisfactory
smears, n

A (too much blood)

B (too many leucocytes)

C (few epithelial cells)

...........................................................................................................
...........................................................................................................
...........................................................................................................

D (badly fixated)

A plus B

A plus C

B plus C

A plus B plus C

...........................................................................................................
...........................................................................................................
...........................................................................................................
...........................................................................................................
...........................................................................................................

Total

23

...........................................................................................................

WNL, within normal limits.

de Bie. Failures of cervical cancer prevention. Am
J Obstet Gynecol 2011.

women with a WNL smear within 5

years preceding the diagnosis of
cervical can- cer, compared with the
total group (22.7%).
Remarkably, one-fourth
of the
reviewed smears were unsatisfactory for
evaluation. The cervical lesion might
have been de- tected if these smears
would have been re- peated after 6
weeks, according to the guidelines. The
majority (89%) of these unsatisfactory
smears were conventional smears. This
might suggest that conven- tional
smears are more likely to be
unsatisfactory than liquid-based cytology,
as previously reported.30,31 However,
this suggestion completely depends on the
dis- tribution of conventional smears vs
liquid- based smears in the screening
population. During the study period, the
use of solely conventional cytology
slowly shifted to- ward a combination
of conventional and liquid-based
methods.
The sensitivity of cytology for the detection of cervical lesions may be increased by improving the technical stan5,32-35
dards for smears and their reading.
Recently it has been shown that improving the sensitivity of the initial
screening step by using an additional
high-risk hu- man papillomavirus
(hrHPV) test might further reduce the
proportion
of false- negative

Diagram of the total 401 women with cervical cancer, subdivided into categories of explanations why
screening did not prevent these cases.
de Bie. Failures of cervical cancer prevention. Am J Obstet Gynecol 2011.

7,36,37

results.
The
nonsquamous mainly adenocarcinomas, are detectable
cervical cancers in this study, which as well by hrHPV testing.
were
Additionally, cervicovaginal self-samples appear to be as reliable as physiciantaken samples.38,39 Screening by selfsamples performed in the privacy of
womens own homes might provide a
better attendance than screening by
samples taken by a physician or other
health care providers.40,41 A self-sampling method for hrHPV performed by
the woman herself might be a possible
way for current nonresponders to lower
the threshold to attend and increase the
coverage of screening.40,42
Although hrHPV testing has a higher
sensitivity than cytological screening to
detect cervical abnormalities, it has a
lower specificity. It is important to
search for a balance between harms and
benefits. Triage strategies for women
who are hrHPV positive, for example, by
repeat hrHPV testing, subsequent cytology, or the use of biomarkers, increases
specificity and prevents overtreatment.
However, concerning this study, we
have to consider that the NCSP started in
1988 and women diagnosed just after the
beginning of the national program could
not have optimally benefited from
screening. After all, the sensitivity of the
screening program is higher due to a repetition of a moderate sensitive test. Fur-

thermore, the CTs reviewed all smears

with full knowledge of the study. The
purpose of this study was to scrutinize
the smears for abnormal cells to distinguish interpretation errors, sampling errors, or progressive forms of cancer. The
aim was not to repeat a normal
screening setting. Therefore, the
sensitivity of the detection
of
abnormal smears in this study is not
completely comparable with that in a
12
screening setting.
A limitation of this study is that the
study population was drawn from a
single medical center, although the
RUNMC renders
referral
medical
services for
1,500,000
people
and
therefore
practically reflects the general population.
A long in- clusion period is required to
achieve a large cohort in a single center.
However, this study does provide us the
opportunity
to
detect
where
improvements are achievable in this
chain of events and which part of the
cervical cancer incidence is attributable
to limited detection of (pre-)malignancies
of cervical cancer.
Another limitation is that women with
cervical cancer stage IA are not
necessar- ily referred to the RUNMC
and often treated at regional hospitals,
as a result of which our study
population contains rel- atively fewer
stage IA cervical cancers. Additionally,
the RUNMC is a national referral
center for radical trachelectomy

for small stage IBI cervical cancers. A

maximum of 30 women were referred
with this indication during the study
period.
In conclusion, new cases of cervical
cancer occur because of the following:
(1) nonattendance to the NCSP, (2) a
narrow target age range of 30-60 years,
and (3) limited sensitivity of the screening test caused by sampling and/or
inter- pretation errors. Therefore, the
target age range of the current NCSP
in The Netherlands may need to be
reevaluated, and
shortening
the
screening interval might decrease the
percentage of WNL smears before the
diagnosis of cervical cancer.
The incidence and mortality rate from
cervical cancer can be reduced further
by interventions to increase the
participa- tion rate of the NCSP and by
improving the sensitivity of the
screening test. Using additional hrHPV
testing and/or hrHPV self-sampling for
nonresponders are possibilities to reach
this goal.41
f
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