EUROPEAN UROLOGY 60 (2011) 493–500

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Review – Bladder Cancer

Long-term Cancer-specific Survival in Patients with High-risk,

Non–muscle-invasive Bladder Cancer and Tumour Progression:
A Systematic Review

Sven van den Bosch, J. Alfred Witjes *

Department of Urology, Radboud University Nijmegen Medical Centre, The Netherlands

Article info Abstract

Article history: Context: Some studies report that tumour progression in patients with non–
Accepted May 23, 2011 muscle-invasive bladder cancer (NMIBC) is associated with a poor prognosis.
Published online ahead of However, no systematic evidence is available.
print on June 1, 2011 Objective: The aim of the study was to systematically review literature to
determine the long-term cancer-specific survival in patients with high-risk
Keywords: NMIBC (T1G3, multifocal, highly recurrent, or carcinoma in situ) having tumour
Bladder cancer progression.
High-risk Evidence acquisition: A systematic review was conducted by searching PubMed
Long-term and the Cochrane library for studies published between 2006 and 2011. Additional
Non–muscle-invasive bladder studies were identified by scanning reference lists of relevant papers. We
cancer attempted to retrieve missing data by contacting the corresponding author. Key-
Progression words used included bladder cancer, high-risk, high grade, carcinoma in situ, non-
Urothelial carcinoma muscle invasive bladder cancer, progression, and survival. Studies were included
Survival when they met the following criteria: inclusion of at least 75 patients having high-
Systematic review risk NMIBC, patients were initially treated conservatively with transurethral
resection of the bladder tumour and intravesical instillations, a median follow-
up of at least 48 mo, and reporting data on progression to muscle-invasive bladder
cancer (MIBC) and death resulting from bladder cancer (BCa).
Evidence synthesis: Literature was systematically reviewed, and 19 trials were
included, producing a total of 3088 patients, of which 659 (21%) showed progres-
sion to MIBC and 428 (14%) died as a result of BCa after a median follow-up of
48–123 mo. Survival after progression from high-risk NMIBC to MIBC was 35%.
Progression to MIBC and BCa-related death in high-risk NMIBC were found to be
relatively early events, occurring mainly within 48 mo. Finally, even in cases of
early cystectomy in patients with high-risk NMIBC, a relevant proportion of these
patients appear not be cured of their disease.
Conclusions: This study provides systematically gathered evidence showing a poor
prognosis for patients with high-risk NMIBC and tumour progression.
# 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Department of Urology, Radboud University Nijmegen Medical Centre, PO

Box 9101, 6500 HB Nijmegen, The Netherlands.
E-mail address: F.Witjes@uro.umcn.nl (J.A. Witjes).

0302-2838/$ – see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2011.05.045
494 EUROPEAN UROLOGY 60 (2011) 493–500
1. Introduction
Bladder cancer (BCa) is the second most common malig-
nancy of the urinary tract. In 2008, the estimated incidence
of BCa in Europe was 110 500 cases, of which 86 300 were
diagnosed in men and 24 200 were diagnosed in women [1];
in men, BCa was the fourth most commonly diagnosed type
of cancer. BCa accounted for 4.1% of all cancer-related
deaths in men and 1.8% in women [1]. In newly diagnosed
cases of urothelial carcinoma of the bladder, approximately
75% present as non–muscle-invasive BCa (NMIBC), and 25%
present as muscle-invasive BCa (MIBC) [2].
Transurethral resection of the bladder tumour (TURBT) in
combination with intravesical chemotherapy or immuno-
therapy is considered standard therapy for NMIBC. However,
despite intravesical treatment, patients are still at risk for
tumour recurrence and progression to MIBC. Important risk
factors for progression or recurrence are tumour size, stage
and grade, multiplicity, prior recurrences, and the presence
of carcinoma in situ (CIS) [3]. Depending on patient risk
profile, rates of recurrence can be as high as 78% within 5 yr,
and rates of progression can be as high as 45% [3]. For
individual patients, recurrence and progression rates can be
estimated using the European Organisation for Research and
Treatment of Cancer (EORTC) risk tables [3].
In high-risk patients, conservative treatment with TURBT
and intravesical instillations with bacillus Calmette-Guérin
(BCG) can prevent recurrence, but the results with regard to
progression are conflicting [4–6], and whether intravesical
instillations have beneficial effects on cancer-specific
survival (CSS) is still controversial [5,6]. In contrast, high-
risk patients treated conservatively for too long may have a
decreased CSS by deferring radical treatment and allowing
progression to muscle-invasive disease [7–9].
In cases of MIBC without lymph node or distant metastasis,
radical cystectomy (RC) is the treatment of choice. A subset of
patients subjected to RC for MIBC will present with a history of
NMIBC in which the tumour finally progressed to muscle-
invasive disease despite conservative treatment [10]. In
normal daily practice, primary and progressive MIBC are
treated equally, assuming similar CSS in both groups.
However, a retrospective study of Schrier et al, for
example, showed that progression in patients with NMIBC
is associated with a poor prognosis that significantly worse
than in primary MIBC. The 3-yr CSS in the group with
progression to MIBC was 37% versus 67% in the group with
primary MIBC [11]. These findings suggest that patients with
high-risk NMIBC could benefit from early radical treatment,
especially if survival is poor in cases of progression to MIBC.
The objective of this study was to systematically review
recent literature with an emphasis on CSS in patients with
high-risk NMIBC and tumour progression.
2. Evidence acquisition
The first step was to specify and document inclusion criteria
and methods of the analysis, using methodologic recom-
mendations for systematic reviews [12]. The primary end
point of this study was to determine CSS in patients with
tumour progression; therefore, the search was focused on
retrieving data on progression to MIBC and death resulting
from BCa. Progression was defined as the development of
muscle-invasive disease (T2) or the presence of metastatic
disease in patients with a history of NMIBC.
2.1. Eligibility criteria
Studies were included when they met the following criteria:
inclusion of at least 75 patients having high-risk NMIBC
(according to European Association of Urology [EAU]
guidelines: T1G3, multifocal or highly recurrent, CIS),
patients were initially treated conservatively (TURBT
and intravesical instillations), a median follow-up of at
least 48 mo, reporting data on progression to MIBC and
death resulting from BCa, and availability of the full text in
English. Studies with both prospective and retrospective
designs were included in this review.
These criteria for inclusion were chosen because they
offered sufficient information on progression to MIBC and
death from BCa. The minimum follow-up of at least 48 mo was
chosen based on the EORTC risk tables [3]. This study showed
that in high-risk NMIBC, approximately 80–85% of those
patients who will progress to MIBC will do so within 48 mo.
2.2. Information sources and study selection
Studies were identified by searching the National Library of
Medicine (PubMed) and the Cochrane library for the period
2006–2011. To perform the search, the keyword bladder
cancer was used in combination with each of the following
individual keywords: (high risk OR high grade); (grade 3 OR
T1G3); (non-muscle invasive OR superficial); carcinoma in
situ; progression; and survival. In addition, reference lists of
relevant articles were scanned to identify other relevant
studies. The last search was run on 30 January 2011.
Study selection was performed in a standardised
manner. Abstracts of papers were read and, when they
were considered relevant, the full papers were obtained and
reviewed to assess the eligibility criteria. Included papers
were assessed for duplicates by checking included studies
in meta-analysis. Retrospective studies were checked for
using the same patient series. In case of duplicity, the most
recent publication was used.
2.3. Data collection and quality assessments
For eligible studies, relevant data were obtained using a
data-extraction sheet. We attempted to retrieve missing or
unclearly reported data by contacting the corresponding
author of the study. All data obtained were verified for
consistency and compared with the data in the publication.
2.4. Statistical analysis
When data on progression to MIBC and death from BCa were
available, CSS was calculated for those patients having
tumour progression. In this calculation, it was assumed that
death resulting from BCa was only possible after progression
 EUROPEAN UROLOGY 60 (2011) 493–500 495

to MIBC or because of the presence of metastatic disease.
The following formula was used: CSS = 1  (patients died of
BCa/patients with progression to MIBC)  100%.
Statistical analysis was carried out using SPSS v.17.0.0
statistical software for Windows (IBM Corp., Somers, NY,
USA). Continuous variables not conforming to a normal
distribution were compared using the Mann-Whitney
U test. Tests for trends were performed only when there
was a prior hypothesis of a trend; p  0.05 was considered
statistically significant.

[(Fig._1)TD$IG]

Fig. 1 – Flow of information through the different stages of this review.

TURBT = transurethral resection of the bladder tumour.
496 EUROPEAN UROLOGY 60 (2011) 493–500

3. Evidence synthesis
3.1. Results
In total, 1367 results were identified, of which 1354 were
identified by searching PubMed and an additional 13 results
were identified by screening reference lists. All 1367 records
were screened, and 1227 studies were discarded, because
these papers clearly did not meet the inclusion criteria after
reviewing their abstracts. The full-text papers of the
remaining 140 studies were obtained and examined in more
detail, after which another 118 studies were excluded.
Reasons for exclusion were short follow-up (n = 58), not
mainly high-risk NMIBC (n = 35), included <75 subjects
(n = 12), not mainly treated with TURBT or intravesical
instillations (n = 10), or duplicate patient series (n = 3).
Four studies did not report data on progression to
MIBC or death from BCa [13–16]. The corresponding
authors of these studies were contacted by e-mail and
all responded, except one [15]. Data on progression to MIBC
or death from BCa were not available for three of these
studies [14–16], which were therefore excluded. Figure 1
shows the flow of information through this systematic
review.
In total, 19 studies were identified for inclusion in this
review. For each study, the methodologic design, duration of
follow-up, numbers of patients, proportions of tumour stages
(Ta, T1, CIS, and concomitant CIS), restaging, progression to
MIBC, and death from BCa were extracted. Based on the
methodologic design of the trials, the included studies were
sorted into two groups: prospective and retrospective trials,
listed in Table 1 and Table 2, respectively.
The prospective group included 7 trials with a total
of 1183 patients, of which 258 (22%) progressed to MIBC
and 176 (15%) died from BCa after a median follow-up of
52–123 mo. The long-term CSS after progression to MIBC
was 32% (range: 13–64). The retrospective group included
12 trials with a total of 1905 patients, of which 401 (21%)
progressed to MIBC and 252 (13%) died of BCa after a
median follow-up of 48–107 mo. The long-term CSS after
progression to MIBC was 37% (range: 7–59).
Median CSS was 30% (interquartile range [IQR]: 17–45)
for prospective studies and 39% (IQR: 20–47) for retrospec-
tive studies ( p = 0.47; Fig. 2). Studies with a long (60-mo)
follow-up had a median CSS of 33% (IQR: 15–46) compared
to 33% (IRQ: 24–48) for studies with a short (48–60-mo)
follow-up ( p = 0.47), illustrating that progression to MIBC
and BCa-related death in high-risk NMIBC are relatively
early events and mainly occur within 48 mo. Median CSS in
studies that reported performing a standard restaging
TURBT was 31% (IQR: 20–46) compared to 36% (IQR: 18–47)
for studies in which a restaging TURBT was not standard of
care ( p = 0.66).
3.2. Discussion
In the current study, CSS was determined in patients with
high-risk NMIBC and tumour progression. The literature
was systematically reviewed, and 19 trials were included,
providing a total of 3088 patients, of which 659 (21%)
showed progression to MIBC and 428 (14%) died of BCa after
a median follow-up of 48–123 mo. This translates into a
long-term CSS of 35% in patients with high-risk NMIBC and
tumour progression.
Prospective and retrospective studies were initially
analysed separately, because we expected to find a worse
CSS in retrospective studies dealing with high-risk NMIBC.
This outcome could be the result of selective inclusion of
more patients with high-risk cancers in retrospective
studies. However, we did not find such a difference.
Two assumptions were used for this study. First, it was
assumed that death from BCa in cases of NMIBC was not
possible without progression to MIBC or the presence of
metastatic disease. Second, it was assumed that progression
to MIBC and death from BCa are relative early events
(within 48 mo) when they occur. This assumption was
based on the EORTC risk tables, which show that in high-
risk NMIBC, approximately 80–85% of those patients who

Table 1 – Included trials having a prospective design

Source No. of Median Restaging Proportion Progression Death from CSS in case
patients follow-up TURBT of Ta/T1/ to MIBC, disease, of progression,
CIS*/cCIS**, % no. (%) no. (%) %

Di Stasi et al, 2006 [30] 212 88 (IQR: 63–110) Yes 0/100/0/27 33 (16) 23 (11) 30
Dalbagni et al, 2007 [31] 89 52 (range: 16–90) Yes 0/100/0/38 22 (25) 15 (17) 32
Gradmark et al, 2007 [36] 250 123 (range: 46–176) NR 42/25/33y 58 (23) 45 (18) 22
Esuvaranathan 80 54 (range: 6–114) NR 24/49/27y 6 (8) 5 (6) 17
et al, 2007 [37]
Gofrit et al, 2009 [38] 104 75 NR 38/25/37/63 22 (21) 12 (12) 45
Zieger et al, 2009 [39] 125 80 (range: 6–142) NR 39/61/0/31 67 (54) 58 (46) 13
Sylvester et al, 2010 [5] 323 110 No NR 50 (15) 18 (6) 64
Totals 1183 52–123 – – 258 (22) 176 (15) 32 (range:
13–64)

TURBT = transurethral resection of the bladder tumour; CIS = carcinoma in situ; cCIS = concomitant carcinoma in situ; MIBC = muscle-invasive bladder cancer;
CSS = cancer-specific survival; IQR = interquartile range; NR = not reported.
*
Isolated CIS without concomitant papillary tumour.
**
Papillary tumour with concomitant CIS.
y
The presence of concomitant and isolated CIS were reported together.
 EUROPEAN UROLOGY 60 (2011) 493–500 497

Table 2 – Included trials having a retrospective design

Source No. of Median Restaging Proportion of Progression to Death from CSS in case of
patients follow-up, mo TURBT Ta/T1/CIS*/cCIS**, % MIBC, no. (%) disease, no. (%) progression, %

Kamel et al, 2006 [32] 105 48 (range: 8–156) Yes 0/100/0/14 25 (24) 19 (18) 24
Moonen et al, 2007 [40] 105 58 (range: 3–161) NR NR 25 (24) 13 (12) 48
Margel et al, 2007 [41] 78 107 (range: 16–238) NR 0/100/0/22 14 (18) 12 (15) 14
Queipo-Zaragoza et al, 2007 [42] 83 Mean: 58  28 NR 0/100/0/27 31 (37) 17 (20) 45
Denzinger et al, 2007 [33] 132 68 (range: 1–180) Yes 0/100/0/65 54 (41) 50 (38) 7
Serretta et al, 2008 [43] 165 103 No 0/100/0/0 14 (8) 9 (5) 36
Palou et al, 2009 [25] 92 91 (range: 3–173) No 0/100/0/60 17 (18) 14 (15) 18
Park et al, 2009 [13] 144 65 No 0/100/0/12 19 (13) 10 (7) 47
Chade et al, 2010 [34] 476 61 (IQR: 30–98) Yes 54/0/46/54 57 (12) 33 (7) 42
van Rhijn et al, 2010 [44] 164 77 (range: 4–259) No 15/81/0/34 48 (29) 26 (16) 46
Alkhateeb et al, 2010 [35] 191 48 Yes 0/100/0/29 61 (32) 25 (13) 59
Alvarez-Mugica et al, 2010 [45] 170 53 (range: 3–190) NR 0/100/0/24 36 (21) 24 (14) 33
Totals 1905 48–107 – – 401 (21) 252 (13) 37 (range:
7–59)

TURBT = transurethral resection of the bladder tumour; CIS = carcinoma in situ; cCIS = concomitant carcinoma in situ; MIBC = muscle-invasive bladder cancer;
CSS = cancer-specific survival; NR = not reported; IQR = interquartile range.
*
Isolated CIS without concomitant papillary tumour.
**
Papillary tumour with concomitant CIS.

will progress to MIBC will do so within 48 mo [3].
Consequently, to include most events of progression to
MIBC and death from BCa, only studies with a median
follow-up of at least 48 mo were included. For the included
studies, analysis showed no statistically significant differ-
ence in CSS between studies with a long (60-mo) and short
[(Fig._2)TD$IG]
Fig. 2 – Box-plot graphs consisting of mean value, quartiles, and range for
cancer-specific survival after progression to muscle-invasive bladder
cancer compare the study designs of the included studies.
CSS = cancer-specific survival.
(48–60-mo) follow up, supporting the second assumption
that progression to MIBC followed by cancer-related death
are relative early events when they occur. This assumption
made it possible to combine all data on progression to MIBC
and BCa-related death to calculate a long-term CSS for the
whole group.
Literature reports are limited and contradictory with
regard to the prognosis of patients with NMIBC and tumour
progression. In a retrospective study by Schrier et al. [11],
the difference in prognosis between progressive and
primary MIBC in 163 patients was studied. A CSS rate of
37% was found in 74 patients with progressive disease,
compared to 67% for 89 patients with de novo MIBC after a
follow-up of 3 yr ( p = 0.0015). Patients from both groups
were matched for stage and grade. This study clearly
showed a poor prognosis for patients with MIBC and a
history of NMIBC. These CSS data correspond with the
findings in the current study. However, Schrier et al. found
this CSS rate after a follow-up of 3 yr [11], where the current
study included studies with a much longer median follow-
up, ranging from 48 to 123 mo. Another example is the
recent individual patient data meta-analysis on the impact
of BCG on progression by Malmström et al. [6], which also
revealed a 60% cancer-related death rate in those patients
showing progression of their bladder tumour with a median
follow-up of 4.8 yr. Similar results were found in other
studies [14,17].
In contrast, there is literature reporting an equal survival
rate for both progressive and de novo MIBC. In a
retrospective study by Lee et al. [18], 422 patients were
included and divided into three groups based on the final
clinical stage before RC. The first group included 183
patients with high-risk NMIBC; the second group included
70 patients with progressive disease to clinical stage T2
BCa; the third group included 169 patients with de novo
clinical stage T2 BCa. After a follow-up of 3 yr, the CSS rates
were 76%, 63%, and 64%, respectively. The group with
progressive MIBC had no survival disadvantage in compari-
498 EUROPEAN UROLOGY 60 (2011) 493–500
son to the group with de novo MIBC ( p = 0.46). The authors
concluded that surveillance in high-risk NMIBC does not
compromise survival if there is progression to MIBC
compared with de novo MIBC. The lack of difference
between the two groups with clinical T2 BCa, however, is in
part likely to be caused by understaging, because under-
staging was reported to be a major problem in both groups
(59% and 60%, respectively) [18]. Ferreira et al. [19] also did
not find a difference in CSS between patients with and
without a history of NMIBC.
If indeed survival decreases significantly after progres-
sion to MIBC, the question arises whether aggressive
therapy such as RC in high-risk NMIBC is able to improve
the outcome of these patients. Therefore, early versus
deferred RC is an important related subject. There are few
retrospective studies in which long-term CSS has been
studied, comparing early (within 3 mo after initial
diagnostic TURBT) and deferred cystectomy in high-risk
NMIBC [8,20,21]. These studies show that primary treat-
ment of high-risk NMIBC with early RC provides good long-
term oncologic results, having a CSS of 80% at 5 yr [20] and
76–78% at 10 yr [8,21]. For deferred cystectomy, the long-
term oncologic results are worse, showing a CSS of 69% at
5 yr [20] and 51–61% at 10 yr [8,21]. In another
retrospective study, CSS was compared among 46 patients
having cystectomy for NMIBC that was refractory to
conservative treatment and 262 patients having MIBC at
the time of cystectomy [22]. After a median follow-up of 58
mo, CSS was 67% in both groups ( p < 0.05), despite a similar
rate of understaging compared to other studies [22].
These findings illustrate that despite early RC, a relevant
proportion of patients with high-risk NMIBC appears not be
cured of their disease. However, survival is worse in
patients with deferred RC, suggesting that early cystectomy
does improve oncologic outcome. Apparently, a worst
outcome is seen when progression to MIBC has occurred,
as is shown in the current study. These findings support the
suggestion that the increased use of conservative treatment
in high-risk NMIBC might be related to a decrease in
survival [9].
In contrast, these early versus late cystectomy series
show that understaging is an important problem in high-
grade NMIBC. Approximately 10–30% of cases were initially
understaged and were therefore muscle invasive [8,21–23].
In addition, in a large study on the issue of understaging in
high-risk NMIBC, approximately 50% of the patients treated
with RC for clinical T1G3 BCa were upstaged to MIBC [24].
Therefore, correct staging is crucial for the choice of
treatment between NMIBC and MIBC. A restaging TURBT
is standard of care after the initial diagnosis of high-grade or
stage T1 NMIBC in the current EAU guidelines. In a
retrospective study by Dalbagni et al. [23], a similar survival
was found between early and deferred cystectomy in
carefully staged patients using restaging TURBT.
The results from this study emphasise that the manage-
ment of high-risk NMIBC is one of the most challenging
issues in urologic oncology. To decide whether a patient
with high-risk NMIBC should have radical surgery or can be
treated conservatively remains a difficult question. Obvi-
ously, critical risk factors such as concomitant CIS and early
BCG failure must be considered [3,25,26]. Unfortunately, no
markers to date can differentiate between indolent and
aggressive tumours in high-risk NMIBC on an individual
level [27,28].
To the best of our knowledge, this is the first study to
systematically examine the prognosis of patients with high-
risk NMIBC and tumour progression. CSS was calculated
using numbers on progression to MIBC and death from BCa
in a large population, included from a total of 19 studies
with a sufficient long-term follow-up to study progression
to MIBC and BCa-related death.
This study has several limitations. Almost two-thirds of
the study population was included from retrospective
studies. Selective inclusion of patients with different high-
risk profiles between the included study populations (for
example, different proportions of concomitant CIS or large
tumours) could explain the wide variation in the rates of
progression (8–54%) and CSS (7–64%).
Moreover, if any standard treatment protocol was
reported in the included studies, some of the studies had
different treatment protocols that were not always stan-
dardised or evidence based. This could also have introduced
bias into the results, because treatment intensity and
variation could influence CSS [29]. Treatment advise in
cases of progression to MIBC was comparable between the
studies (RC in the case of nonmetastasised tumours and
chemotherapy in cases of metastasised tumours).
In addition, only a few studies included in this review
reported that restaging was performed as a standard after
the initial diagnosis of high-grade NMIBC [30–35]. Inclusion
of studies without restaging could have introduced bias into
the results because of treatment delay of missed and thus
untreated MIBC in cases of understaging. However, in the
current study, no significant difference in CSS was found
between included studies with or without standard
restaging TURBT.
Finally, an important limitation of this study is the lack
of time-dependent data. CSS was not based on individual
patient data but calculated from reported numbers on
progression to MIBC and death from BCa. Therefore, there
are no specific results available on time to progression
to MIBC, time to RC, time to death from BCa, or survival
in specific strata. This was also the reason that it was
not possible to determine the exact follow-up of the
calculated CSS.
4. Conclusions
This study provides systematically gathered evidence
showing a poor prognosis for patients with high-risk
NMIBC and tumour progression. Progression to MIBC and
BCa-related death in high-risk NMIBC are relatively early
events and occur mainly within 48 mo. However, even in
cases of early cystectomy, a relevant proportion of patients
appears not be cured of their disease. Still, the worst
outcome is seen when progression to MIBC has occurred.
It remains unclear why the CSS in these patients is so
much worse.
 EUROPEAN UROLOGY 60 (2011) 493–500
Deferring RC obviously has a continuing risk of progres-
sion to MIBC as well as a continuing risk of understaging
because of the inadequacy of current staging tools. Therefore,
a more aggressive approach, such as early RC, should be
strongly considered in the treatment of high-risk NMIBC.
Author contributions: J. Alfred Witjes had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Witjes.
Acquisition of data: van den Bosch.
Analysis and interpretation of data: van den Bosch.
Drafting of the manuscript: van den Bosch.
Critical revision of the manuscript for important intellectual content:
van den Bosch, Witjes.
Statistical analysis: van den Bosch.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Witjes.
Other (specify): None.
Financial disclosures: I certify that all conflicts of interest, including
specific financial interests and relationships and affiliations relevant
to the subject matter or materials discussed in the manuscript
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents filed,
received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
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