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Original Article

Skeletal Muscle Density Predicts Prognosis in Patients With

Metastatic Renal Cell Carcinoma Treated With Targeted
Therapies
Sami Antoun, MD1; Emilie Lanoy, PhD2; Roberto Iacovelli, MD3,4; Laurence Albiges-Sauvin, MD3; Yohann Loriot, MD3;
Mansouriah Merad-Taoufik, MD1; Karim Fizazi, MD, PhD3; Mario di Palma, MD1; Vickie E. Baracos, PhD5; and
Bernard Escudier, MD3

BACKGROUND: Studies have shown that skeletal muscle and adipose tissue are linked to overall survival (OS) and progression-free
survival (PFS). Because targeted therapies have improved the outcome in patients with metastatic renal cell carcinoma (mRCC), new
prognostic parameters are required. The objective of the current study was to analyze whether body composition parameters play a
prognostic role in patients with mRCC. METHODS: Adipose tissue, skeletal muscle, and skeletal muscle density (SMD) were assessed
with computed tomography imaging by measuring cross-sectional areas of the tissues and mean muscle Hounsfield units (HU). A
high level of mean HU indicates a high SMD and high quality of muscle. OS and PFS were estimated using the Kaplan-Meier method
and compared with the log-rank test. The multivariable Cox proportional hazards model was adjusted for Heng risk score and treat-
ment. RESULTS: In the 149 patients studied, the median OS was 21.4 months and was strongly associated with SMD; the median OS
in patients with low SMD was approximately one-half that of patients with high SMD (14 months vs 29 months; P 5.001). After adjust-
ment for Heng risk score and treatment, high SMD was associated with longer OS (hazards ratio, 1.85; P 5.004) and longer PFS (haz-
ards ratio, 1.81; P 5.002). Adding SMD will separate the intermediate-risk and favorable-risk groups into 3 groups, with different
median OS periods ranging from 8 months (95% confidence interval [95% CI], 6 months-12 months) for an intermediate-risk Heng
score=low SMD to 22 months (95% CI, 14 months-27 months) for an intermediate-risk Heng score=high SMD and a favorable-risk
Heng score=low SMD to 35 months (95% CI, 24 months-43 months) for a favorable-risk Heng score=high SMD. CONCLUSIONS: High
muscle density appears to be independently associated with improved outcome and could be integrated into the prognostic scores
thereby enhancing the management of patients with mRCC. Cancer 2013;119:3377-84. V C 2013 American Cancer Society.

KEYWORDS: renal cell carcinoma; body composition; muscle density; prognosis; targeted therapy.

INTRODUCTION
Tumors of the kidney represent approximately 2% to 3% of new cancer cases diagnosed each year and approximately one-
third of patients will eventually develop metastatic disease. Better knowledge of prognostic and predictive factors could
improve the management of metastatic renal cell cancer (mRCC) by identifying those patients at a higher risk of death or
disease progression. The most commonly used prognostic scores are the Memorial Sloan-Kettering Cancer Center score
and the recent Heng risk score for patients receiving targeted therapies.1,2
Since the introduction of targeted therapies, survival has doubled. However, if new drugs have proven efficacy with
regard to progression-free survival (PFS) in patients with mRCC, the discordance between the response to treatment and
overall survival (OS) has been noted.3 Therefore, predictive as well as prognostic markers need to be studied extensively.
Many prognostic scores incorporate clinical and biological factors, but to the best of our knowledge none integrate meas-
urements of body composition such as quantity of fat or skeletal muscle. Patients with RCC who have a higher body mass
index (BMI) have been reported to have a significantly better prognosis than those with a lower BMI.4,5 However, the favor-
able prognostic roles of overweight and obesity have been challenged.6,7 In addition, body composition parameters (ie, adipose
tissue and skeletal muscle) have been shown to be linked with prognosis in patients with cancer. Previous studies have shown
that low skeletal muscle mass (ie, sarcopenia) is linked to a shorter OS in obese patients with colorectal cancer and in obese

Corresponding author: Sami Antoun, MD, Department Ambulatory Care, Institut Gustave-Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France; Fax: (011) 331
4211 5202; Sami.antoun@igr.fr
1
Department of Ambulatory Care, Institut Gustave-Roussy, Villejuif, France; 2Biostatistics and Epidemiology Unit, Institut Gustave-Roussy, Villejuif, France; 3Depart-
ment of Cancer Medicine, Institut Gustave-Roussy, Villejuif, France; 4Department of Radiology, Oncology, and Human Pathology, “Sapienza” University of Rome,
Rome, Italy; 5Department of Oncology, University of Alberta, Edmonton, Alberta, Canada

DOI: 10.1002/cncr.28218, Received: April 4, 2013; Revised: May 17, 2013; Accepted: May 20, 2013, Published online June 25, 2013 in Wiley Online Library
(wileyonlinelibrary.com)

Cancer September 15, 2013 3377


Original Article
patients with pancreatic cancer.8,9 High levels of muscle per-
formance as have been reported in lung cancer,10,11 or high
skeletal muscle density (SMD) as has been described in the
elderly and in patients with stage III melanoma, are also
prognostic of a longer OS.12,13 With regard to adipose tis-
sue, the results are conflicting. High adipose tissue and espe-
cially visceral adipose tissue (VAT) have been reported as
either related to better OS14,15 or to shorter survival.16 The
objective of the current study was to analyze whether skeletal
muscle (either muscle mass or muscle function based on the
SMD) and adipose tissue play a prognostic role in patients
with mRCC who are treated with targeted therapy.
MATERIALS AND METHODS
Patients
We selected all patients treated at the Institut Gustave-
Roussy in Paris, France who were enrolled in 3 prospec-
tive multicenter trials: the TARGET trial (Treatment
Approaches in Renal Cancer Global Evaluation Trial)
(n 5 83), which assessed the efficacy of a dose of sorafenib
of 400 mg given twice daily versus placebo17; the RE-
CORD trial (Renal Cell cancer treatment with Oral
RAD001 given Daily) (n 5 28), which assessed the effi-
cacy of an oral dose of 10 mg=day of everolimus versus
placebo18; and the sunitinib phase 2 trial (n 5 38), which
assessed the efficacy of sunitinib at a continuous daily
dose of 37.5 mg.19 Of note, the 83 patients from the
TARGET trial were included in previous studies assessing
the prognostic role of sarcopenia.22
For the original trials, patients provided informed
consent, and these studies were approved by the research
ethics board of all centers according to good clinical prac-
tice, the Declaration of Helsinki, and applicable regula-
tions. Additional analysis of clinical data and the
interpretation of body composition from computed to-
mography (CT) images were approved by the Institu-
tional Review Board of the Institut Gustave-Roussy.
The inclusion criteria for these 3 studies were very
similar: histologically proven clear cell mRCC and evi-
dence of measurable disease, after at least 1 line of therapy.
Full details of the main studies have been previously
described.17-19
Anthropometry and Body Composition by
Analysis of CT Imaging
Weight and height were measured prospectively at base-
line as part of the protocol. Body mass index (BMI) was
calculated (ie, BMI 5 weight in kg=height in m2).
Body composition features were evaluated using the
same CT images obtained at baseline for tumor assess-
3378
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ment. Baseline CT scans were performed within 28 days
before the initiation of therapy and all the measurements
were performed by 1 technician who was blinded to
patient information, clinical treatment, and outcome.
Directly measured variables in the current study were
lumbar cross-sectional areas (cm2) of skeletal muscle,
VAT, and subcutaneous adipose tissue (SAT) as described
in previous studies.20 Total adipose tissue (TAT) was cal-
culated as TAT 5 VAT 1 SAT. The third lumbar verte-
bra (L3) was chosen as a landmark because L3 cross-
sectional areas and whole-body measurements are linearly
related.21 CT images were analyzed using SliceOMatic
software (version 4.3; TomoVision, Magog, Quebec,
Canada). To evaluate the density of the skeletal muscle,
we measured the mean radiation attenuation of skeletal
muscle, which describes the input images read by the Sli-
ceOMatic software. The pixel values of these images dis-
played in shades of gray represent the physical properties
of the scanned tissue expressed in a numerical form. The
mean attenuation (expressed as the mean Hounsfield unit
[HU]) has been extensively studied as a correlate of mus-
cle density.12 Muscle density assessed by this method
reflects fatty muscle infiltration, with a lower mean HU
indicating lower density and more fatty infiltration. This
highly reproducible method correlates with muscle tri-
glyceride contents on muscle biopsy.12 As in previous
studies, these values were normalized for height scale and
are expressed as cm2=m2.20,22
Statistical Analysis
Since the distribution of adipose tissue, skeletal muscle,
and SMD differs greatly according to sex, for each param-
eter the population was dichotomized in 2 groups:
patients with a value under the median value in patients of
the same sex and patients with a value that was equal to or
above the median value in patients of the same sex. Base-
line values (at the time of treatment initiation in the trial)
of body parameters were expressed as the median, inter-
quartile range, and coefficient of variation corresponding
to the standard deviation divided by the mean (noise-to-
signal ratio). PFS was defined as the time from treatment
to the first documentation of disease progression or death
from any cause, whichever occurred first. Disease progres-
sion was defined as a  20% increase in SLD as per
Response Evaluation Criteria In Solid Tumors (RECIST,
version 1.0). OS was defined as the time from treatment
to death or last contact. The PFS and OS were estimated
using the Kaplan-Meier method with Rothman 95% con-
fidence intervals (95% CI) and compared across the
groups using the log-rank test.
Cancer September 15, 2013

Figure 1. Flow chart of the study is shown. HU, Hounsfield unit.
The association between each body parameter with
death and disease progression was evaluated using the Cox
proportional hazards model. Univariable analysis assessed
the association between OS and PFS and the following
variables: sex (male vs female), Heng score risk groups
(favorable-risk vs intermediate-risk vs poor-risk groups),
active therapy (yes if sorafenib, sunitinib, or everolimus;
no if placebo), type of therapy (vascular endothelial
growth factor [VEGF] inhibitor-containing therapy vs
other therapies), and BMI (< 18.5 kg=m2 vs 18.5-24.9
kg=m2 vs  25 kg=m2). The interaction between sex and
all body parameters was systematically tested. Multivari-
able analyses were adjusted for variables with a P value
< .20 in the univariable models using a backward stepwise
strategy to eliminate nonsignificant variables at a P value
Cancer September 15, 2013
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Prognostic Role of Muscle Density/Antoun et al
< .05. All analyses were performed using the SAS statisti-
cal software (version 9.3; SAS Institute Inc, Cary, NC).
RESULTS
Patients
After the exclusion of patients who did not meet the crite-
ria for inclusion (n 5 40), 142 patients and 119 patients
had data available regarding tissue areas and SMD, respec-
tively (Fig. 1). Among the 101 patients receiving active
therapies, 83 received VEGF inhibitor therapy.
The Heng risk score classified 61% of the patients as
being of favorable risk, 36% as being of intermediate risk,
and 3% as being of poor risk. Body composition parame-
ters differed between men and women, reflecting the
3379
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Original Article

TABLE 1. Baseline Characteristics: Age and Body Parameters

Male Female

Characteristic No. Median (Q1-Q3) CV No. Median (Q1-Q3) CV

Age, y 113 60 (52-66) 16% 36 58 (54-65) 17%

Weight, kg 113 80 (72-88) 17% 36 62 (52-69) 23%
BMI, kg/m2 113 26 (24-29) 16% 36 23 (20-26) 23%
VAT, cm2 109 153 (90-219) 61% 33 44 (22-77) 107%
VAT index, cm2/m2 109 50 (28-72) 62% 33 16 (9-29) 113%
SAT, cm2 109 157 (114-209) 47% 33 160 (95-183) 57%
SAT index, cm2/m2 109 53 (37-66) 47% 33 60 (38-72) 56%
TAT, cm2 109 326 (211-407) 49% 33 201 (117-317) 63%
TAT index, cm2/m2 109 106 (75-133) 49% 33 78 (50-110) 64%
VAT-to-TAT, % 109 48 (38-55) 23% 33 23 (14-30) 55%
Skeletal muscle, cm2 109 161 (147-173) 13% 33 99 (91-110) 21%
Skeletal muscle index, cm2/m2 109 53 (48-58) 14% 33 37 (35-42) 25%
Mean muscle HU 90 38 (31-43) 22% 29 36 (30-44) 30%

Abbreviations: BMI, body mass index; CV, coefficient of variation; HU, Hounsfield unit; VAT, visceral adipose tissue; VAT index, visceral adipose tissue index;
SAT index, subcutaneous adipose tissue index; SAT, subcutaneous adipose tissue; TAT, total adipose tissue (TAT 5 VAT 1SAT); Q1-Q3: 1st quartile -3rd
quartile.

higher surface area of VAT and skeletal muscle in men
(Table 1). Adipose tissue parameters were scattered, espe-
cially VAT, which presented high coefficients of variation
in men (61%) and women (107%). Only 4 patients were
considered to be malnourished (BMI of < 18.5 kg=m2).
Overall Survival
In the 149 patients included in the current study, the me-
dian OS was 21.4 months (95% CI, 18.4 months-23.9
months) and was strongly associated with SMD; the me-
dian OS in patients with high SMD (29 months [95%
CI, 21 months-43 months]) was 2-fold longer than that
of patients with low SMD (14 months [95% CI, 10
months-22 months]) (P 5 .001) (Figs. 2a and 2b). No
association between OS and TAT or muscle area was
found. OS was not found to be associated with BMI cate-
gory (P 5 .99).
No interaction was found between the respective
effects of sex and each body parameter on survival.
When adjusted for Heng risk score, SMD below the
median value for patients of the same sex was associated
with higher mortality (hazards ratio [HR], 1.9; 95% CI,
1.3-2.9) (Table 2), whereas OS was not found to be asso-
ciated with either a low level of muscle area (HR, 1.2;
95% CI, 0.8-1.7) (P 5 .40) or a low TAT level (HR, 1.2;
95% CI, 0.8-1.7) (P 5 .38). Adding SMD to the Heng
risk score was found to define 3 groups instead of 2 for the
intermediate-risk and favorable-risk groups, with a differ-
ent median OS ranging from 8 months (95% CI, 6
months-12 months) for an intermediate-risk Heng score-
low SMD to 22 months (95% CI, 14 months-27 months)
for an intermediate-risk Heng score=high SMD and
favorable-riskHeng score=low SMD to 35 months (95%
CI, 24 months-43 months) for a favorable-risk Heng
score=high SMD.
Progression-Free Survival
In the 149 patients included in the current study, the
median PFS was 5.5 months (95% CI, 4.2 months-6.5
months) and was strongly associated with SMD; the
median OS in patients with high SMD (8 months (95%
CI, 6 months-11 months) was 2-fold longer than that
of patients with low SMD (4 months; 95% CI, 4
months-6 months) (P < .001) (Figs. 2c and 2d). No
association was found between PFS and TAT and mus-
cle area. PFS was not associated with BMI category
(P 5 .73)
Multivariable analyses were not stratified based on
sex because there was no interaction noted between the re-
spective effects of sex and each body parameter on PFS.
Active treatment was associated with better PFS (Ta-
ble 2) but in treated patients there was no significant effect
of the type of therapy noted (VEGF receptor [VEGFR]
inhibitor vs mammalian target of rapamycin inhibitor:
HR, 1.0; 95% CI, 0.6-1.7 [P 5 .97]).
When adjusted for Heng risk score and active treat-
ment, PFS was found to be associated with SMD
(P 5 .002); SMD below the median value for patients of
the same sex was associated with a higher rate of death or
disease progression (HR of death or disease progression,
2.0; 95% CI, 1.3-2.9) (Table 2), but the PFS was not
associated with either a low level of muscle area (HR, 1.0;
95% CI, 0.7-1.4 [P 5 .86]) or with a low TAT level (HR,
0.9; 95% CI, 0.6-1.2 [P 5 .37]).

3380 Cancer September 15, 2013

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Prognostic Role of Muscle Density/Antoun et al

Figure 2. Kaplan-Meier estimates of (a and b) overall survival and (c and d) progression-free survival in the strata of skeletal
muscle density (SMD; a and c) are shown. Black dashed line indicates greater than or equal to the median value in patients of
the same sex; gray dashed line, less than the median value in patients of the same sex and (b and d) in the strata of SMD and
Heng risk score. (1a) Favorable-risk Heng score and SMD greater than or equal to the median values are indicated by the black
dashed line. (1b) Favorable-risk Heng score and SMD less than the median values are indicated by the gray solid line. (2a) Inter-
mediaterisk Heng score and SMD greater than the median values are indicated by the black dashed line. (2b) Intermediate-risk
Heng score and SMD less than the median values are indicated by the gray dotted line.

DISCUSSION associated with an OS and PFS that appear to be reduced

The results of the current study of patients with mRCC by approximately one-half (P 5 .001 and P < .001,
who were treated with targeted therapies (VEGF inhibi- respectively). By adding SMD obtained by the simple
tors and mammalian target of rapamycin inhibitors), have analysis of CT images, we were able to determine a new
demonstrated that muscle density as measured by CT was subcategory between favorable-risk and intermediate-risk

Cancer September 15, 2013 3381


Original Article
Figure 2. (Continued)
groups based on Heng risk score. Instead of the 2
intermediate-risk and favorable-risk groups, we were able
to establish 3 groups classified by an 8-month median OS
(95% CI, 6 months-12 months) for patients with an
intermediate-risk Heng score and low SMD to a
22-month median OS (95% CI, 14 months-27 months)
for patients with an intermediate-risk Heng score and
high SMD and a favorable-risk Heng score and low
3382
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SMD, to a 35-month median OS (95% CI, 24 months-
43 months) for patients with a favorable-risk Heng score
and high SMD. We did not find any effect of BMI or
VAT, SAT, or TAT on OS and PFS and, contrary to what
was expected, we did not find any association between
skeletal muscle area and OS or PFS.
Epidemiological studies have described a strong
association between overweight or obesity and the
Cancer September 15, 2013

TABLE 2. Crude Estimates and Adjusted Estimated Ratio of Death and of Death or Disease Progression
OS HR of Death
Crude Estimates
HR (95% CI) P HR (95% CI)
Heng score Poor 1 <.001
Intermediate 2.6 (1.8-3.8)
Favorable 7.5 (2.9-19.4)
Treatment Placebo 1 .76
Active 0.9 (0.6-1.4)
SMD Mediana 1 .002
<Mediana 2.0 (1.3-3.0)
Abbreviations: 95% CI, 95% confidence interval; HR, hazards ratio; OS, overall survival; PFS, progression-free survival; SMD, skeletal muscle density.
a
Median indicates the median value in patients of the same sex.
incidence of mRCC. A high percentage of overweight or
obese patients was found in the current study (68%) and in
2 other therapeutic trials (56% and 58%, respectively).14,16
The relations between RCC and overweight or obesity
appear to be seem more complex than expected. The influ-
ence of BMI on OS and PFS has been found in patients
before nephrectomy and removal of the tumor might affect
outcome.5,15 With the exception of the study by Tang et
al,23 studies focusing on mRCC, including the current one,
failed to demonstrate a prognostic role for BMI.6 Over-
weight or obese patients appear to have a more favorable
prognosis than those with a normal BMI among those with
organ-confined RCC only, when surgery is planned and
may be in a specific ethnic population.5
Adipose tissue, and especially VAT, is not simply a
way to store energy, but should be considered as a true
endocrine compartment with the secretion of various hor-
mones that interact with tumor progression.24 Two studies
have found opposite results. In a study of 64 patients with
mRCC who were treated with anti-VEGF, Ladoire et al
demonstrated that high VAT was associated with a shorter
OS and PFS (HR, 6.3) (P < .001).16 Conversely, the study
by Steffens et al reported that high VATs and SATs were
both found to be independently associated with longer PFS
and OS.14 Two criticisms can be made in both studies: the
cutoff points were not defined according to sex and both
studies analyzed CT images measured at the umbilicus,
which has never been correlated to the whole adipose and
muscle tissue. Using measurements at L3 and adjusting the
results to patient sex, we did not find any influence of VAT
and SAT on either OS or PFS.
Muscle mass, as well as muscle functional status,
have been shown to be linked with clinical outcomes. In
patients with cancer, low skeletal muscle mass was shown
to be linked to anticancer treatment toxicity22,25 and to
Cancer September 15, 2013
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Prognostic Role of Muscle Density/Antoun et al
PFS HR of Death or Disease Progression
Multivariable
Multivariable Estimates Crude Estimates Estimates
P HR (95% CI) P HR (95% CI) P
1 <.001 1 <.001 1 <.001
2.4 (1.6-3.9) 2.3 (1.6-3.3) 2.1 (1.4-3.3)
24.9 (5.0-123.0) 4.7 (1.8-11.9) 7.5 (1.7-32.7)
1 <.001 1 <.001
0.4 (0.3-0.6) 0.5 (0.3-0.7)
1 .002 1 <.001 1 <.001
1.9 (1.3-2.9) 1.9 (1.3-2.7) 2.0 (1.3-2.9)
OS in sarcopenic obese patients.8,9 Muscle function as
assessed by a low level of peak oxygen consumption and a
6-minute walk test of < 400 meters (clinically significant
cutoff) was found to be strongly associated with survival
in patients with non-small cell lung cancer.10,11
We did not find any correlation between skeletal
muscle mass and OS. The discrepancy we observed in the
current study between results for muscle mass and SMD
could be similar to what has been previously reported in
elderly patients for SMD measures and risk of hospitaliza-
tion,26 and in patients with stage III melanoma.13 In this
latter study, which was performed among 101 patients,
SMD was found to be significantly associated with both
disease-free survival (P 5 .04) and distant disease-free sur-
vival (P < .001). It is interesting to note that, similar to
the results of the current study, no significant association
was found between outcomes and muscle area. Muscle
density has been shown to be closely related to muscle
lipid content and muscle function,12 and it is linked to
inflammatory processes, whereas skeletal muscle mass
may be associated with the imbalance between proteolysis
and muscle anabolism. These 2 concepts are very similar
but do not reflect the same mechanisms.
It is interesting to note that the current study en-
rolled only patients from clinical trials, and therefore the
prognostic role of SMD should be validated in a real-
world experience. However, 2 recent studies have demon-
strated a similar relationship between SMD and patient
outcome. Sabel et al13 reported that the SMD was an im-
portant predictor of outcome in a cohort of patients with
stage III melanoma. Martin et al also recently published
interesting results.27 They demonstrated that patients
with cancers of the gastrointestinal and respiratory tracts,
with involuntary weight loss, muscle depletion, and low
SMD, shared a poor prognosis.27.
3383

Original Article
Conclusions
There is increasing evidence of a close association between
body composition and outcome in patients with mRCC.
The main finding of the current study is that patients with
a high quality of muscle (high muscle density) have an OS
and PFS that are twice that of patients with a low quality
of muscle (low muscle density). By integrating the SMD
status in the Heng risk score, we were able to add a new
prognostic group among the patients with intermediate-
risk and favorable-risk Heng scores. There is a gradient in
OS and PFS from the group with an intermediate-risk
Heng score and low SMD, to the group with an
intermediate-risk Heng score and high SMD or a
favorable-risk Heng score and low SMD, to the group
with a favorable-risk Heng score and high SMD, present-
ing the longest OS and PFS.
Prognostic factors for improved OS are lacking for
patients with mRCC because the prognosis has been
improved with targeted therapies. The results of the cur-
rent study indicate that muscle density could be used as a
prognostic factor and could improve the usual prognostic
scores. However, further studies are needed to better
define the threshold values for muscle density.
FUNDING SUPPORT
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
Dr. Escudier has acted as a consultant and in an advisory role at
Bayer Pharma, Pfizer, Novartis, GlaxoSmithKline, and Aveo and
has received honoraria from Bayer, Roche, Pfizer, Genentech,
Novartis, Aveo, and GlakoSmithKline. Dr. Lanoy has received
travel support from GlaxoSmithKline for the 48th Annual Meeting
of the American Society of Clinical Oncology, held June 1 to 5,
2012 in Chicago, Illinois. Dr. Albiges-Sauvin acts as a consultant
and in an advisory role at and has received research funding from
Novartis.
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