E U R O P E A N U R O L O G Y 6 0 ( 2 0 1 1 ) 3 6 6 – 3 7 3

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Kidney Cancer

Renal Cell Carcinoma (RCC) in Patients With End-Stage Renal

Disease Exhibits Many Favourable Clinical, Pathologic, and

Outcome Features Compared With RCC in the General Population

Yann Neuzillet a,*, Xavier Tillou b, Romain Mathieu c, Jean-Alexandre Long d, Marc Gigante e,Philippe Paparel f, Laura Poissonnier g, Herve Baumert h, Bernard Escudier i, Herve Lang j,Nathalie Rioux-Leclercq k, Pierre Bigot l, Jean-Christophe Bernhard m, Laurence Albiges i,Laurence Bastien n, Jacques Petit b, Fabien Saint b, Franck Bruyere o, Jean-Michel Boutin o,Nicolas Brichart o, Georges Karam p, Julien Branchereau p, Jean-Marie Ferriere m,Herve Wallerand m, Sebastien Barbet m, Hicham Elkentaoui m, Jacques Hubert q, Benoit Feuillu q,Pierre-Etienne Theveniaud q, Arnauld Villers r, Laurent Zini r, Aurelien Descazeaux s,Morgan Roupret t, Benoit Barrou t, Karim Fehri t, Thierry Lebret a, Jacques Tostain e,Jean-Etienne Terrier e, Nicolas Terrier d, Lucille Martin u, Fabrice Dugardin v, Ismael Galliot v,Frederic Staerman w, Marie-Dominique Azemar w, Jacques Irani x, Baptiste Tisserand x,Marc-Olivier Timsit y, Federico Sallusto z, Pascal Rischmann z, Laurent Guy A, Antoine Valeri B,Charles Deruelle B, Abdel-Rahmene Azzouzi l, Denis Chautard l, Arnaud Mejean y,Laurent Salomon n, Jerome Rigaud p, Christian Pfister v, Michel Soulie z, Francois Kleinclauss u,Lionel Badet g, Jean-Jacques Patard C, the members of the Comite de Transplantationde l’Association Francaise d’Urologie, the Comite de Cancerologie de l’AssociationFrancaise d’Urologie

a Department of Urology, Foch Hospital, Suresnes, Franceb Department of Urology, Amiens University Hospital, Amiens, Francec Department of Urology, Pontchaillou University Hospital, Rennes, Franced Department of Urology, Michallon University Hospital, Grenoble, Francee Department of Urology, Saint-Etienne University Hospital, Saint Etienne, Francef Department of Urology, Lyon University Hospital, Pierre-Benite, Franceg Department of Urology, Edouard Herriot University Hospital, Lyon, Franceh Department of Urology, Saint Joseph Hospital, Paris, Francei Department of Oncology, Gustave Roussy Institute, Villejuif, Francej Department of Urology, Strasbourg University Hospital, Strasbourg, Francek Department of Pathology, Pontchaillou University Hospital, Rennes, Francel Department of Urology, Angers University Hospital, Angers, Francem Department of Urology, Pellegrin University Hospital, Bordeaux, Francen Department of Urology, Henri Mondor University Hospital, Creteil, Franceo Department of Urology, Bretonneau University Hospital, Tours, Francep Department of Urology, Hotel Dieu University Hospital, Nantes, Franceq Department of Urology, Brabois University Hospital, Nancy, Francer Department of Urology, Claude Huriez University Hospital, Lille, France

* Corresponding author. Hospital Foch, Department of Urology, 40, rue Worth, 92150 Suresnes,France. Tel. +33 1 46 25 21 75.E-mail address: y.neuzillet@hopital-foch.org (Y. Neuzillet).

0302-2838/$ – see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2011.02.035

E U R O P E A N U R O L O G Y 6 0 ( 2 0 1 1 ) 3 6 6 – 3 7 3 367

s Department of Urology, Dupuytren University Hospital, Limoges, Francet Department of Urology, La Pitie University Hospital, Paris, Franceu Department of Urology, Saint Jacques University Hospital, Besancon, Francev Department of Urology, Charles Nicolle University Hospital, Rouen, Francew Department of Urology, Robert Debre University Hospital, Reims, Francex Department of Urology, La Miletrie University Hospital, Poitiers, Francey Department of Urology, Necker University Hospital, Paris, Francez Department of Urology, Rangueil University Hospital, Toulouse, FranceA Department of Urology, Gabriel Montpied University Hospital, Clermont-Ferrand, FranceB Department of Urology, La Cavale Blanche University Hospital, Brest, FranceC Department of Urology, Bicetre Hodpital, Paris XI University, France

Article info

Article history:Accepted February 20, 2011Published online ahead ofprint on March 2, 2011

Keywords:

End-stage renal disease

Pathology

Prognosis

Renal cell carcinoma

Transplantation

Abstract

Background: Patients with end-stage renal disease (ESRD) are at risk of developing

renal tumours.

Objective: Compare clinical, pathologic, and outcome features of renal cell carci-

nomas (RCCs) in ESRD patients and in patients from the general population.

Design, setting, and participants: Twenty-four French university departments of

urology participated in this retrospective study.

Intervention: All patients were treated according to current European Association

of Urology guidelines.

Measurements: Age, sex, symptoms, tumour staging and grading, histologic sub-

type, and outcome were recorded in a unique database. Categoric and continuous

variables were compared by using chi-square and student statistical analyses.

Cancer-specific survival (CSS) was assessed by Kaplan-Meier and Cox methods.

Results and limitations: The study included 1250 RCC patients: 303 with ESRD and

947 from the general population. In the ESRD patients, age at diagnosis was younger

(55 � 12 yr vs 62 � 12 yr); mean tumour size was smaller (3.7 � 2.6 cm vs

7.3 � 3.8 cm); asymptomatic (87% vs 44%), low-grade (68% vs 42%), and papillary

tumours were more frequent (37% vs 7%); and poor performance status (PS; 24% vs

37%) and advanced T categories (�3) were more rare (10% vs 42%). Consistently, nodal

invasion (3% vs 12%) and distant metastases (2% vs 15%) occurred less frequently in

ESRD patients. After a median follow-up of 33 mo (range: 1–299 mo), 13 ESRD patients

(4.3%), and 261 general population patients (27.6%) had died from cancer. In univariate

analysis, histologic subtype, symptoms at diagnosis, poor PS, advanced TNM stage,

high Fuhrman grade, large tumour size, and non-ESRD diagnosis context were adverse

predictors for survival. However, only PS, TNM stage, and Fuhrman grade remained

independent CSS predictors in multivariate analysis. The limitation of this study is

related to the retrospective design.

Conclusions: RCC arising in native kidneys of ESRD patients seems to exhibit many

favourable clinical, pathologic, and outcome features compared with those diag-

nosed in patients from the general population.sociation of Urology. Published by Elsevier B.V. All rights reserved.

# 2011 European As

1. Introduction

Renal cell carcinoma (RCC) is the third most common

urologic cancer. In specific populations, the risk of developing

RCC is increased due to genetic predispositions such as von

Hippel-Lindau (VHL) or Bourneville’s tuberous sclerosis

diseases [1]. Acquired cystic kidney disease (ACKD), which

is commonly associated with end-stage renal disease (ESRD),

also has been reported as a condition predisposing patients to

an increased risk of RCC [2]. However, data from the literature

are limited to a few small and noncomparative RCC series in

dialysed patients [3–8] and in renal transplant patients

[9–16]. These studies have individually suggested specific

clinical, pathologic, or outcome features for ESRD native renal

tumours. Moudouni et al, for example, have demonstrated in

10 transplant recipients that incidental diagnosis and

papillary RCC subtype accounted for two-thirds and 50% of

native kidney RCC cases, respectively [14]. Similarly,

Schwartz et al in a series with 25 transplant patients

suggested that low-stage, incidentally diagnosed, and papil-

lary RCCs were predominant in this population and that

ACKD played a predisposing role [10].

E U R O P E A N U R O L O G Y 6 0 ( 2 0 1 1 ) 3 6 6 – 3 7 3368

It seemed justified to conduct a multicentre, compre-

hensive analysis of RCC cases occurring in ESRD and/or

kidney transplant patient populations and to compare

patients’ epidemiologic, pathologic, and outcome features

with those of patients in the general population with

sporadic RCC tumours.

2. Materials and methods

2.1. Data collection and patient management

This retrospective study included data from 24 academic centres in France.

After approval by institutional review boards at all centres, patients with

RCCs arising in the context of ESRD (defined as chronic renal failure treated

by dialysis or transplantation) and/or who underwent a renal transplan-

tation were identified at each centre. The following variables were

recorded: age, sex, symptoms at diagnosis, Eastern Cooperative Oncology

Group performance status (ECOG PS), duration of exposure to ESRD,

presence of ACKD (defined by more than five cysts on each native kidney

assessed by computed tomography [CT] or ultrasound imaging [2]), mode

and duration of dialysis, renal transplantation, tumour staging and

grading, histologic subtype, renal transplant, cancer-specific survival

(CSS), and overall survival. For ESRD patients, surgical treatment of

localised RCC was radical nephrectomy. For the general population, radical

nephrectomy or nephron-sparing surgery was performed according to

tumour characteristics, centre preferences, and current European

Association of Urology guidelines when appropriate. In ESRD patients,

monitoring of native kidneys included one annual CT or ultrasound

imaging analysis. In case of RCCs arising in transplant recipients, it was the

general policy of most centres in recent years to switch to a regimen based

on mammalian target of rapamycin.

Exclusion criteria were RCCs diagnosed before ESRD, histologically

proven transitional cell carcinoma of the upper urinary tract for 2

patients, and missing data for 13 patients. This cohort was compared

with a no-ESRD control group operated in France during the same period

(1985–2009) and identified from a multicentre surgical database.

2.2. Tumour classification

Tumour stage was determined according to the 2002 TNM classification

[17]. Histologic subtype was recorded according to the 2004 World

Health Organisation classification [18]. Tumours were graded according

to the Fuhrman grading scheme by pathologists at each institution [19].

2.3. Statistical methods

Variables of interest in both groups were compared by using chi-square

(or Fisher) and t tests for categoric and continuous variables,

respectively. The Kaplan-Meier method and the Cox proportional

hazards model were used for uni- and multivariate analysis, with

RCC-specific survival as an end point. In univariate analysis, a p value of

0.05 was used to select explanatory variables for multivariate analysis.

Results were given as hazard ratios and 95% confidence intervals. A

p value <0.05 was considered significant. All tests were carried out with

SPSS v.16 (IBM Corp., Somers, NY, USA).

3. Results

3.1. Characteristics of the renal cell carcinoma study

population

The study included 1250 patients with renal tumours. The

ESRD cohort was composed of 303 cases that were

identified in 206 men (76.3%) and 64 women (23.7%).

Transplant and nontransplant patients accounted for 213

cases (70.3%) and 90 cases (29.7%), respectively. ACKD

was found in 83 ESRD patients (30.7%). Mean age at

ESRD diagnosis was 44 � 16 yr. Mean delay between ESRD

diagnosis and beginning of replacement therapy was 46 � 39

mo. Forty-one patients (15.2%) were treated with haemodia-

lysis, and 229 patients (84.8%) were treated with peritoneal

dialysis. Renal transplantation was performed after 71 � 64

mo of haemodialysis. Mean delay between start of haemo-

dialysis and RCC diagnosis in nontransplant ESRD patients was

65 � 60 mo. Total duration of exposure to ESRD before RCC

diagnosis was 104� 96 mo. Tumours were discovered

incidentally in 264 cases (87%), including 5 cases by pathologic

examination.

The control group was composed of 947 RCC cases in 586

men (61.9%) and 361 women (38.1%). Median follow-up for

the entire population and for ESRD and non-ESRD groups

were 33 mo (range: 1–299), 36 mo (range: 1–277), and 38

mo (range: 1–299) ( p > 0.05), respectively. At the end of

follow-up, 274 patients (21.9%) had died from cancer.

3.2. Comparison of renal cell carcinoma groups with and

without end-stage renal disease

In the ESRD group, RCC occurred in younger patients

(55 � 12 yr vs 62 � 12 yr; p < 0.0001) and more often in male

patients (3.2 men vs 1.6 women; p < 0.0001). Tumours were

more frequently discovered incidentally in the ESRD group

(87% vs 44%; p < 0.0001), and local symptoms (12% vs 31%;

p < 0.0001) or systemic symptoms (0% vs 24%; p < 0.0001)

were more rare in the ESRD group. Good ECOG PS was more

frequent in the ESRD group (76% vs 63%; p < 0.0001).

Mean RCC tumour size was smaller in the ESRD group

(3.7 � 2.6 cm vs 7.3� 3.8 cm; p < 0.0001), and rate of ad-

vanced T category (�3) was decreased in the ESRD group (10%

vs 42%; p < 0.0001). Moreover, nodal invasion (3% vs 12%;

p < 0.0001) and metastatic disease (2% vs 15%; p < 0.0001)

were rare in ESRD patients. Clear cell histology was less

frequent (59% vs 88%; p < 0.0001) and papillary RCC rate was

higher (37% vs 7%; p < 0.0001) in the ESRD group than in the

general RCC population. Finally, low Fuhrman grade tumours

were frequently associated with ESRD ( p < 0.0001). Main

comparison data are summarised in Table 1.

3.3. Predictive factors for survival in uni- and multivariate

analyses

Cancer-specific mortality rate was decreased (4.3% vs

27.6%; p < 0.0001) in ESRD patients. RCC-specific survival

time was longer in ESRD patients than in non-ESRD patients

(log-rank test, p < 0.0001; Fig. 1). Five-year survival rates

were 90.1% and 69.0% in ESRD and non-ESRD patients,

respectively ( p < 0.0001). This survival advantage for ESRD

patients remained even after stratifying for histologic

subtype (Fig. 2a and 2b).

In univariate analysis, histologic subtype ( p = 0.006),

symptoms at diagnosis, poor performance status (PS),

advanced TNM stage, high Fuhrman grade, large tumour

Table 1 – Comparison of clinical, pathologic, and outcome features of end-stage renal disease (ESRD) and non-ESRD renal cell carcinomapatients

Variables ESRD RCC patientsn = 303

Non-ESRD RCC patients,n = 947

p value

Age at diagnosis, yr, mean � SD 55 � 12 62 � 12 <0.0001

Male gender, no. (%) 231 (76.5) 586 (61.9) <0.0001

Incidental diagnosis, no. (%) 264 (87) 417 (44) <0.0001

Local symptoms at diagnosis, no. (%) 39 (13) 303 (32) <0.0001

Systemic symptoms at diagnosis, no. (%) 0 227 (24) <0.0001

Good ECOG PS (= 0), no. (%) 230 (76) 597 (63) <0.0001

Tumour size, cm, mean � SD 3.7 � 2.6 7.3 � 3.8 <0.0001

Papillary histology, no. (%) 112 (37) 66 (7) <0.0001

Clear cell histology, no. (%) 179 (59) 843 (89) <0.0001

Fuhrman grade �2, no. (%) 206 (68) 398 (42) <0.0001

T category �2, no. (%) 273 (90) 549 (58) <0.0001

N category �1, no. (%) 9 (3) 114 (12) <0.0001

M category = 1, no. (%) 6 (2) 142 (15) <0.0001

Death from cancer, no. (%) 13 (4.3) 261 (27.6) <0.0001

ECOG PS = Eastern Cooperative Oncology Group performance status; RCC = renal cell carcinoma; SD = standard deviation.

[()TD$FIG]

Fig. 1 – Comparison of renal cell carcinoma (RCC)–specific survival time for end-stage renal disease (ESRD) and non-ESRD patients.

E U R O P E A N U R O L O G Y 6 0 ( 2 0 1 1 ) 3 6 6 – 3 7 3 369

size, and non-ESRD diagnosis context were all adverse

predictors for survival ( p < 0.0001) (Table 2). However,

only symptoms at diagnosis, PS, TNM stage, and Fuhrman

grade remained independent CSS predictors in multivariate

analysis (Table 3).

4. Discussion

It is now well established from epidemiologic data that ESRD

is a predisposing environment for native kidney RCC

development. Our study confirms that RCC arising in native

kidneys of ESRD patients exhibits many favourable features.

In the present series, asymptomatic, small, low-stage, and

low-grade tumours were more frequent in ESRD patients

than in the general RCC population. Moudouni et al. [14],

Ianhez et al. [13], and Neuzillet et al. [12] reported a grade

distribution similar to that observed in the general popula-

tion, whereas in other series, low-grade tumours were

predominant [10,11]. Our study, which represents the largest

series of RCC in ESRD patients, confirms the predominance of

low-grade tumours in ESRD-associated tumours.

Similarly, we noticed a very small proportion of tumours

with nodal (3%) or metastatic (2%) disease. Consistently, in

previously published studies, the incidence of distant

metastases in transplant and dialysed patients was 0–10%

[11,13] and 0–12.5% [6,7], respectively. This may be due

[()TD$FIG]

Fig. 2 – Comparison of renal cell carcinoma (RCC)–specific survival time stratified by histologic subtype (a) for clear cell RCCs arising in end-stage renaldisease (ESRD) and non-ESRD patients and (b) for papillary RCCs arising in ESRD and non-ESRD patients.

E U R O P E A N U R O L O G Y 6 0 ( 2 0 1 1 ) 3 6 6 – 3 7 3370

either to the constitutional low aggressiveness of ESRD

tumours, related in part to their favourable histologic

phenotype, or to early diagnosis of renal tumours in the

ESRD setting. In our series, the incidental RCC diagnosis rate

was in 87% compared with 44% in the general population.

Such a high rate (75–100%) of incidental diagnosis had

already been reported [3,12]. We also reported more

pronounced incidence for the male gender among ESRD

patients than in the general RCC population. We hypothesise

that this finding may be related to the epidemiology of ESRD

[20]. Even though patients suffered from chronic kidney

failure, PS was clearly more favourable in the ESRD RCC

population.

The more specific difference between ESRD and

sporadic RCCs is histologic profile. Clear cell carcinomas

were less frequent (59% vs 89%) and, in parallel, papillary

carcinomas were more frequent (37%) than in the general

population (7%). In previous ESRD RCC series, the

Table 2 – Prognostic factors in 1250 renal cell carcinoma patientsincluding 303 end-stage renal disease cases in univariate analysis

Variables p value HR (95% CI)

Histologic subtype

(clear cell vs non–clear

cell RCC)

0.006 2.08 (1.37–3.14)

Tumour size >6 cm <0.0001 4.14 (3.13–5.47)

Symptoms at diagnosis <0.0001 8.25 (5.83–11.68)

ECOG PS �1 <0.0001 3.94 (3.15–4.92)

T category �3 <0.0001 7.15 (5.42–9.44)

N category �1 <0.0001 3.22 (2.66–3.91)

M category = 1 <0.0001 8.22 (6.36–10.62)

Fuhrman grade �3 <0.0001 4.65 (3.44–6.28)

Non-ESRD RCC <0.0001 4.74 (2.71–8.29)

CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group

performance status; ESRD = end-stage renal disease; HR = hazard ratio;

RCC = renal cell carcinoma.

Table 3 – Prognostic factors in 1250 renal cell carcinoma patientsincluding 303 end-stage renal disease cases in multivariateanalysis

Variables p value HR (95% CI)

T category �3 <0.0001 2.4 (1.8–3.3)

N category �1 0.004 1.4 (1.7–2.3)

M category = 1 <0.0001 3.0 (2.3–4.0)

ECOG PS �1 <0.0001 1.8 (1.4–2.4)

Presence of symptoms

at diagnosis

<0.0001 2.7 (1.8–4.0)

Fuhrman grade �3 <0.0001 1.8 (1.3–2.5)

ESRD tumours 0.58 NA

CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group

performance status; ESRD = end-stage renal disease; HR = hazard ratio.

E U R O P E A N U R O L O G Y 6 0 ( 2 0 1 1 ) 3 6 6 – 3 7 3 371

frequency of papillary RCC ranged from 23% to 50%

[12,14]. This finding is not likely to be explained by the

mode of diagnosis of ESRD RCC tumours. It suggests,

together with the presence of AKCD, that molecular

pathways distinct from the VHL/hypoxia-inducible factor/

vascular endothelial growth factor pathways are involved

in such tumours.

We demonstrated that the presence of ESRD, besides

usual prognostic factors such as TNM stage, tumour size,

Fuhrman grade, PS, and histologic subtype, was a favour-

able prognostic factor in univariate analysis. However, it

disappeared together with histologic subtype in multivari-

ate analysis. This finding means that the general favourable

outcome of ESRD RCC tumours is explained at least in part

by the mode of diagnosis of such tumours. This is consistent

again with published data reporting that incidental

diagnosis was more frequent in the ESRD setting

[3,12,21]. Notably, several studies have shown that

patients with ESRD, especially those with kidney trans-

plant, were more likely to have an abdominal imaging

examination [22,23]. The transplant–nontransplant ratio

that we observed in our series certainly favours this latter

hypothesis.

ESRD RCC is a unique model for identifying molecular

pathways leading to renal carcinogenesis; however, the

extent to which basic science information that can be

derived from this model is useful for understanding

conventional clear cell or papillary RCC is not clear. Up to

now, ACKD has been the main hypothesis for explaining the

epidemiology of RCC in ESRD patients. ACKD incidence

increases with dialysis time reaching 90% after 5–10 yr [2].

In this study, patients were transplanted after 71 � 64 mo of

haemodialysis, and mean duration of haemodialysis in

nontransplant patients was 65 � 60 mo. The incidence of

ACKD observed in this study was in accordance with these

durations. Cheuk et al suggested that in atypical epithelial

proliferations associated with ACKD, some chromosomal

aberrations, including chromosome 7 gains, may represent

early neoplastic lesions [24]. Hori et al have shown that

oxidative stress was more intense in ESRD RCCs than in

sporadic cases [25]. However, the intimate molecular

mechanisms leading to ACKD in the context of ESRD are

largely hypothetical and further malignant transformation is

even less understood. Moreover, the papillary–clear cell

histology ratio in the ESRD setting has not been explained

sufficiently to date. Recently, Pan et al performed immuno-

histochemical and molecular genetic analyses in 11 tumours,

including nine ACKD-associated RCCs, from three patients

with ACKD [26]. Based on immunohistochemical and molec-

ular analysis, tumours did not correspond to any usual form of

renal cortical epithelial neoplasm. Among 14 ESRD RCC cases,

Inoue et al found VHL gene mutation in three of eight clear cell

carcinomas and in no ACKD-associated RCCs [27]. A particular

clinical setting, a specific histologic profile, and certain

immunophenotypic and genetic characteristics support the

concept of ACKD-associated RCC as a unique neoplasm [26].

Ikeda et al showed that cell proliferation was less active in the

ACKD-associated RCC than in sporadic cases [28]. Finally, some

specific molecular pathways have been mentioned, including

hepatocyte growth factor, activated B-cell lymphoma 2, and c-

met for explaining renal cyst formation and subsequent tumour

transformation [29]. In summary, there are arguments for

supporting specific oncogenesis mechanisms in ESRD RCC

tumours; however, these arguments are inconclusive and need

further examination.

We acknowledge some limitations of our study that are

inherent in any retrospective study. For example, the

exhaustive identification of RCC cases in our ESRD popula-

tion may be questioned. Some RCC cases possibly could

have been managed in departments of urology distinct from

the transplantation centre. For logistical reasons, no central

pathology review has been performed. Consequently, new

entities that have been recently identified in ESRD have not

been taken into account [4,30]. Moreover, we were not able

to provide information about transformation of ACKD cysts

into RCCs and whether or not RCC was observed outside

cystic lesions. Finally, no molecular analysis has been

conducted from our specimens to date.

5. Conclusions

This study is the first comparing a large series of RCCs in

ESRD patients with those arising in the general population

and shows that these cancers are more often asymptomatic,

E U R O P E A N U R O L O G Y 6 0 ( 2 0 1 1 ) 3 6 6 – 3 7 3372

of lower stage and grade, and thus have a better prognosis.

The extent to which a relatively indolent outcome is due

only to the mode of diagnosis and not to specific ESRD-

related molecular pathways is still to be determined. The

more important frequency of papillary tumours in this

model also deserves further basic science investigation.

Author contributions: Yann Neuzillet 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: Neuzillet, Patard, Badet.

Acquisition of data: Neuzillet, Tillou, Mathieu, Long, Gigante, Paparel,

Poissonnier, Bigot, Bastien, Brichart, Branchereau, Elkentaoui, Theveniaud,

Descazeaux, Fehri, Terrier, Martin, Galliot, Azemar, Tisserand, Timsit,

Sallusto, Guy, Deruelle.

Analysis and interpretation of data: Neuzillet.

Drafting of the manuscript: Neuzillet.

Critical revision of the manuscript for important intellectual content: Patard.

Statistical analysis: Neuzillet, Patard.

Obtaining funding: None.

Administrative, technical, or material support: Baumert, Escudier, Lang,

Rioux-Leclercq, Bernhard, Albiges, Petit, Saint, Bruyere, Boutin, Karam,

Ferriere, Wallerand, Barbet, Hubert, Feuillu, Villers, Zini, Descazeaux,

Roupret, Barrou, Lebret, Tostain, Terrier, Dugardin, Staerman, Irani,

Timsit, Sallusto, Rischmann, Guy, Valeri, Azzouzi, Chautard, Mejean,

Salomon, Rigaud, Pfister, Soulie, Kleinclauss, Badet, Patard.

Supervision: Baumert, Escudier, Lang, Rioux-Leclercq, Bernhard, Albiges,

Petit, Saint, Bruyere, Boutin, Karam, Ferriere, Wallerand, Barbet, Hubert,

Feuillu, Villers, Zini, Descazeaux, Roupret, Barrou, Lebret, Tostain, Terrier,

Dugardin, Staerman, Irani, Timsit, Sallusto, Rischmann, Guy, Valeri,

Azzouzi, Chautard, Mejean, Salomon, Rigaud, Pfister, Soulie, Kleinclauss,

Badet, Patard.

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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