C Bendifallah

P Huchon

A Collinet

C Bricou

L Mimoun

O Lecointre

E Graesslin

Raimond
email: eraimond@chu-reims.fr

E Sangnier

L Ouldamer

S Bendifallah

C Huchon

P Collinet

A Bricou

C Mimoun

L Lecointre

O Graesslin

MD Emilie Raimond

Risk factors for recurrence of borderline ovarian tumors in France: A multicenter retrospective study by the FRANCOGYN group

Keywords: Borderline, ovarian tumor, recurrence, risk factors Borderline Ovarian Tumor

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Borderline ovarian tumors (BOTs) account for 10%-20% of epithelial tumors of the ovary [START_REF] Hart | Borderline epithelial tumors of the ovary[END_REF][START_REF] Fischerova | Diagnosis, Treatment, and Follow-Up of Borderline Ovarian Tumors[END_REF][START_REF] Tropé | Borderline ovarian tumours[END_REF]. They are rare tumors, but their incidence is increasing, estimated at 1.8 to 4.8 per 100,000 women per year worldwide [START_REF] Ray-Coquard | Rare ovarian tumours: therapeutic strategies in 2010, national website observatory for rare ovarian cancers and delineation of referent centers in France[END_REF][START_REF] Harlow | Epidemiology of borderline ovarian tumors[END_REF].

BOT is defined as a tumor with a borderline quota of strictly more than 10% [START_REF] Hart | Borderline epithelial tumors of the ovary[END_REF]. They differ clinically from ovarian cancers by showing good prognosis and the patients are 10 years younger at the time of diagnosis, with a higher proportion of patients in the reproductive age group [START_REF] Fischerova | Diagnosis, Treatment, and Follow-Up of Borderline Ovarian Tumors[END_REF][START_REF] Vasconcelos | Serous and mucinous borderline ovarian tumours: differences in clinical presentation, high-risk histopathological features, and lethal recurrence rates[END_REF]. Although the survival rate is estimated to be 100% and 92% at 5 and 10 years, respectively, the recurrence rate is estimated to be between 5% and 34% depending on the studies [START_REF] Vasconcelos | Serous and mucinous borderline ovarian tumours: differences in clinical presentation, high-risk histopathological features, and lethal recurrence rates[END_REF][START_REF] Uzan | Influence of histological subtypes on the risk of an invasive recurrence in a large series of stage I borderline ovarian tumor including 191 conservative treatments[END_REF][START_REF] Bendifallah | Nomogram to predict recurrence in patients with early-and advanced-stage mucinous and serous borderline ovarian tumors[END_REF]. Most often, the recurrence is in the form of BOT but there are recurrence in the invasive cancer form [START_REF] Vasconcelos | Serous and mucinous borderline ovarian tumours: differences in clinical presentation, high-risk histopathological features, and lethal recurrence rates[END_REF][START_REF] Uzan | Influence of histological subtypes on the risk of an invasive recurrence in a large series of stage I borderline ovarian tumor including 191 conservative treatments[END_REF][START_REF] Bendifallah | Nomogram to predict recurrence in patients with early-and advanced-stage mucinous and serous borderline ovarian tumors[END_REF].

Conservative surgery is recommended in young women who wish to preserve their fertility, regardless of the stage of the tumor [START_REF] Bendifallah | Nomogram to predict recurrence in patients with early-and advanced-stage mucinous and serous borderline ovarian tumors[END_REF][START_REF] Fauvet | Fertility after conservative treatment for borderline ovarian tumors: A French multicenter study[END_REF][START_REF] Margueritte | Tumeurs frontières de l'ovaire. Recommandations pour la pratique clinique du CNGOF -Épidémiologie et facteurs de risques de récidive, modalités de surveillance et intérêt d'une chirurgie de clôture[END_REF][START_REF] Canlorbe | Borderline Ovarian Tumours: CNGOF Guidelines for Clinical Practice -Therapeutic Management of Early Stages[END_REF][START_REF] Raimond | Borderline Ovarian Tumours: CNGOF Guidelines for Clinical Practice -Surgical Management of Advanced Stages of Borderline Ovarian Tumours[END_REF]. The challenge in the surgical management of BOT is to facilitate conservative treatment while allowing complete staging in order to limit the risk of recurrence in the invasive form [START_REF] Margueritte | Tumeurs frontières de l'ovaire. Recommandations pour la pratique clinique du CNGOF -Épidémiologie et facteurs de risques de récidive, modalités de surveillance et intérêt d'une chirurgie de clôture[END_REF]. A number of studies have attempted to identify the risk factors for recurrence of BOTs; however, these were mainly small studies with short followup periods and not consensual histopathological definition of borderline ovarian tumors, which have led to classification bias and inconsistent results depending on the study.

The objective of our study was to identify risk factors for recurrence of BOTs.

MATERIALS AND METHODS

Population

This retrospective multicenter study was conducted from January 2001 to December 2018 by obtaining data from 7 French cancer centers belonging to the FRANCOGYN research group.

Patient epidemiological data, medical and surgical history, tumor markers, surgical procedures performed, histological characteristics of tumors, and International Federation of Gynaecology and Obstetrics (FIGO) stages were collected from each center and anonymized.

French-speaking women aged ≥15 years (parental consent was obtained for minors) affiliated with the social security system who had undergone surgery for treatment of serous or mucinous BOT between January 2001 and December 2018 were included in the study.

Patients with borderline quotas of <10% after centralized re-reading of the slides, missing data concerning recurrence status, and rare histological types (clear cell tumors, Brenner's tumors, and endometrioid tumors) were excluded from the study.

In accordance with the French law, this retrospective study of medical records was authorized by MR-004. Participants were informed that their information might be used for biomedical research purposes and that they had the right to object.

Definitions and procedures

Patients were divided into 2 groups according to whether they had a recurrence (group R, 7.5%) or not (group NR, 92.5%). Recurrence was suspected based on clinical, biological, or radiological data and after histological confirmation. The recurrence could be of BOT type or infiltrating cancer type.

The tumor stage was defined according to the FIGO 2014 classification of ovarian tumors [START_REF] Prat | Staging classification for cancer of the ovary, fallopian tube, and peritoneum[END_REF]. Peritoneal implants were classified as invasive and non-invasive [START_REF] Mccluggage | Ovarian borderline tumours: a review with comparison of serous and mucinous types[END_REF]. Microinvasive tumors were defined as those with <5 mm invasion of the stroma (6).

Conservative treatment was defined as a surgical procedure preserving the uterus and at least part of an ovary to allow subsequent fertility [START_REF] Uzan | Prognostic factors for recurrence after conservative treatment in a series of 119 patients with stage I serous borderline tumors of the ovary[END_REF]. The recommended peritoneal staging included peritoneal cytology, extensive omentum biopsy or omentectomy, multiple peritoneal biopsies, and appendectomy in the case of mucinous type tumor [START_REF] Margueritte | Tumeurs frontières de l'ovaire. Recommandations pour la pratique clinique du CNGOF -Épidémiologie et facteurs de risques de récidive, modalités de surveillance et intérêt d'une chirurgie de clôture[END_REF][START_REF] Canlorbe | Borderline Ovarian Tumours: CNGOF Guidelines for Clinical Practice -Therapeutic Management of Early Stages[END_REF][START_REF] Raimond | Borderline Ovarian Tumours: CNGOF Guidelines for Clinical Practice -Surgical Management of Advanced Stages of Borderline Ovarian Tumours[END_REF]. This was performed during the initial surgery (Surgery 1) when the diagnosis of BOT was confirmed by extemporaneous examination. Otherwise, or in case of incomplete staging, it was performed during a second surgery (Surgery 2).

The recurrence period in months was defined as the time elapsed between the date of the first surgery and the date of discovery of the recurrence.

Statistical analyses

A univariate analysis was used to assess :

-patient characteristics : age, hormonal status, smoking, use of hormone replacement therapy (HRT), past medical history.

-tumor characteristics : bilateral involvement, micropapillary contingent, FIGO stage, peritoneal implants, peritoneal cytology.

-the surgical procedure performed : surgery approach, conservative or non-conservative treatment.

Categorical variables were compared using the chi-squared test or the Fisher exact test when the validity conditions for chi-squared test were not met. To compare a continuous variable with a categorical variable, we used the Student's t-test or the Wilcoxon's test when the variable did not follow a normal distribution.

Multivariate analysis was performed using a logistic regression model including factors that were significant in the univariate analysis.

For the survival data, the curves were produced by the Kaplan-Meier method. The survival analysis was performed with a Cox model. Odds ratio was calculated with a 95% confidence interval. The test results were considered significant when the p-value was <0.05.

The data were managed in an Excel database (Microsoft, Redmond, WA). The statistical analyses were performed using the software R 2.15.3 package and library Verification, HMISC, survival, RMS, and stats available online (http://lib.stat.cmu.edu/R/CRAN/).

RESULTS

From January 2001 to December 2018, 564 patients were treated for BOT. After centralized re-reading of the slides, 71 patients were excluded from the analysis, of whom 43 had missing recurrence status data, 22 had rare histological types, 2 had BOTs with a borderline quota <10%, and 4 had invasive carcinomas. A total of 493 patients were included from 7 French cancer centers: Lariboisière hospital in Paris (n=59), the intermunicipal hospital center in Poissy (n=36), Jean Verdier hospital in Bondy (n=27), and the University Hospital Centers in Tours (n=142), Lille (n=104), Strasbourg (n=93), and Reims (n=32). Of these patients, 37 showed recurrence (group R, 7.5%) and 456 did not (group NR, 92.5%).

The mean age at diagnosis was 48.8 years (15-92 years). In 33.3% of cases, patients were less than 40 years old (n=164) and 29.6% were nulliparous (n=146). A laparoscopy was performed first in 59.2% of cases (n=292). In 28% of cases, the final treatment was conservative (n=138) and complete final staging was performed as recommended in 74% of cases (n=365).

The mean tumor size was 11.7 cm (1-35 cm), and the intraoperative tumor rupture rate was 13.8% (n=68). Histologically, 51.9% of cases showed serous tumors, while the remaining 48.1% of cases were mucinous. Peritoneal implants were found in 13.4% of patients (n=66) and in 2% were invasive (n=10). As for the FIGO stage, a majority of patients had FIGO I (83.4%, n=411).

The clinical characteristics of the patients included in the study have been summarized in Table 1.

The average follow-up of patients was 30.5 months (1-276 months). The overall recurrence rate was 7.5% (n=37). Recurrence was BOT and invasive types in 5.7% (n=28) and 1.4% (n=7) of cases, respectively. The mean overall recidivism time was 44. Conservative treatment was performed in 67.6% compared to 24.8% in the R group (OR=6.29 [95% CI 2.9-14.2]; p<0.05). The implant rate was higher in the R group (43.2%) than that in the NR group (OR=6.15 [95% CI 2.8-13.3]; p<0.05). Lastly, there were 40.5% of advanced FIGO stage in the R group compare to 10% in the NR group (OR=6.19 [95% CI 2.78-13.5]; p<0.05) (Table 2).

In multivariate analysis, the type of surgical treatment, particularly conservative treatment (OR=7 [95% CI 3.01-16.23]; p<0.05), and the advanced FIGO stage of the tumor (OR=5.86 [95% CI 2.21-15.5]; p<0.05) appeared to significantly influence the risk of recurrence (Table 3). Similarly, the survival curves showed a reduction in the recurrence-free survival with conservative treatment and with advanced FIGO stage (II/III) (p<0.05) (Figures 1 and2).

DISCUSSION

This study identified two risk factors for BOT's recurrence: conservative treatment BOTs mainly affect young patients of childbearing age, hence it is challenging to provide conservative treatment to patients who so wish, without increasing the risk of recurrence, despite excellent prognosis [START_REF] Vasconcelos | Serous and mucinous borderline ovarian tumours: differences in clinical presentation, high-risk histopathological features, and lethal recurrence rates[END_REF][START_REF] Uzan | Influence of histological subtypes on the risk of an invasive recurrence in a large series of stage I borderline ovarian tumor including 191 conservative treatments[END_REF][START_REF] Bendifallah | Nomogram to predict recurrence in patients with early-and advanced-stage mucinous and serous borderline ovarian tumors[END_REF].

In this study, conservative treatment was observed as a risk factor for recurrence (OR=7 [95% CI 3.01-16.2]; p<0.05), which is in accordance with reports in the literature [START_REF] Bendifallah | Nomogram to predict recurrence in patients with early-and advanced-stage mucinous and serous borderline ovarian tumors[END_REF][START_REF] Fauvet | Fertility after conservative treatment for borderline ovarian tumors: A French multicenter study[END_REF][START_REF] Uzan | Prognostic factors for recurrence after conservative treatment in a series of 119 patients with stage I serous borderline tumors of the ovary[END_REF][START_REF] Vasconcelos | Conservative surgery in ovarian borderline tumours: a metaanalysis with emphasis on recurrence risk[END_REF][START_REF] Fauvet | Laparoscopic management of borderline ovarian tumors: results of a French multicenter study[END_REF][START_REF] Helpman | Fertility preservation in women with borderline ovarian tumors -how does it impact disease outcome? A cohort study[END_REF].

Helpman et al. showed that conservative surgery was independently associated with recurrence (HR=2.57 [95% CI 1.1-6.0]; p=0.029) without impact on overall survival, while Vasconcelos et al. showed that among conservative treatments, unilateral cystectomy was associated with increased rate of recurrence than unilateral adnexectomy (p<0.0001) [START_REF] Vasconcelos | Conservative surgery in ovarian borderline tumours: a metaanalysis with emphasis on recurrence risk[END_REF][START_REF] Helpman | Fertility preservation in women with borderline ovarian tumors -how does it impact disease outcome? A cohort study[END_REF]. These results were confirmed by two studies that proposed a predictive model of recurrence risk in which cystectomy was associated with an increased risk of recurrence at 5 years (OR=11.35 [95% CI 4.01-32.1]; p<0.001) [START_REF] Bendifallah | Nomogram to predict recurrence in patients with early-and advanced-stage mucinous and serous borderline ovarian tumors[END_REF][START_REF] Ouldamer | Improving the clinical management of women with borderline tumours: a recurrence risk scoring system from a French multicentre study[END_REF]. Despite this, cystectomy is preferred in young women wishing to preserve their fertility, regardless of the FIGO stage of the tumor. Indeed, a study by Palomba et al precised that for ultra conservative fertility surgery, time to first recurrence was significantly shorter but without any difference in the recurrence free survival between bilateral cystectomy group and unilateral adnexectomy with contralateral cystectomy group (p=0,41). Moreover, this study showed a higher pregnancy rate (OR=8.05 [95% CI 1.20-9.66]; p<0.01) with a shorter delay (p<0.02) in bilateral cystectomy [START_REF] Palomba | Ultra-conservative fertilitysparing strategy for bilateral borderline ovarian tumours: an 11-year follow-up[END_REF]. In addition, increase in the recurrence rate after conservative surgery had no impact on the overall survival (p=0.91), which explains the preference for cystectomy in young women with a desire for pregnancy and adnexectomy in postmenopausal women [START_REF] Margueritte | Tumeurs frontières de l'ovaire. Recommandations pour la pratique clinique du CNGOF -Épidémiologie et facteurs de risques de récidive, modalités de surveillance et intérêt d'une chirurgie de clôture[END_REF][START_REF] Canlorbe | Borderline Ovarian Tumours: CNGOF Guidelines for Clinical Practice -Therapeutic Management of Early Stages[END_REF][START_REF] Raimond | Borderline Ovarian Tumours: CNGOF Guidelines for Clinical Practice -Surgical Management of Advanced Stages of Borderline Ovarian Tumours[END_REF][START_REF] Park | Surgical management of borderline ovarian tumors: The role of fertility-sparing surgery[END_REF]. Therefore, extraovarian extent of the disease appears to increase the risk of recurrence, even in the case of complete carcinologic surgery.

Patients with recurrence were significantly younger than those without (35.1 versus 51 years; OR=0.94 [95% CI 0.92-0.96]; p<0.05). However, multivariate analysis did not show a relationship between patient age and risk of recurrence. In the literature, age was found to be a prognostic factor for recurrence of BOTs [START_REF] Uzan | Prognostic factors for recurrence after conservative treatment in a series of 119 patients with stage I serous borderline tumors of the ovary[END_REF][START_REF] Ouldamer | Improving the clinical management of women with borderline tumours: a recurrence risk scoring system from a French multicentre study[END_REF][START_REF] Azuar | Laparoscopic restaging of borderline ovarian tumours (BLOT): a retrospective study of 142 cases[END_REF]. Indeed, owing to longer life expectancy, young patients are theoretically at greater risk of recurrence, as recurrence of BOTs may occur after a long period, sometimes more than 15 years after initial management [START_REF] Vasconcelos | Serous and mucinous borderline ovarian tumours: differences in clinical presentation, high-risk histopathological features, and lethal recurrence rates[END_REF]. This study had a shorter follow-up period (30.5 months) compared with that reported in the literature; this may explain why this factor was not found to be associated with recurrence in the multivariate analysis. In fact, 24.3% of our patients had a follow-up of 12 months or less (n=120), explained by the post-operative monitoring often carried out by the patient's usual gynecologist outside the expert center that carried out the study (Table 4).

In this study, 74% of the staging was performed as recommended (n=365) and no link with recurrence was found. Similarly, the study by Fauvet et al. found no link between recurrence and restaging surgery [START_REF] Fauvet | Restaging surgery for women with borderline ovarian tumors: Results of a French multicenter study[END_REF]. Conversely, several studies observed an increase in the recurrence rate proportional to the number of missing procedures, with omentectomy being the procedure with the greatest impact (HR=1.91 [95% CI 1.15-3.19]; p=0.013) [START_REF] Azuar | Laparoscopic restaging of borderline ovarian tumours (BLOT): a retrospective study of 142 cases[END_REF][START_REF] Trillsch | Surgical staging and prognosis in serous borderline ovarian tumours (BOT): a subanalysis of the AGO ROBOT study[END_REF][START_REF] Shim | Impact of surgical staging on prognosis in patients with borderline ovarian tumours: A meta-analysis[END_REF]. These studies also found a low rate of procedures, between 31.7% and 49.7%, in compliance with the recommendations, which was a bias in the analysis of recurrences with a risk of under-evaluating the FIGO stages and performing incomplete resection with tumor residue. The main interest of a complete staging would be to avoid missing the presence of implants in order not to under-diagnose patients. The high rate of complete staging reported in this study (74%) was a strength, and was probably an explanation of the low recurrence rate (7.5%) (Table 4).

CONCLUSION

To the best of our knowledge, this multicenter study is the largest French study on the risk factors for BOTs and one of the largest internationally. Conservative treatment and advanced FIGO stage of the tumor were found as risk factors.

These results confirms the need for restaging surgery for patients who have not had optimal initial surgical staging by to avoid to ignore an advanced tumor stage. Referring patients to an oncology center may allow us to optimize their management.

  1 months (3-251 months), the mean BOT recidivism time was 47.6 months (3-251 month), and the mean invasive relapse time was 26.6 months (8-54 months). The mean age of patients at the time of recurrence was 35.1 years (18-70 years). Patients with recurrence were significantly younger than those without (35.1 versus 51 years; OR=0.94 [95% CI 0.92-0.96]; p<0.05) (Table 2). Univariate analysis for comparison of patients in the R and NR groups found that conservative treatment was associated with risk of recurrence compared to radical treatment (OR=0.14 [95% CI 0.004-0.450]; p<0.05). Similarly, advanced FIGO stage and serous type of tumor were associated with risk of recurrence compared, respectively, to early FIGO stage (OR=6.88 [95% CI 3.6-14.5]; p<0.05) and to mucinous type of tumour (OR=2.03 [95% CI 1.0-4.1]; p=0.05).

(

  OR=7 [95% CI 3.01-16.3]; p<0.05) and advanced FIGO stage of the tumor (OR=5.86 [95% CI 2.21-15.5]; p<0.05).

  Advanced FIGO stage (II/III) was a risk factor for recurrence of BOT in this study (OR=5.86 [95% CI 2.21-15.5]; p<0.05). This result was consistent with that reported in the literature, particularly in the studies by Ewald-Riegler et al. (HR=37.1 [95% CI 4.5-155.5]), Delle Marchette et al. (HR=3.18 [95% CI 2.11-4.78]; p<0.001) and Vo et al. (HR=4.44 [95% CI 1.60-12.38]) in which advanced FIGO stage increased the risk of BOTs recurrence (23-25).

Table 1 : Clinical and paraclinical characteristics of the population

 1

	Characteristics

Data : average (minimum-maximum) et number (%), BMI : Body Masse Index, HRT : Hormone Replacement Therapy FIGO : International Federation of Gynaecology and Obstetrics, Surgery 1 : Initial procedure, Surgery 2 : Restaging procedure

Table 2 : Population characteristics about recurrence status in univariate analysis

 2

	Characteristics	Group R (n = 37)	Group NR (n = 456)	OR [CI 95%]	P value
	Population
	Mean age (years)	35.1 (18-70)	51 (15-92)		<0.05
	Age under 40 yo	28 (75.7%)	62 (13.6%)		0.06
	Mean BMI (kg/m2)	25.5 (18.4-45.2) 26.4 (15.6-66.6)		<0.05
	Nulliparity	22 (59.5%)	60 (13.2%)	9.6 [4.5-21.1]	<0.05
	Menopause	5 (13.5%)	79 (17.3%)		0.66
	Taking of SHT	0	5 (1.1%)		0.88
	Active smoking	4 (10.8%)	25 (5.5%)		0.71
	Medical past history
	Ovarian stimulation	2 (5.4%)	11 (2.4%)		0.93
	Endometriosis	1 (2.7%)	5 (1.1%)		1
	Family ovarian cancer	0	3 (0.7%)		0.82
	Surgical procedures
	Surgical approach (1)
	Laparotomy	12 (32.4%)	188 (41.2%)		0.3
	Laparoconversion	4 (10.8%)	56 (12.3%)		0.62
	Surgical treatment (2)
	Unilateral adnexectomy and controlateral cystectomy	5 (13.5%)	9 (2%)		0.08
	Unilateral adnexectomy	16 (43.2%)	126 (27.6%)		0.67
	Blateral adnexectomy	6 (16.2%)	270 (59.2%)		<0.05
	Bilateral cystectomy	3 (8.1%)	5 (1.1%)		0.11
	Conservative treatment
	Initial (surgery 1)	30 (81.1%)	172 (37.7%)	7.07 [2.95-19.4]	<0.05
	Final (chirurgie 1 et 2)	25 (67.6%)	113 (24.8%)	6.29 [2.9-14.2]	<0.05
	Recommended staging
	Initiale (chirurgie 1)	9 (24.3%)	220 (48.2%)	0.35 [0.14-0.77]	<0.05
	Final (surgery 1 and 2)	24 (64.9%)	341 (74.8%)		0.2
	Anatomopathology
	Histological type
	Serous tumor	25 (67.6%)	231 (50.7%)		0.06
	Mucinous tumor	12 (32.4%)	225 (49.3%)		0.06
	Bilateral	13 (35.1%)	61 (13.4%)	3.5 [1.5-7.6]	<0.05
	Positive peritoneal cytology	14 (37.8%)	55 (12.1%)	4.42 [1.98-9.59]	<0.05
	Micropapillary content	4 (10.8%)	38 (8.3%)		0.83
	Implants
	Total (3)	16 (43.2%)	50 (11%)	6.15 [2.8-13.3]	<0.05
	Non invasive	13 (35.1%)	43 (9.4%)		<0.05
	Invasive	3 (8.1%)	7 (1.5%)		<0.05
	Definitive FIGO stage
	All	-	-
	Early stage (I)	19 (51.4%)	392 (86%)	0.17 [0.08-0.37]	<0.05
	Advanced stage (≥ II)	15 (40.5%)	45 (10%)	6.19 [2.78-13.5]	<0.05

Data : average (minimum-maximum) et number (%) (1) Reference parameter : laparoscopy, (2) Reference parameter : Unilateral cystectomy , (3) Reference parameter : No implant BMI : Body Masse Index, HST : Hormonal Substitutive treatment FIGO : Fédération Internationale de Gynécologie Obstétrique Surgery 1 : Initiale, Surgery 2 : Restaging procedure

Table 3 : Recurrence risk factors in multivariate analysis

 3 Data : average (minimum-maximum) et number (%), FIGO : International Federation of Gynaecology and Obstetrics CI: Confidence Intervalle

	Characteristics	OR [CI 95%]	P value
	Age at diagnosis	0.98 [0.94-1.02]	0.29
	Type of treatment	0.20 [0.036-1.62]	<0.05
	Histological type	1.15 [0.45-2.93]	0.77
	FIGO stage	5.86 [2.21-15.5]	<0.05

Fauvet et al. (27) Fauvet et al. (18) Romagnolo et al. (30)) Fauvet et al. (10) Park et al. (22) Zapardiel et al. (31) Ewald-Riegler et al. (23) Azuar et al. (26)