Melanoma of unknown primary (MUP) account for 3% of all melanomas. Clinical outcomes of advanced MUP in the era of novel therapies including immunotherapies (ICI) and targeted therapies (TT) have been only scarcely studied, whereas a possibly different biologic background might introduce changes in its management. Recent retrospective studies suggested that patients with advanced MUP could benefit at least as much from novel therapies as patients with known primary cutaneous melanoma (cMKP).

OBJECTIVE

To investigate the efficacy and safety of systemic treatments (ICI, TT and chemotherapy (CT)) in patients with advanced MUP compared to patients with stage-matched cMKP.

Liste des figures

MATERIAL AND METHODS

Based on the nationwide MelBase prospective database (NCT02828202) this retrospective study included patients with advanced melanoma treated with first-line ICI, TT or CT. MUP was defined as the upfront occurrence of (sub)cutaneous, nodal and/or visceral metastasis without any known prior or concomitant primary tumor. Patients with primary mucosal or ocular melanoma were excluded. Both progression-free survival (PFS) and overall survival (OS) were analyzed as co-primary variables in MUP vs cMKP, stratified by treatment subset (ICI vs TT vs CT vs whole cohort). Secondary outcome was treatment-related toxicities.

Multivariate and propensity score analyses were performed.

RESULTS

A total of 1882 patients were analyzed, including 265 (14.1%) MUP. Most patients were treated with first-line ICI, followed by first-line TT. The median follow-up duration was 16 months.

MUP patients more often displayed unfavorable initial prognostic factors. PFS and OS did not differ significantly between the two groups (P= 0.73 and P= 0.93; respectively). Stratification by treatment type and application of propensity score did not lead to data modification. The treatment-related toxicity rate and severity did not differ between MUP and cMKP patients, regardless of treatment type, especially for immune-related adverse events in ICI cohort.

CONCLUSIONS AND RELEVANCE

Our results suggest that advanced MUP should be managed with similar strategies as advanced cMKP. In our cohort, MUP patients benefited from novel therapies as much as cMKP patients despite less favorable baseline prognostic factors. Exploratory studies investigating mutational burden and host immunity are needed to identify the underlying mechanisms.

Résumé

INTRODUCTION

Le mélanome de primitif inconnu (MPI) représente environ 3 % des mélanomes et est défini par une atteinte d'emblée métastatique sans lésion primitive antérieure ou synchrone identifiée.

Plusieurs hypothèses physiopathologiques ont été émises parmi lesquelles la transformation maligne de mélanocytes ectopiques localisés dans les tissus extra-cutanés ou encore la régression du mélanome primitif sous l'effet d'une réaction immunitaire impliquant des mécanismes humoraux et cellulaires.

A l'ère des nouveaux traitements systémiques par immunothérapie (ICI) et thérapie ciblée (TC) qui ont révolutionné la prise en charge des mélanomes avancés, les essais cliniques n'ont pas spécifiquement évalué les résultats cliniques de ces thérapies dans la population des MPI alors que ces considérations immunologiques pourraient impliquer une prise en charge thérapeutique plus spécifique. Plusieurs études rétrospectives ont suggéré que les patients atteints de MPI avancé répondraient aussi bien à ces nouveaux traitements, voire mieux à l'ICI, que les mélanomes avec primitif cutané connu (cMPC).

OBJECTIF

Aussi, avons-nous évalué l'efficacité et la tolérance des différents traitements systémiques (ICI, TC et chimiothérapie (CT)) chez les MPI comparativement aux cMPC.

MATÉRIEL ET MÉTHODES

Cette étude rétrospective a été menée à partir de la cohorte française prospective MelBase. Les patients atteints de mélanome avancé (stade III non résécable ou IV selon AJCC) traités en 1 ère ligne par ICI, TC et CT entre mars 2013 et juin 2021 étaient inclus.

Les MPI étaient définis par une atteinte d'emblée métastatique (sous-)cutanée, ganglionnaire ou viscérale documentée histologiquement, sans identification d'un primitif synchrone ou antérieur. Les patients qui présentaient un mélanome muqueux ou choroïdien étaient exclus.

Les co-critères de jugement principaux étaient l'association entre survie sans progression (SSP) et survie globale (SG) selon le statut MPI ou cMPC, stratifiés selon l'âge, le sexe et le traitement (tout type de traitement vs ICI vs TC vs CT). La tolérance était analysée comme critère de jugement secondaire. Des analyses multivariées et un score de propension ont été pratiqués.

RÉSULTATS

II-INTRODUCTION

Melanoma of unknown primary (MUP) accounts for 3% of all melanomas. MUP is defined as the upfront occurrence of (sub)cutaneous, nodal and/or visceral metastasis without any known prior or concomitant primary tumor. [START_REF] Vries | Changing epidemiology of malignant cutaneous melanoma in Europe 1953-1997: rising trends in incidence and mortality but recent stabilizations in western Europe and decreases in Scandinavia[END_REF][START_REF] Waal | Melanoma of unknown primary origin: a population-based study in the Netherlands[END_REF] This condition appears to be twice as frequent in males than in females with a peak age in the fourth and fifth decades of life. [START_REF] Chang | The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade[END_REF][START_REF] Bae | Metastatic melanomas of unknown primary show better prognosis than those of known primary: a systematic review and meta-analysis of observational studies[END_REF] The first diagnosis of MUP dates back to 1917 [START_REF] Pack | End results in the treatment of malignant melanoma; a report of 1190 cases[END_REF] , but its first formal description was established by Das Gupta et al. in 1963, who defined exclusion criteria including prior orbital exenteration or enucleation, previous skin intervention on a mole, freckle, birthmark, paronychia or skin blemish without pathological examination, nodal metastasis with a scar in the skin drainage area, and lack of a complete physical examination including ophthalmological and anogenital evaluations. [START_REF] Gupta | Malignant melanoma of unknown primary origin[END_REF] Several hypotheses have been proposed to explain the occurrence of a MUP, which could result from the malignant transformation of ectopic melanocytes in extracutaneous tissues or the complete regression of a primary melanoma after metastasis has occurred. [START_REF] Song | Melanoma of unknown primary[END_REF][START_REF] Kamposioras | Malignant melanoma of unknown primary site. To make the long story short. A systematic review of the literature[END_REF][START_REF] Ost | Primary pulmonary melanoma: case report and literature review[END_REF][START_REF] Mccarthy | Naevus cells in lymph nodes[END_REF][START_REF] Smith | Spontaneous regression of primary malignant melanomas with regional metastases[END_REF][START_REF] Panagopoulos | Metastatic malignant melanoma of unknown primary origin: a study of 30 cases[END_REF] This immune-mediated regression involves both cellular and humoral mechanisms, including an increased number of tumor-infiltrating lymphocytes. [START_REF] Gambichler | Patients with melanoma of unknown primary show better outcome under immune checkpoint inhibitor therapy than patients with known primary: preliminary results[END_REF][START_REF] Mcgovern | Spontaneous regression of melanoma[END_REF][START_REF] Giuliano | Clinical aspects of unknown primary melanoma[END_REF][START_REF] Scott | Melanoma of Unknown Primary[END_REF] Molecularly, MUP shares a mutational pattern similar to cutaneous ones, with comparable rates of BRAF and NRAS mutations, as well as a high mutational burden consistent with the ultraviolet signature, which suggests a cutaneous origin. Mutations in the TERT-promoter have also been hypothesized to function as driver mutations in MUP pathogenesis. Finally, KIT mutations are uncommon in MUP and may differentiate them from mucosal melanomas. [START_REF] Dutton-Regester | Melanomas of unknown primary have a mutation profile consistent with cutaneous sun-exposed melanoma[END_REF][START_REF] Gos | Molecular characterization and patient outcome of melanoma nodal metastases and an unknown primary site[END_REF][START_REF] Egberts | Metastatic melanoma of unknown primary resembles the genotype of cutaneous melanomas[END_REF] This biological background might confer better survival for patients with MUP compared to those with stage-matched melanoma of known primary (MKP), as suggested by a metaanalysis and several retrospective studies conducted before the era of novel therapies. [START_REF] Bae | Metastatic melanomas of unknown primary show better prognosis than those of known primary: a systematic review and meta-analysis of observational studies[END_REF][START_REF] Lee | Improved survival for stage IV melanoma from an unknown primary site[END_REF][START_REF] Cormier | Metastatic melanoma to lymph nodes in patients with unknown primary sites[END_REF][START_REF] Kuk | Prognosis of Mucosal, Uveal, Acral, Nonacral Cutaneous, and Unknown Primary Melanoma From the Time of First Metastasis[END_REF] However, contradictory findings have also been reported, suggesting an equal or worse prognosis for patients with MUP. [START_REF] Schlagenhauff | Metastatic melanoma of unknown primary origin shows prognostic similarities to regional metastatic melanoma: recommendations for initial staging examinations[END_REF][START_REF] Hughes | Patients undergoing lymphadenectomy for stage III melanomas of known or unknown primary site do not differ in outcome[END_REF][START_REF] Varey | Epidemiological study of unknown primary melanoma patients from the French national melanoma database RIC-Mel[END_REF] Over the past decade, the advent of targeted therapy (TT) and immune checkpoint inhibitors (ICIs) has considerably improved the survival of patients with advanced melanoma. The response rates of ICIs and TT significantly exceed those of conventional chemotherapy (CT), ranging from 40% to 60% -70% in case of combination therapies, with prolonged responses over time. [START_REF] Ugurel | Survival of patients with advanced metastatic melanoma: The impact of MAP kinase pathway inhibition and immune checkpoint inhibition -Update 2019[END_REF][START_REF] Ascierto | Melanoma[END_REF][START_REF] Robert | Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma[END_REF][START_REF] Larkin | Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma [published correction appears in[END_REF][START_REF] Wolchok | Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma[END_REF] Thus, the question arises whether these treatments are more effective in MUP since both ICIs and TT have the potential to enhance the robust anti-tumoral immune response of the host at baseline. [START_REF] Ascierto | Immunological effects of BRAF+MEK inhibition[END_REF] Indeed, clinical outcomes of advanced MUP in the era of novel therapies have been scarcely studied, whereas a possibly different biological background might introduce changes in its management.

The adverse side of this increased request of immunity, both related to immunomodulatory therapies and MUP biology, could be a substantial increase in the frequency and/or severity of immune-related adverse events (irAEs).

In this current study, we aimed to investigate the clinical outcomes of systemic therapies used for patients with advanced MUP compared to those with stage-matched cutaneous MKP (cMKP) in a large multicenter retrospective cohort of metastatic melanoma treated with ICIs, TT and CT.

III-MATERIAL AND METHODS

Study design and population

This retrospective study enrolled patients from the French multicenter prospective cohort MelBase, dedicated to the prospective follow-up of adults with advanced melanoma Patients with primary mucosal or ocular melanoma were excluded.

(
Four treatment cohorts were defined, including whole treatment, ICI, TT and CT cohorts.

Definition of melanoma of unknown primary

MUP was defined as the upfront occurrence of (sub)cutaneous, nodal and/or visceral metastasis, without any known prior or concomitant primary tumor according to Das Gupta's 6 criteria, which is based on the patient's medical history and clinical skin, ophthalmological, otorhinolaryngological and anogenital examinations, along with the histopathology of a metastatic sample confirming the presence of malignant melanocytes. The diagnosis of MUP was left to the discretion of the physicians from each participating center.

Outcomes

Both progression-free survival (PFS) and overall survival (OS) were analyzed as co-primary outcomes in MUP compared with cMKP, stratified by treatment type (ICI vs TT vs CT vs whole treatment cohorts), sex and age.

Secondary outcomes were overall responses, prognostic variables affecting survival, treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs) in MUP compared with cMKP, stratified by treatment type (ICI vs TT vs CT vs whole treatment cohorts), sex and age (integrated in the propensity score).

PFS was defined as the time from the start of the first systemic therapy to the date of disease progression or death, whichever occurred first. Patients who were alive without disease progression were censored on the date of their last disease assessment. OS was defined as the time from the start of the first systemic therapy to death. Patients who were still alive were censored at the date of the last contact.

Disease progression and response were evaluated using the Response Evaluation Criteria in Solid Tumors (version 1.1) by radiologists from each participating institution. [START_REF] Eisenhauer | New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)[END_REF] Data on the incidence of TRAEs and irAEs were collected and graded according to the US

Statistical analysis

Statistical analyses were performed for the whole MUP and cMKP cohorts and subsequently stratification by treatment subtype (ICI, TT and CT).

Baseline demographic and disease characteristics are presented as numbers and percentages for categorical variables, and as mean with standard deviation (SD) and median with interquartile range (IQR), and range for continuous variables, as appropriate.

Comparison of variable distribution between MUP and cMKP populations was performed using either Chi-squared test and Fisher's exact test for categorical variables and Student's ttest for continuous variables.

Missing baseline data were processed using multiple imputations for survival data, and all predictors considered in the model development were used in the imputation model. We imputed 25 independent data sets, generated and analyzed them separately and pooled all imputations according to the standard rules by Rubin to provide point estimates for each parameter.

A multivariate Cox proportional hazard model was used to determine the prognostic variables in the treated MUP and cMKP populations. The propensity score, defined as the probability of treatment assignment conditional on observed baseline characteristics, was applied, using inverse probability of treatment weighting (IPTW). To assess whether the propensity score model was successful in balancing the groups, imbalance in patient characteristics between groups before and after weighting, was measured by standardized differences. We considered standardized differences above 10% as meaningful imbalance.

Survival analysis was performed using the Kaplan-Meier method and Cox regression model in weighted sas. The PFS and OS values across subgroups were compared using the log-rank test.

All statistical tests were two-sided, with p<0.05 indicating statistical significance.

All analysis were performed using R statistical software version 3.5.2 (The R Foundation for Statistical Computing, Vienna, Austria).

Patient's consent and ethical approval

The MelBase protocol, registered in the National Institute Health Clinical Trials Database (NCT02828202), was approved by the French Ethics Committee (Comité de Protection des Personnes Ile-de-France XI, n°12027, 2012), the local ethics committee, and the ethics committees of all participating institutions. Written informed consent was obtained from all the patients.

IV-RESULTS

Population characteristics

A total of 1882 patients with advanced melanoma treated with ICI, TT or CT, between March 2013 and June 2021, were included. Among them, 265 patients (14.1%) had advanced MUP;

the remaining 1617 patients (85.9%) had advanced cMKP.

The median patient age was 66 years (interquartile range [IQR]: 18-97), and men accounted for a major proportion of these patients (60%). Most patients received first-line ICI (65%), followed by first-line TT (31%), with no difference between the MUP and cMKP cohorts (P = 0.44). The median follow-up duration for the MUP cohort was 11 months (IQR: 4.5-21.1 months) and for the cMKP cohort was 16.3 months (IQR: 6.2-33.3 months).

Patients in the MUP cohort more often displayed unfavorable initial prognostic factors, such as more stage IV disease cases (97% vs 85 %, P < 0.001), higher number of metastatic sites (48 % had ≥ 3 metastatic sites vs 39 % in the cMKP group, P = 0.01), higher proportion of central nervous system (CNS) metastasis (38% vs 18 %, P < 0.001) and LDH levels > 2xULN (12% vs 8%, P = 0.01). Other characteristics, including baseline ECOG performance status and BRAF-mutated status were comparable in both groups (Table 1). Of the 1224 patients who received first-line ICI, 165 had MUP (13.5%). Among them, 62% were treated with anti-PD1, 13% with anti-CTLA4 monotherapy and 25% with combination therapy, which was similar to that observed in patients with cMKP (P = 0.56, P= 0.46 and P= 0.15 respectively). MUP patients displayed significantly more unfavorable initial prognostic factors. Particularly, the presented with more stage IV disease cases (96% vs 84%, P< 0.001), with a higher number of metastatic sites (42 % had ≥ 3 metastatic sites vs 34 %, P = 0.01), more CNS metastasis (34% vs 16 %, P < 0.001) and LDH levels > 2xULN (12% vs 7%, P = 0.01). The median follow-up duration was significantly shorter in the MUP cohort (8.8 months, IQR: 3.2-26.0 vs 15.4 months, IQR: 5.6-32.3 for the cMKP cohort, P < 0.001, Supplementary Table 1).

Of the 574 patients who received first-line TT, 86 had MUP (15%). Among them, 62% were treated with BRAFi + MEKi, 38% with BRAFi monotherapy and none received MEKi alone, which did not differ from that observed in the cMKP cohort (P = 0.42, P= 0.25 and P= 0.37, respectively). Once again, MUP patients more often displayed unfavorable initial prognostic factors, presenting significantly more stage IV disease cases (99% vs 90% in cMKP cohort, P = 0.007) and CNS metastasis (39% vs 23% P < 0.001). The median follow-up duration did not differ significantly between the two cohorts (Supplementary Table 2).

Of the 84 patients who received first-line CT, 14 had MUP (16.7%). Among them, 93% were treated with mono-CT and 7% with polyCT, with no difference compared with that observed in patients with cMKP (P = 1.00). MUP patients more often displayed unfavorable baseline prognostic factors (Supplementary Table 3). The median follow-up duration was significantly shorter in the MUP cohort (3.5 months, IQR: 1.3-7.7 for MUP vs 5.7 months IQR: 2.5-12.5, P < 0.001).

Survival analysis

After applying the propensity score, the PFS duration of patients with MUP did not differ from that of patients with cMKP in the whole treatment cohort (Figure 1A 4 and5 respectively.

Prognostic factors for survival

The prognostic factors affecting PFS in the total MUP cohort were BRAF-mutated status (HR = 0.56, P <0.001), CNS metastasis (HR = 1.49, P <0.01) and LDH level (HR = 2.00, P <0.001). In particular, treatment subtype did not impact nor OS neither PFS in patients with MUP, and only affected the OS in patients with cMKP (HR = 1.43, P <0.001, Supplementary Table 6).

Multivariate analysis indicated

For the sub-group treated with ICI, multivariate analysis indicated that LDH level (HR = 1.78, P < 0.001) and number of metastatic sites (HR = 1.38, P = 0.04) were the most prognostic factors for PFS, and AJCC stage (HR = 2.68, P < 0.001) and LDH level (HR = 1.97, P < 0.001) the most prognostic factors for OS in the MUP cohort (Supplementary Table 7).

For the TT-treated cohort, multivariate analysis indicated that ECOG performance status (HR = 1.64, P = 0.04) was the most prognostic factor for PFS, and the number of metastatic sites (HR = 2.63, P < 0.001) remained the most prognostic factor for OS in the MUP cohort (Supplementary Table 8).

For theCT-treated cohort, age (HR = 0.34, P <0.01) and BRAF-mutated status (HR = 0.41, P = 0.02) were the most prognostic factors for PFS, whereas there was no prognostic factor affecting OS in the MUP cohort (Supplementary Table 9).

Response rates

The response to systemic therapies were not significantly different between the MUP and cMKP cohorts, regardless of treatment type (Table 2). An objective response was observed in 42% of the patients with MUP versus 46% of the patients with cMKP, with no difference between the two groups in the whole treatment cohort (P = 0.36).

In the ICI cohort, 47% of the patients with MUP and 52% of the patients with cMKP experienced an objective response, with no difference between the groups (P = 0.19).

Particularly, for ICI treatment, 20% of patients with MUP experienced complete response, 25% experienced partial response, and 27% presented with stable disease (vs 27%, P = 0.10, 25%, P = 0.9 and 22%, P = 1.0, respectively in patients with cMKP).

Similarly, an objective response was observed in 62% of patients with MUP and 60 % of patients with cMKP treated with TT, with no difference between the two groups (P = 0.69).

Similar results were observed in CT cohort (Table 2).

Tolerance data

A total of 1320 (70%) patients experienced AEs of any grade and 438 (23%) experienced grade 3-4 AEs. The incidence rate and severity of AEs did not significantly differ between the cMKP and MUP groups in the whole treatment cohort (all grades: 71% [cMKP] vs 66%

[MUP]; P = 0.18, and grade 3-4: 24% [cMKP] vs 22% [MUP]; P = 0.73, Table 3).

The occurrence of AEs of any grade in the cMKP and MUP groups, categorized according to the different organs/systems involved, is presented in Supplementary Table 10.

In

V-DISCUSSION

To our knowledge, the present study is the first to compare the efficacy and tolerance of novel therapies, especially ICI and TT, used in patients with advanced MUP and stage-matched cMKP.

Our cohort, which is one of the largest about advanced MUP and cMKP, included 14% of patients with MUP, a rate that is consistent with that in previous reports. [START_REF] Lee | Improved survival for stage IV melanoma from an unknown primary site[END_REF][START_REF] Verver | Clinical outcome of patients with metastatic melanoma of unknown primary in the era of novel therapy[END_REF][START_REF] Lee | Improved survival after lymphadenectomy for nodal metastasis from un unknown primary melanoma[END_REF] Majority of the patients in both groups received first-line ICI, followed by first-line TT, with no imbalance in the distribution of treatments (monotherapy or combined treatments), which shows that patients were treated according to similar strategies. We observed that OS, PFS and response rates were similar between patients with advanced MUP and cMKP, as well as in the whole treatment cohort and the ICI and TT-treated cohorts. Nevertheless, it is interesting to note that patients with MUP exhibited significantly more unfavorable prognostic factors at baseline (higher frequency of stage IV disease, higher number of metastatic sites, higher prevalence of CNS metastasis and LDH levels > 2xULN) compared with that observed in patients with cMKP, as reported in previous studies. [START_REF] Lee | Improved survival for stage IV melanoma from an unknown primary site[END_REF][START_REF] Verver | Clinical outcome of patients with metastatic melanoma of unknown primary in the era of novel therapy[END_REF] Moreover, these studies, conducted before and at the era of novel treatments, demonstrated improved OS for MUP patients in the adjusted analysis, suggesting that MUP patients might display favorable but still unknown factors, independent of the type of treatment. In addition, the multivariate analysis we performed highlighted that OS and PFS for MUP patients were not affected by any treatment subtype contrary to OS for cMKP patients. OS for MUP appeared to be affected by LDH level and AJCC stage, whereas PFS was affected by BRAF-mutated status, CNS metastasis and LDH level, in the whole treatment cohort. Moreover, it is interesting to note that the neutrophil-tolymphocyte count did not affect nor OS neither PFS in any of the cohorts.

In accordance with our results, Ellebaek et al. [START_REF] Ellebaek | The real-world outcome of metastatic melanoma: Unknown primary vs. known cutaneous[END_REF] concluded on a similar prognosis between patients with advanced MUP and MKP in the current modern treatment era, in a real-world Danish population involving 80 patients with MUP who displayed more M1C stages, which is similar to that observed in our cohort and seems representative to real-world patients with advanced MUP. Similarly, Ludwig et al. [START_REF] Ludwig | Survival and therapeutic response in patients with melanoma of unknown and known primary: a singlecentre retrospective analysis[END_REF] reported similar outcomes in MUP and MKP patients undergoing ICI therapy in a single-center retrospective study. We did not observe an improved survival in MUP patients, especially those treated with ICI while this population might be particularly sensitive to ICI, considering a favorable biological background. [START_REF] Gambichler | Patients with melanoma of unknown primary show better outcome under immune checkpoint inhibitor therapy than patients with known primary: preliminary results[END_REF][START_REF] Mcgovern | Spontaneous regression of melanoma[END_REF][START_REF] Giuliano | Clinical aspects of unknown primary melanoma[END_REF][START_REF] Scott | Melanoma of Unknown Primary[END_REF] In contrast, a recent pilot study conducted on a small population with better baseline characteristics suggested an improved PFS and a non-significant trend for better response in patients with MUP treated with ICI. [START_REF] Gambichler | Patients with melanoma of unknown primary show better outcome under immune checkpoint inhibitor therapy than patients with known primary: preliminary results[END_REF] Our results may also be explained by a higher rate of stage IV melanoma cases in our MUP cohort, especially since our multivariate analysis indicated that AJCC stage was a prognostic factor for OS in the total and ICI-treated cohorts of MUP.

Furthermore, Verver et al. [START_REF] Verver | Treatment of melanoma of unknown primary in the era of immunotherapy and targeted therapy: A Dutch population-based study[END_REF] suggested that first-line ICI therapy compared to first-line TT was a more favorable prognostic factor for OS in patients with MUP. This could be explained by the higher rate of V600K mutations in MUP patients, as observed by Beasley et al. [START_REF] Beasley | Melanomas of Unknown Primary May Have a Distinct Molecular Classification to Explain Differences in Patient Outcomes[END_REF] Indeed, this mutated profile possibly displays a higher mutational load and uses alternative pathways to the ERK pathway, explaining the improved response to ICI and decreased response to TT.

Additionally, our study demonstrated that the treatment-related toxicity rate and severity did not differ between advanced MUP and cMKP, regardless of treatment type, especially irAEs in the ICI cohort, which has never been explored in previous studies. Considering the specific biological background of MUP, we can hypothesize that MUP patients would develop more irAES, with a higher risk of grade III-IV AEs.

This study has several limitations, one of which is inherently related to its retrospective design, posing the risk of missing data (e.g., mutation data). Another limitation is the possibility of misclassification bias, given that there is no record of standard diagnostic criteria of MUP used in all participating centers.

Despite these limitations, our study has several strengths, including a large sample size (one of the largest in the MUP literature), multicentric design and long-term follow-up. All data were collected from a common and standardized electronic case report form used across all participating centers. Furthermore, because the proportion of missing data was small, the accuracy of our analysis is high. Finally, the use of propensity score analysis helped us prevent indication bias, which supported the robustness of our data.

VI-CONCLUSION

In conclusion, our results suggest that advanced MUP should be managed with strategies similar to those for advanced cMKP. In our cohort, despite the less favorable baseline prognostic factors in patients with MUP, they benefited from novel therapies as much as patients with cMKP. Exploratory studies investigating mutational burden and host immunity are required to identify the underlying mechanisms.

Figure 1 :

 1 Figure 1: Progression-free survival according to treatment types ………………………….27

Figure 2 :

 2 Figure 2: Overall survival according to treatment types ……………………………………28

  Un total de 1882 patients a été inclus, parmi lesquels 265 (14.1%) MPI. La majorité était traitée par une 1 ère ligne d'ICI, suivie par une 1 ère ligne de TC. Le suivi médian étaitde 16 mois. Les MPI présentaient plus fréquemment des caractéristiques initiales péjoratives. La SSP et la SG n'étaient significativement pas différentes entre MPI et cMPC (P= 0.73 et P= 0.93 respectivement). L'analyse multivariée, stratifiée selon l'âge, le sexe et le type de traitement ainsi que l'application d'un score de propension ne modifiaient pas ces résultats. Le taux de réponse objective ne différait pas non plus entre MPI et cMPC, dans la cohorte totale ainsi que dans chaque sous-groupe de traitement. La fréquence et la sévérité des effets secondaires ne différaient pas entre MPI et cMPC, dans la cohorte globale (tout grade : 71% (cMPC) vs 66% (MPI); P = 0.18 et grade 3-4: 24% (cMPC) vs 22% (MPI) ; P = 0.73) et dans chaque sous-groupe de traitement. CONCLUSION Nos résultats suggèrent que la stratégie thérapeutique des MPI doit être similaire à celle des cMPC avancés, compte tenu d'une efficacité et d'un profil de tolérance similaires malgré des caractéristiques initiales plus péjoratives chez ces patients. Malgré l'hypothèse préalablement suggérée d'un terrain immunologique plus favorable chez les patients MPI, nous n'avons pas identifié de différence d'efficacité ni de tolérance dans le sous-groupe traité par ICI. Des études exploratoires, évaluant la charge mutationnelle et l'immunité de l'hôte sont nécessaires pour comprendre les mécanismes sous-jacents.

*

  Vemurafenib + Cobimetinib (N= 51), Dabrafenib + Trametinib (N = 321), Encorafenib + Binimetinib (N= 7); ** Vemurafenib (N= 120), Dabrafenib (N= 66); *** Cobimetinib (N= 9); • Dacarbazine (N= 47), Temozolomid (N= 19), Fotemustine (N= 13); ┼ Carboplatin-Paclitaxel (N= 4), Dacarbazine-Temozolomid (N=1)

  : 5.6 months for MUP vs 5.6 months for cMKP, P = 0.73). Stratification by treatment type did not lead to data modification and showed the following results: 5.5 months for MUP treated with ICI versus 5.3 months, P = 0.81 (Figure1B), 6.3 months for MUP treated with TT versus 5.9 months, P = 0.38 (Figure1C), and 5.2 months for MUP treated with CT vs 3.2 months, P = 0.38 (Figure1D).

Figure 1 .Figure 2 .

 12 Figure 1. Progression-free survival according to known or unknown advanced primary melanoma, after applying the propensity score Known (red arrow) or unknown (blue curve) advanced primary melanoma. Progression-free survival among patients in the (A) whole, (B) immune checkpoint inhibitor, (C) targeted therapy, and (D) chemotherapy cohorts.

  only the AJCC stage (HR = 2.91, P < 0.001) and LDH level (HR = 2.25, P <0.001) affected the OS in the whole MUP cohort, whereas AJCC stage (HR = 1.22, P= 0.04), ECOG performance status (HR = 1.28, P < 0.001), LDH level (HR = 1.51, P <0.01), hepatic and CNS metastasis (HR = 1.31, P < 0.01 and HR = 1.48 P < 0.001, number of metastatic sites (HR = 1.31, P < 0.01) and treatment subtype (HR = 1.43, P <0.001) remained the most prognostic factors in the whole cMKP cohort.

Table des matières

 des ABRÉVIATIONS ........................................................................................................................................

Table 1 .

 1 Patient characteristics in whole population, cMKP and MUP cohorts regardless treatment subset

	Baseline Characteristics	Whole population	cMKP	MUP	p-value
	Number of patients	1882	1617	265	-
	Age, years
	-Mean, years	64	64	64	1.0
	-Median (range), years	66 (18-97)	66 (21-97)	64 (18-92)
	-≥ 65 years, N (%)	1007 (53)	876 (54)	131 (49)	0.16
	Sex, N (%)
	Men	1129 (60)	965 (60)	164 (62)	0.54
	Women	753 (40)	652 (40)	101 (38)
	AJCC 7th edition, N (%)
	III	255 (14)	247 (15)	8 (3)	<0.001
	IV	1627 (86)	1370 (85)	257 (97)
	-M1a	199 (11)	167 (10)	32 (12)
	-M1b	310 (16)	290 (18)	20 (8)
	-M1c	1118 (59)	913 (56)	205 (77)

Table 2 .

 2 Response rates of patients according to treatment types

	TOTAL POPULATION
	Whole cohort	MKP	MUP	p-value
	(n=1882)	(n=1617)	(n=265)

Table 3 .

 3 Rate and severity of adverse events according to treatment type in the two patient groups

	the ICI-treated cohort, 1104 (70%) patients experienced irAEs of any grade and 369 (23%)
	experienced grade 3-4 AEs. The incidence rate and severity of irAEs did not significantly
	differ between the cMKP and MUP groups (all grades: 70% [cMKP] vs 65% [MUP]; P =
	0.09, and grade 3-4: 23% [cMKP] vs 23% [MUP]; P = 0.92).
	In the TT-treated cohort, 610 (80%) patients experienced AEs of any grade and 261 (34%)
	experienced grade 3-4 AEs. The incidence rate and severity of AEs did not significantly differ
	between the cMKP and MUP groups (all grades: 80% [cMKP] vs 77% [MUP]; P = 0.62, and
	grade 3-4: 34% [cMKP] vs 33% [MUP]; P = 0.89).

In the CT-treated cohort, 184 (52%) patients experienced AEs of any grade and 84 (24%) experienced grade 3-4 AEs. The incidence rate and severity of AEs did not significantly differ

Table 2 .

 2 Patient characteristics in whole population, cMKP and MUP cohorts treated with targeted therapy

	Sex, N (%)
	Men	954 (60)	814 (60)	140 (64)	0.29
	Women	631 (40)	551 (40)	80 (36)
	AJCC 7th edition, N (%)
	III	224 (14)	216 (16)	8 (4)	<0.001
	IV	1361 (86)	1149 (84)	212 (96)
	-M1a	162 (10)	137 (10)	25 (11)
	-M1b	267 (17)	248 (18)	19 (8)
	-M1c	932 (59)	764 (56)	168 (76)
	Brain metastasis, N (%)
	Yes	296 (19)	222 (16)	74 (34)	<0.001
	Symptomatic	61 (4)	42 (3)	19 (9)
	Liver metastasis, N (%)
	Yes	354 (22)	298 (22)	56 (25)	0.27
	Number of disease sites, N (%)
	<3	995 (63)	902 (66)	93 (58)	0.02
	≥3	590 (37)	463 (34)	127 (42)
	ECOG PS, N (%)
	0	1117 (70)	978 (72)	139 (63)	0.22
	1	340 (22)	284 (21)	56 (26)
	≥2	128 (8)	103 (7)	25 (11)
	Mutations Status, N (%)
	BRAF V600	510 (32)	445 (33)	65 (30)	0.20
	LDH, N (%) > ULN ; IC (95%)
	N > ULN	455 (29)	385 (29)	70 (32)	0.22
	N > 2 x ULN	125 (8)	98 (7)	27 (12)	0.01
	First line treatment, N (%)
	Immune checkpoint inhibitors	1224 (77)	1059 (78)	165 (75)
	-Anti PD1	785 (64)	683 (65)	102 (62)	0.56
	-Ipilimumab	183 (15)	162 (15)	21 (13)	0.46
	-Ipilimumab + Nivolumab	256 (21)	214 (20)	42 (25)	0.15
	Treatment lines received, N (%)
	One line	652 (41)	549 (40)	103 (47)	0.22
	Two lines	381 (24)	329 (24)	52 (24)
	Three lines	310 (20)	271 (20)	39 (18)
	Four line and more	242 (15)	216 (16)	26 (12)

Table 3 .

 3 Patient characteristics in whole population, cMKP and MUP cohorts treated with chemotherapy

	<0.001

Table 6 .

 6 Prognostic factors in the whole treatment cohort on: overall survival in univariate (A) and multivariate (B) analysis progression-free survival in univariate (C) and multivariate (D) analysis Proportionality over time was studied for all variables. American Joint Committee on Cancer; ECOG, Eastern Cooperative Oncology Group; CNS, Central Nervous System Abbreviations: AJCC, American Joint Committee on Cancer; ECOG, Eastern Cooperative Oncology Group; CNS, Central Nervous System American Joint Committee on Cancer; ECOG, Eastern Cooperative Oncology Group; CNS, Central Nervous System

	0.96
	)

Serment d'Hippocrate

« Au moment d'être admise à exercer la médecine, je promets et je jure d'être fidèle aux lois de l'honneur et de la probité.

Mon premier souci sera de rétablir, de préserver ou de promouvoir la santé dans tous ses éléments, physiques et mentaux, individuels et sociaux.

Je respecterai toutes les personnes, leur autonomie et leur volonté, sans aucune discrimination selon leur état ou leurs convictions. J'interviendrai pour les protéger si elles sont affaiblies, vulnérables ou menacées dans leur intégrité ou leur dignité. Même sous la contrainte, je ne ferai pas usage de mes connaissances contre les lois de l'humanité. J'informerai les patients des décisions envisagées, de leurs raisons et de leurs conséquences.

Je ne tromperai jamais leur confiance et n'exploiterai pas le pouvoir hérité des circonstances pour forcer les consciences.

Je donnerai mes soins à l'indigent et à quiconque me le demandera. Je ne me laisserai pas influencer par la soif du gain ou la recherche de la gloire.

Admise dans l'intimité des personnes, je tairai les secrets qui me seront confiés. Reçue à l'intérieur des maisons, je respecterai les secrets des foyers et ma conduite ne servira pas à corrompre les moeurs.

Je ferai tout pour soulager les souffrances. Je ne prolongerai pas abusivement les agonies.

Je préserverai l'indépendance nécessaire à l'accomplissement de ma mission. Je n'entreprendrai rien qui dépasse mes compétences. Je les entretiendrai et les perfectionnerai pour assurer au mieux les services qui me seront demandés. J'apporterai mon aide à mes confrères ainsi qu'à leurs familles dans l'adversité.

Que les hommes et mes confrères m'accordent leur estime si je suis fidèle à mes promesses ; que je sois déshonorée et méprisée si j'y manque. »

Liste des tableaux

 4: Overall survival and progression-free survival at 6 months, 12 months and 24 months in the whole cohort, the immunotherapy-treated cohort, the targeted therapy-treated cohort, and chemotherapy-treated cohort, before propensity score………….41 Supplementary Table 5: Overall survival and progression-free survival at 6 months, 12 months and 24 months in the whole cohort, the immunotherapy-treated cohort, the targeted therapy-treated cohort, and chemotherapy-treated cohort, after propensity score…………....42

Supplementary


est destinée au dépôt

Modelling the growth stress distribution during the life of tree branches: impact of different growth strategies

A van Rooij, Eric Badel, Jean-François Barczi, Yves Caraglio, Tancrede Almeras, Joseph J. Gril

To cite this version:

A van Rooij, Eric Badel, Jean-François Barczi, Yves Caraglio, Tancrede Almeras, et al.. Modelling the growth stress distribution during the life of tree branches: impact of different growth strategies.

Abstract

This work aims to model the consequences of different strategies used by tree branches to ensure a given posture. If tree branches were simple beams, they would collapse under their weight. Of course, branches have the ability to control their orientation, and thus compensate for the effect of gravity, which increases every year by the way of the primary and secondary growths that respectively increase the length and diameter of the organ. The two known strategies of the branch to straighten itself are the asymetry of maturation stress, including reaction wood formation, and eccentric growth. Both strategies are generally observed simultaneously in nature and influence the stress distribution developed in the branch each year. This so-called growth stress reflects the mechanical state of the branch. In this work, a growth stress model was developed at the cross-section level in order to quantify the biomechanical impact of each strategy. To provide realistic input to the model, branch profiles were modelled using the growth simulation software AMAP Sim. These modelling results provided different loading laws that evolved with space and time. For different types of branches, the impact of the two postural control strategies was then examined. In a final step, a profiling of the branch at different points of its final shape allowed to follow the evolution of the stress distribution along the branch. Figure 1 illustrates the approach. On the left, the main axis of a maritime pine branch Pinus Pinae is shown at different stages of development. On the right, the stress profile in a section at the branch insertion is proposed. In this case, the eccentricity is zero, so the branch must produce reaction wood (compression wood for a softwood) to maintain its posture. This is shown by the compressive stress in the lower section of the branch.

Figure 1 :

 1 Figure 1: Left: Evolution of the shape of a maritime pine branch at different stages of its life. Right: Longitudinal growth stress distribution in the cross-section close to the insertion of the branch.

  10th Plant Biomechanics conference, ENS Lyon, Aug 2022, Lyon, France. hal-03727687

	1. Université Clermont-Auvergne, CNRS, Institut Pascal, F-63000, Clermont-Ferrand, France
	2. Université Clermont-Auvergne, INRAE, PIAF F-63000 Clermont-Ferrand, France
	3. CIRAD, CNRS, INRAE, IRD, Université Montpellier 2, AMAP, F-34000 Montpellier, France
	4. CNRS, Université Montpellier 2, LMGC, F-34000 Montpellier, France


Magali Aubert
email: magali.aubert@inrae.fr

Laurent Parrot
email: laurent.parrot@cirad.fr

Paula Fernandès Ce

Eric Roux
email: eric.roux.er@nouvelle-aquitaine.fr

Jean-Pierre Devin
email: jean-pierre.devin@agriculture.gouv.fr

Geoffroy Enjolras
email: geoffroy.enjolras@grenoble-iae.fr

Isabelle Jean-Baptiste
email: isabelle.jean-baptiste@martinique.chambagri.fr

Paula Fernandes
email: paula.fernandes@cirad.fr

Éric Roux

When formal and informal networks promote agroecology: a case study of Martinique Island

Keywords:

Martinique, a French island and overseas department, faces many environmental challenges including a humid tropical climate prone to the development of pests, the decline of its agricultural sector and a deterioration of its environment. Despite these constraints, Martinique has to meet both national and European environmental requirements. In order to understand the main drivers of agroecological transition on the island, our study considers the role of both formal and informal networks in addition to individual and structural characteristics of farms.

Based on a representative database of Martinican farms, our study highlights two main results.

First, the individual characteristics of farmers influence their productive practices, while the structural characteristics of their farms have no impact. For farmer-owners, a farm has a value in terms of transmission translating into a desire to protect soil quality and hence to implement agroecological principles. Second, networks play an important role in the implementation of more environmentally-friendly practices. In Martinique, the main drivers are informal networks as Martinican farmers observe at the neighbourhood level both positive and negative impacts of the implementation of alternative practices.

Introduction

The agricultural intensification after the Second World War largely relied on synthetic pesticides. Nowadays, there is a general consensus concerning the negative effects of such products and all stakeholders, whether private or public, agree on the fact that pesticides should be reduced because of their impacts on the environment and human health. From a regulatory and legislative standpoint, a large array of rules, standards, certifications, labels and specifications already influence food systems. Directive 2009/128/EC of the European Parliament and of the Council of 21 October 2009 establishes a framework for Community action to achieve a sustainable use of pesticides. It states that : "this Directive establishes a framework to achieve a sustainable use of pesticides by reducing the risks and impacts of pesticide use on human health and the environment and promoting the use of integrated pest management and of alternative approaches or techniques such as non-chemical alternatives to pesticides" (European Parliament and the Council, 2009). Furthermore, in light of the increasing number of stringent norms and standards that regulate the international trade, we might expect the quantities of synthetic pesticides used for production and storage to be falling, but this is not the case in France.

In recent years, France has set up and developed a regulatory framework and incentives specifically aimed at reducing the use of synthetic pesticides by half. The Ecophyto I (2008), Ecophyto II (2015) and Ecophyto II+ (2018) plans were designed to reduce dependency on synthetic pesticides by focusing on the systemic approaches found in the field of agroecology.

The French government defines agroecology as "the application of ecological science to the study, design and management of sustainable agrosystems", and as a "set of agricultural practices favouring biological interactions aiming at an optimal use of the possibilities offered by agrosystems"1 . The challenge is therefore to adopt a systemic approach involving all stakeholders to achieve an agroecological transition [START_REF] Fao | Agroecology for food security and nutrition: proceedings of the FAO international symposium[END_REF].

One of the reference indicators for these plans, in accordance with European standards, is the "quantity of active substances" sold each year in the country (QSA: Quantité de Substances Actives). Statistics from the French Government (2020) show that total QSA was 85,876 tons in 2018. Despite the implementation of the Ecophyto plans, the observed dynamics of the QSA display an upward trend: +21% between 2017 and 2018, and +22% between 2009-2011 and 2016-2018 (three-year average) (French Government, 2020). A similar trend concerns pesticide sales in France between 2013 and 2016 according to the European Environment Agency2 .

We focus our analysis on the context of Martinique, an island and a French department in the Caribbean. Martinique is a relevant case study for several reasons. First, Martinique has to comply with national and European phytosanitary requirements. Second, Martinique has a humid tropical climate with no winter season during which the prevalence of bioagressors (pests, diseases, weeds) is dramatically reduced. The almost uninterrupted rains and the warm temperatures all year long favour constant pest attacks. This situation makes the fight against pests more difficult than in temperate countries. These two factors combined provide a glimpse of what awaits developing tropical countries in their quest for pesticide reduction.

Moreover, Martinique faces the challenges of a declining agricultural sector and environmental degradation. In 2019, the 2,700 farms covered 21% of the surface of the island, employing 4% of the wage-earning population and accounting for 3% of gross production (Direction de l'Alimentation de l'Agriculture et de la Forêt de la Martinique, 2019). From 1973 to 2019, the number of farms decreased from 16,900 to 2,700 while the area of farmland fell from 51,100 ha to 23,196 ha (Direction de l'Alimentation de l'Agriculture et de la Forêt de la Martinique, 2019, [START_REF] Saffache | Contexte de l'agriculture martiniquaise : atouts et contraintes pour l'agriculture biologique[END_REF]. Between 2010 and 2017, the area farmed decreased by 12% (Direction de l'Alimentation de l'Agriculture et de la Forêt de la Martinique, 2011). Beyond agricultural decline, Martinique is also facing environmental degradation. In 2018, for example, the persistent insecticide chlordecone received large media coverage [START_REF] Vincent | Chlordécone ; Les Antilles empoisonnées pour des générations[END_REF]. Banned in 1993 in the French West Indies, this insecticide contaminated arable land, staple crops and the population. This contamination led to a significant increase in the risk of prostate cancer with an increased concentration of plasma chlordecone [START_REF] Multigner | Chlordecone Exposure and Risk of Prostate Cancer[END_REF][START_REF] Woignier | Chlordecone retention in the fractal structure of volcanic clay[END_REF]. Herbicides currently account for 80% of all synthetic pesticides (as active substances) sold in Martinique (Préfecture de Martinique, 2016).

Finally, like most small island economies, Martinique is largely dependent on imports with only a 9.8% export/import ratio (IEDOM, 2019). Mainly consisting of banana and sugar cane-rum production, the agricultural sector plays an important role in the social and territorial balance of the island. Vegetable production, for example, meets only 36% of local demand (Direction de l'Alimentation de l'Agriculture et de la Forêt de la Martinique, 2015).

For all these reasons, Martinique is a relevant case study to assess the agroecological transition necessary to reduce the use of pesticides. While large-scale banana and sugar cane plantations are engaged in environmentally-friendly practices (Direction de l'Alimentation de l'Agriculture et de la Forêt de la Martinique, 2013), less is known about all the smaller farms involved in vegetable production. In the second section, we present the theoretical hypotheses on which we base our study. In the third section, we present the database and the econometric model. In the fourth section, we discuss the results before concluding.

Theoretical framework

The literature underlines the relevance of several key drivers for the implementation of environmentally-friendly practices. More than being stimulated by national and European requirements, the implementation of these practices is facilitated upstream by improved agronomic and technical support, favoured by collective organization, whether formal or informal, and dependent on farmers' and farm characteristics.

Networks

Farmers can belong to social or private groups. Either formal [START_REF] Zhou | Implementation of food safety and quality standards: A case study of vegetable processing industry in Zhejiang, China[END_REF][START_REF] Adsadpur | Socio-economic factors affecting the development of biological technologies stem borer pest in rice fields of Mazandaran[END_REF][START_REF] Pereira De Herrera | Adoption of maize conservation tillage in Azuero, Panama[END_REF][START_REF] Traoré | On-farm adoption of conservation practices: The role of farm and farmer characteristics[END_REF][START_REF] Mcdonald | Difficulties in measuring adoption of apple IPM : A case study[END_REF] or informal [START_REF] Bultena | Factors affecting farmers' adoption of conservation tillage[END_REF][START_REF] Warriner | Kinship and personal communication network influences on the adoption of agricultural conservation technology[END_REF][START_REF] Saltiel | Adoption of sustainable agricultural practices: Diffusion, farm structure, and profitability[END_REF][START_REF] Bonabana-Wabbi | Assessing factors affecting adoption of agricultural technologies : The case of Integrated Pesti Management (IPM) in Kumi district, Eastern Uganda[END_REF][START_REF] Sharma | Impact evaluation indicators of an Integrated Pest Management program in vegetable crops in the subtropical region of Jammu and Kashmir, India[END_REF], these groups incite farmers to reduce the use of chemical inputs [START_REF] Enjolras | French labour-force participation in organic farming[END_REF]. As a matter of fact, groups can act as learning forums [START_REF] Arocena | Interactive Learning Spaces and Development Policies in Latin America[END_REF] or innovation platforms [START_REF] Hounkonnou | An innovation systems approach to institutional change: Smallholder development in West Africa[END_REF]. Considering producer organizations (POs) more specifically, their rolebeyond concentrating productionis to train and support producers in changing their productive practices (Adsadpur, 2011, Pereira de Herrera and[START_REF] Pereira De Herrera | Adoption of maize conservation tillage in Azuero, Panama[END_REF]. POs "also assist producers in the management of their crops" (Bonnaud, 2012). These structures train farmers by providing them with an up-to-date inventory of approved products and corresponding authorized doses. POs offer information about long-term environmental effects of pesticide use and alternative practices. Through technical experts who are members of POs, farmers also benefit from technical and agronomy advice [START_REF] Enjolras | French labour-force participation in organic farming[END_REF].

Hypothesis 1.1. Being a member of a PO increases the likelihood of implementing more environmentally-friendly practices

In addition to these POs, farmers can be members of an informal network. These networks are defined by the informal dimension of the relationship and not by the number of relationships.

Regardless of the size of the network, the key point is the access of farmers to information regarding farming practices. The main type of network is the neighbourhood [START_REF] Adsadpur | Socio-economic factors affecting the development of biological technologies stem borer pest in rice fields of Mazandaran[END_REF][START_REF] Pereira De Herrera | Adoption of maize conservation tillage in Azuero, Panama[END_REF][START_REF] Fernandes | Innovations agroécologiques en Martinique : freins et leviers organisationnels, institutionnels, techniques et économiques[END_REF]. Informal discussions can help farmers to benefit from the experience and feedback of farmers involved in more environmentally-friendly practices. This can encourage non-adopters to change their productive practices by observing agronomic and economic implications among their neighbours who have adopted certain practices (Pereira de Herrera and Sain, 1999).

Hypothesis 1.2. Benefitting from an informal network increases the likelihood of implementing more environmentally-friendly practices

Institutions also play a key role in spreading information that helps farmers to change their productive practices in favour of more environmentally-friendly ones. In particular, the intervention of technicians from the Chamber of Agriculture allows farmers to benefit from agronomic and technical advice. In France, the Chambers of Agriculture were created at the beginning of the 20 th century to promote agricultural interests vis-à-vis public authorities. In accordance with French Law no. 2014-1170 for the future of agriculture, their role is also to contribute to the development of agroecology. As underlined by the national court of auditors, a chamber of agriculture is a natural relay enabling the state to implement its agricultural development policy, now based on the triptych of economic, social and environmental performance. Technicians from the Chamber of Agriculture support producers, in particular by providing technical and agronomic advice to farmers. Hence, technicians play a leveraging role, inciting farmers to change their productive practices [START_REF] Mcdonald | Difficulties in measuring adoption of apple IPM : A case study[END_REF]Glynn, 1994, Traoré et al., 1998).

Hypothesis 1.3. Information given by technicians from the Chamber of Agriculture plays a positive role in the implementation of more environmentally-friendly practices

Farmers' individual characteristics

The literature highlights farmers' education levels, and more precisely their agricultural education levels, as a key determinant of the implementation of more environmentally-friendly practices [START_REF] Geniaux | Les déterminants de la conversion à l'agriculture biologique : Une revue de la littérature économique[END_REF][START_REF] Alabi | Field evaluation of cowpea cultivars (Vigna unguiculata [L.] Walp.) for resistance to flower bud thrips (Megalurothrips sjostedti Trybom) (Thysanoptera: Thripidae)[END_REF][START_REF] Barzman | The willingness to adopt agro-ecological innovations: Application of choice modelling to Caribbean banana planters[END_REF]. The literature emphasizes that the agricultural education level is more relevant to understanding the implementation of more environmentally-friendly practices than the general education level [START_REF] Morgan | Organic vs. conventional agriculture: knowledge, power and innovation in the food chain[END_REF]. As a matter of fact, to implement these practices, farmers must be able to identify the appearance and assess the spread of pests and diseases in order to take rapid action before the need for pesticide use. Besides their initial education level, farmers usually complement their agricultural education by means of vocational agricultural training. This additional training reflects a dynamic of continuous improvement of farming practices, particularly in favour of environmentally-friendly practices.

Hypothesis 2.1. Vocational agricultural training of farmers has a positive impact on the implementation of more environmentally-friendly practices

Beyond the farmers' education level, the literature underlines the relevance of considering several key individual indicators to understand the changes in productive practices. The first is the fact that a farmer declares themself to be in full-time employment. Farmers who work full time on their farm can spend more time on observation [START_REF] Gould | Conservation tillage: The role of farm and operator characteristics and the perception of soil erosion[END_REF][START_REF] Aubert | The institutional environment: key support for formal market gardeners in Mayotte[END_REF].

Hence, we assume that farmers who have no off-farm activity are more involved and that they are more likely to implement more environmentally-friendly practices.

Hypothesis 2.2. A farmer's involvement on his farm has a positive impact on the implementation of more environmentally-friendly practices

The involvement of farmers in terms of pesticide reduction depends on whether or not the farmer is the owner of the farm. The literature underlines the fact that farmers are much more eager to change their practices if they own their farm [START_REF] Feder | Adoption of agricultural innovations in developping countries : A survey[END_REF][START_REF] Clay | Sustainable intensification in the highland tropics: Rwandan farmers' investments in land conservation and soil fertility[END_REF]. It should be noted that investments in alternative practices cannot necessarily be re-deployed from one plot to another. This represents a potential brake on the implementation of more environmentally-friendly practices. As a matter of fact, in the event of non-renewal of the agricultural land use contract, a farmer loses his investment even if he can benefit from another contract on another plot.

Hypothesis 2.3. Being a farmer-owner has a positive impact on the implementation of more environmentally-friendly practices

Farm structure

Beyond farmers' individual characteristics, the literature identifies a range of other drivers relating to farm structural characteristics which lead to the reduction of pesticide use. The first element is the degree of diversification. Crop diversification is considered a decisive prevention strategy with a positive impact on environmentally-friendly practices (Barzman et al., 2015) and income [START_REF] Ellis | Household strategies and rural livehood diversification[END_REF][START_REF] Parrot | Horticulture, livehoods and urban transition in Africa: Evidence from South-West Cameroon[END_REF]. Mono-cropping systems are more dependent on synthetic pesticides than diversified systems [START_REF] Malézieux | Designing cropping systems from nature[END_REF]. Farmers who operate mixedcropping activities are therefore less dependent on synthetic pesticides.

Hypothesis 3.1. The degree of farm diversification has a positive impact on the implementation of more environmentally-friendly practices

The total cultivated area is universally underlined by the literature to be a key determinant of the implementation of more environmentally-friendly practices and almost all studies demonstrate its positive impact [START_REF] Feder | Adoption of agricultural innovations in developping countries : A survey[END_REF][START_REF] Lefebvre | Incentives and policies for integrated pest management in Europe : a review[END_REF]. The cultivated area is synonymous with capital [START_REF] Feder | Adoption of agricultural innovations in developping countries : A survey[END_REF][START_REF] Galt | Toward an integrated understanding of pesticide use intensity in costa rican vegetable farming[END_REF], economies of scale [START_REF] Jaffee | Food sagety and agricultural health standards : Challenges and opportunities for developing countries[END_REF][START_REF] Caswell | Adoption of agricultural production practices : Lessons learned from the U.S. department of agricultural area studies project[END_REF], access to credit (Feder et al., 1985, Fernandez-Cornejo and[START_REF] Fernandez-Cornejo | The environmental effects of adopting IPM techniques: The case of peach producers[END_REF] and financial resources [START_REF] Knowler | Farmers' adoption of conservation agriculture: A review and synthesis of recent research[END_REF]. Farmers whose total area is higher are therefore more likely to implement more environmentally-friendly practices.

Hypothesis 3.2. The total cultivated area has a positive impact on the implementation of more environmentally-friendly practices

Control variables

Innovations are implemented in relation to biotic and abiotic environmental factors. Farm structure, and more precisely its agroecological environment characteristics, are important factors influencing the adoption of sustainable farming practices. Farmers who consider that the most worrying problems at the agronomic level relate to bioagressors will be more prone to protecting their production and hence to adopting alternative practices (Gould et al., 1989, Ervin and[START_REF] Ervin | Factors affecting the use of soil conservation practices : Hypotheses, evidence and policy implications[END_REF].

Hypothesis 4.1. Farmers who suffered from the pressure of bioagressors during the previous campaign are more likely to implement more environmentally-friendly practices

We control for the geographical location and more precisely the fact that the farm is located on sloping ground. Since these farms cannot use mechanization [START_REF] Aynsau | Determinants of adoption and continued use of stone terraces for soil and water conservation in an Ethiopian highland watershed[END_REF], they are less likely to use pesticides [START_REF] Aubert | The institutional environment: key support for formal market gardeners in Mayotte[END_REF].

Empirical framework

This section describes the database and the econometric model.

Database

From the 2010 Martinique census database, which identifies all farms of the island, we selected farms specializing in vegetable productions. The census mainly collects information about farms and their owners. Because we needed more specific and precise information about farmers' interaction with formal and informal networks, we created an additional sample based on a stratified sampling. Criteria considered for the stratification are the location and the production implemented. We also considered whether a farmer is a member of a PO. The data collected are representative of vegetable farms in Martinique. Hence, among the 3,307 farms of the island, 1,382 produce vegetables and we surveyed 120 of these. Our study focuses on these farms.

In order to understand the extent to which farmers are more or less likely to implement more environmentally-friendly practices, we collected data relating not only to individual characteristics of the farmers, structural characteristics of their farms and the environment in which they operate, but also information relating to various networks, whether formal or informal (Table 1).

Table 1. List of variables and associated hypotheses

Statistical analysis and econometric modelling

Since the measure of such a reduction refers to several dimensions including quantities, active substances, treatments and monetary units, we decided to refer to the general concept of agroecology, which aims to combine competitive agricultural production with the sustainable use of natural resources. In our survey, we questioned farmers to find out if they had implemented alternative practices of any kind that allowed them to reduce their use of phytosanitary products. For the purpose of the analysis, we therefore differentiated farmers depending on whether they had innovated by implementing more environmentally-friendly practices. Because farmers' behaviour is considered to be dichotomic, we implemented a logit model.

The model can be formalized in a synthetic way, as follows:

𝑀𝐸𝐹𝑃 𝑖 = 1 𝑖𝑓 𝑀𝐸𝐹𝑃 𝑖 * > 0; 0 𝑜𝑡ℎ𝑒𝑟𝑤𝑖𝑠𝑒
Farmer (i) decides to implement more environmentally-friendly practices (MEFP) conditional to a continuous effect that is not observed and denoted 𝑀𝐸𝐹𝑃 𝑖 * .

𝑀𝐸𝐹𝑃 𝑖 * = 𝛽 0 + 𝛽 1 𝑁𝑒𝑡𝑤𝑜𝑟𝑘 𝑖 + 𝛽 2 𝐹𝑎𝑟𝑚𝑒𝑟 𝑖 + 𝛽 3 𝐹𝑎𝑟𝑚 𝑖 + 𝛽 4 𝐶𝑜𝑛𝑡𝑟𝑜𝑙 𝑣𝑎𝑟𝑖𝑎𝑏𝑙𝑒𝑠 𝑖 + 𝜀

Where:

𝛽 0 is the constant.

𝛽 1 is a vector of coefficients associated with networks.

𝛽 2 is a vector of coefficients associated with farmers' characteristics.

𝛽 3 is a vector of coefficients associated with farm structure.

𝛽 4 is a vector of coefficients associated with control variables.

𝜀 is the error term

Results

We measured the implementation of more environmentally-friendly practices according to whether or not farmers declared that they implemented practices leading to a reduction in pesticide use. Not all farmers implemented the same practices but they shared the same environmental goals. Among the farmers surveyed, 67.5% had never implemented alternative practices to pesticide use.

Descriptive statistics

Networks

Statistical results underline that being a member of a network differs significantly according to the productive practices implemented (Table 2a andTable 2b).

Table 2a. Qualitative characterization of farmers and their farm according to their environmentally-friendly practices

Table 2b. Quantitative characterization of farmers and their farm according to their environmentally-friendly practices

Whatever the network considered, statistical results highlight the fact that farmers who are members of one of the identified networks are over-represented among innovative farmers.

Respectively 50%, 78% and 28% of innovative farmers are members of a PO, an informal network or enjoy a relationship with a technician from the Chamber of Agriculture, while the figures are 25%, 30% and 13% respectively among non-innovative farmers. Farmers benefiting from information and advice, regardless of their source, seem to be more prone to changing their productive practices.

Farmers' characteristics

Farmers who implement more environmentally-friendly practices are more likely to own all or part of their farms. Property rights seem to act as a lever for the implementation of these practices. Three-quarters of farmers implementing more environmentally-friendly practices own their farm, while only 51.28% of non-owners do the same. Farmer-owners are more sensitive to the long-term quality of their soil and hence more concerned with land quality.

The results highlight a significant difference between innovative farmers and other farmers in terms of time spent on the farm. Farmers who implement alternative practices tend to be those who are more involved on their farm. More than 90% of innovative farmers are full-time farmers. These farmers are also over-represented among farmers who completed a vocational agricultural training. While 44.4% of innovative farmers completed such a training, the figures fall to 28.21% for non-innovative farmers.

Farm structure

Beyond farmer's individual characteristics that seem to differentiate farmers according to their productive practices, statistical results also underline the role of farm structural characteristics.

Farms owned by innovative farmers are larger covering, on average, around 6 hectares while their size is smaller for other farmers, at less than 4 hectares. We also observe that innovative farms are no more diversified than other farms. With an average of 5.5 different types of crop grown on their farm, farmers who are willing to implement more environmentally-friendly practices are no more diversified than others.

Control variables

Concerning control variables, the statistical results highlight the fact that farmers who declare that pests are the most worrying agronomic problem is the only significant variable. While 55% of innovative farmers make such a statement, the figure falls to 47% in the case of noninnovative farmers. We observe that neither the fact that diseases are the most worrying agronomic problem nor the slope of the farm seem to affect productive practices implemented by farmers in Martinique.

Econometric results

The concordance rate, which serves to assess the performance of the prediction, is 85% (Table 3), which represents the validity of our model. Concerning the fact that a farmer is a member of a group, our results underline the fact that, in Martinique, informal networks play a key role. Farmers who are involved in an informal network have a much higher probability (24 times more likely) of implementing more environmentally-friendly practices than other farmers (H 1.2 validated). In this context, an informal network is a relevant driver of a change in productive practices. Such a network, defined in terms of neighbourhood exchanges, provides tangible information on both the positive and negative impacts of such changes, which explains why farmers concerned are much more likely to implement more environmentally-friendly practices. Our study also underlines the key role of chambers of agriculture, as farmers benefiting from technicians' advice are 11 times more likely to implement alternative practices than others (H 1.3 validated). This result underlines the particularity of this insular context. Finally, there is no relationship between being member of a PO and implementing more environmentally-friendly practices (H 1.1 nonvalidated). This structure appears to support farmers at the marketing level more than at the production one.

Since these formal and informal networks are not exclusive, the originality of our approach is to consider the impact of being a member of several networks. Interaction terms specify the contribution of each network, but also their complementarities. More than considering the impact of these networks on the implementation of more environmentally-friendly practices in an independent way, our study therefore demonstrates the importance of combining access to informal information with information from formal networks. While being member of a PO has no impact on the practices implemented by farmers, we demonstrate that farmers who are members of both a PO and of an informal network are much more likely to adopt these practices than farmers who are only part of an informal network. The combination of formal and informal networks thus translates into a higher probability of implementing agroecological practices. In Martinique, informal networks play a more significant role in farmers' behaviour rather than in a continental context. We highlight the fact that this role is much more relevant when it is combined with the formal one. This training provides farmers with the keys to change their productive practices. Our study also demonstrates that farmers who own their farm are 8 times more likely to implement more environmentally-friendly practices than others (H 2.3 validated). Almost all individual characteristics of farmers appear to be relevant to understanding pesticide reduction. However, our results emphasize that in the case of Martinique, the fact that a farmer works full time has no impact on his productive practices (H 2.2 non-validated). This result can be explained by the fact that, in Martinique, the time spent by a farmer on his farm is not a brake to the implementation of more environmentally-friendly practices.

Farm structure

Our results highlight the fact that no structural farm characteristics affect the productive practices implemented by farmers. Neither the number of crops cultivated (H 3.1 non-validated) nor the total area cultivated (H 3.2 non-validated) has an impact on the implementation of more environmentally-friendly practices. These results emphasize the fact that the non-structural characteristics of farms are not an asset to or a break on agroecological transition in Martinique.

Control variables

Our results show that farmers who declare that pests are the most worrying problem at the agronomic level are more likely to implement more environmentally-friendly practices while there is no relationship with diseases (H 4.1 partially validated). Farmers who declare that pests are the most worrying agronomic problem are 4 times more likely to implement alternative practices. As a matter of fact, these practices are a barrier to pests without having any effect on the appearance or dissemination of disease.

Our results also demonstrate that there is no relationship between the location of farms and the productive practices implemented by farmers (H 4.2 non-validated). This highlights the fact that regardless of slope of the land on the farm, the implementation of more environmentallyfriendly practices is technically possible. This geographical characteristic is not a brake on agroecological transition.

Conclusion

Martinique is a French island and overseas department facing several environmental challenges.

Martinique is required to comply with national and European phytosanitary requirements while farmers operate in a humid Caribbean context, that translates into increased difficulty in fighting bioagressors than in temperate countries. At the same time, the agricultural sector is being restructured with the disappearance of small farms and the growth of those that remain. This case study is therefore relevant to understanding the agroecological transition designed to reduce the use of pesticides. The aim of our study is to assess the extent to which farmers are encouraged to implement more environmentally-friendly practices against such a backdrop.

The literature underlines the key role of both farmers' individual characteristics and farm structure. The originality of our study is first and foremost that it highlights these drivers in an insular context and second, that it extends this reflection by considering the impact of networks on productive practices implemented by farmers. Whether formal or informal, we measure the role of these networks and assess the impact of their interactions on farmers' behaviour. To this end, we created a database founded on stratified sampling using the exhaustive census of Martinique's farms in 2010. We collected representative information about farmers, their farms and their networks. The data allow us to determine the key drivers underpinning the implementation of more environmentally-friendly practices.

Two main results are highlighted. First, the individual characteristics of the farmer condition his productive practices, while structural farm characteristics have no impact on it. In Martinique, the implementation of more environmentally-friendly practices is conditioned by the fact that a farmer owns his farm. Farmer-owners have a long-term view of their land, and thus a greater interest in protecting their productive natural resources in the long term. This point explains why the characteristics of the farm have no impact on productive practices implemented by farmers. More than being farmer-owner, a key individual driver of the productive practices is the fact that a farmer has completed a vocational agricultural training.

This point reinforces the fact that farmers need to be accompanied in the agroecological transition process and that training is a relevant way to do so.

Second, informal networks play a key role in the implementation of more environmentallyfriendly practices. Our study shows that a combination of informal and formal networks contributes significantly to changing farmers' practices. Beyond benefiting from advice from technicians of the Chamber of Agriculture, who are key drivers of the implementation of alternative practices, we demonstrate the relevance of considering knowledge provided by informal networks. In Martinique, farmers appear to be very sensitive to their neighbours' experience. Observation of the positive as well as negative impacts of implementing more environmentally-friendly practices on closed plots is a main lever in encouraging farmers to change their productive practices.

The implementation of agroecological principles in Martinique will necessarily require the dissemination of information through both formal and informal networks. The combination of all these networks is a relevant lever for agroecological transition. It would be interesting to extend this research by analysing the whole food supply chain, and more precisely the marketing opportunities for more environmentally-friendly products.

  Figure1summarizes the theoretical hypotheses considered in our study.

Figure 1 .

 1 Figure 1. Synthesis of theoretical hypotheses

Figure 2

 2 Figure 2 sums up the relative impact of each network on the probability of implementing more environmentally-friendly practices.

Figure 2 .

 2 Figure 2. Impact of networks on the implementation of more environmentally-friendly practices

Figure 1 .

 1 Figure 1. Articulation between framework and theoretical hypotheses

Table 3 . Econometric model 4.2.1. Networks

 3

Table 1 . List of variables and associated hypotheses

 1

				Expected
	Variable	Unit	Hypothesis	influence	Definition
				on MEFP
					Agroecology
	MEFP	Yes / No			1 if the farmer has ever adopted more environmentally-friendly practices; 0 otherwise
					Networks
	PO	Yes / No	H1.1	+	1 if the farmer is a member of a producer organization; 0 otherwise
	Informal	Yes / No	H1.2	+	1 if the farmer accesses informal information thanks to other farmers; 0 otherwise
	Chamber	Yes / No	H1.3	+	1 if the farmer accesses information from technicians of the Chamber of Agriculture; 0 otherwise
					Farmer's characteristics
	Agri-training Yes / No	H2.1	+	1 if the farmer has completed a vocational agricultural training; 0 otherwise
	Activity	Yes / No	H2.2	+	1 if the farmer is a full-time farmer; 0 otherwise
	Owner	Yes / No	H2.3	+	1 if the farmer owns all or part of the farm; 0 otherwise
					Farm structure
	Crops	Number	H3.1	+	Number of cultivated crops
	Area	Hectare	H3.2	+	Total area of the farm
					Control variables
	Diseases	Yes / No	H4.1	+	1 if the farmer indicates that diseases are the most worrying problem at the agronomic level; 0 otherwise
	Pests	Yes / No	H4.2	+	1 if the farmer indicates that pests are the most worrying problem at the agronomic level; 0 otherwise
	Slope	Yes / No	H4.3	+	1 if the farm is located on sloping ground; 0 otherwise

Table 2a . Qualitative characterization of farmers and their farm depending on whether or not they have ever adopted environmentally-friendly practices The farmer has adopted more environmentally-friendly practices

 2a The null hypothesis considers equality of means or independence between the two populations. Means are significantly different at the 10% (*), 5% (**) and 1% (***) thresholds. The two populations are independent at the 10% (*), 5% (**) and 1% (***) thresholds.

			No	Yes	Total	Chi2 test
			Farmers' characteristics
	Owner	No Yes	48.72% 51.28%	25.93% 74.07%	33.33% 66.67%	***
	Activity	No Yes	23.08% 76.92%	9.88% 90.12%	14.17% 85.83%	**
	Agri-training	No Yes	71.79% 28.21%	55.56% 44.44%	60.83% 39.17%	*
			Networks
	PO	No Yes	74.36% 25.64%	50.62% 49.38%	58.33% 41.67%	***
	Informal	No Yes	69.23% 30.77%	22.22% 77.78%	37.50% 62.50%	***
	Chamber	No Yes	87.18% 12.82%	71.60% 28.40%	76.67% 23.33%	*
			Control variables
	Diseases	No Yes	76.92% 23.08%	67.90% 32.10%	70.83% 29.17%	ns
	Pests	No Yes	66.67% 33.33%	46.91% 53.09%	53.33% 46.67%	**
		No	66.67%	77.78%	74.17%
	Slope	Yes	33.33%	22.22%	25.83%	ns
	Key:

Table 2b . Quantitative characterization of farmers and their farm depending on whether or not they have ever adopted environmentally-friendly practices The farmer has adopted more environmentally-friendly practices No Yes Equality of means / Std. Dev.

 2b The null hypothesis considers equality of means between the two populations. Means are significantly different at the 10% (*), 5% (**) and 1% (***) thresholds.

		Mean	Std. Dev	Mean	Std. Dev	Mean	Std. Dev.
	Crops	5.5128	2.0374	5.4074	3.0157	ns	***
	Area	3.8202	4.3821	5.6637	5.0455	*	ns
	Key:

Table 3 . Econometric model

 3

		Coefficient	Odds Ratio	Std. Dev.	P>|z|
		Farmers' characteristics
	Owner	2.302***	9.995***	7.977	0.004
	Activity	0.464	1.589	1.291	0.568
	Agri-training	1.215*	3.371*	2.326
		Farm structure
	Crops	0.045	1.046
	Area	0.056	1.058	0.084
		Networks
	PO	-2.029	0.131	0.157
	Informal	3.176***	23.955***	20.947	0.000
	Chamber	2.402*	11.045*	13.695	0.053
	Informal * Chamber	-3.376**	0.034**	0.058	0.047
	Informal * PO	2.937*	18.863*	29.819	0.063
	PO * Chamber	2.633	13.917	25.452	0.150
		Control variables
	Diseases	1.534*	4.635*	3.661	0.052
	Pests	2.006***	7.436***	5.792	0.010
	Slope	-0.203	0.816
	Constant	-5.104	0.006***	0.008	0.000
	Concordance rate		85%

Key: Estimates are significant at the 10% (*), 5% (**) and 1% (***) thresholds.

This definition is published in the Official Journal of the French Republic of 19 August

2015, available at: https://www.legifrance.gouv.fr/jorf/id/JORFTEXT000031053235

According to a note published on its official website: https://www.eea.europa.eu/airs/2018/environment-andhealth/pesticides-sales