Criteres De Milan

Dann Joseph Anthony

Ouizeman Né

Monsieur Le Professeur

Thierry Piche -Président

Monsieur Le Professeur

Rodolphe Anty

Monsieur Le Docteur

Emmanuel Chamorey

Patrick Chevallier

Xavier Hebuterne -Assesseur

Vice-Doyens Patrick

Pr Pédagogie

Alunni Véronique

M Jouan

Mme Amselle

Danièle Directrice

Mme Callea

Isabelle Doyens

Honoraires M Rampal

Patrick M Benchimol

Daniel Professeurs Classe

Exceptionnelle M Amiel

Jean Urologie

M Fenichel

M Gilson Éric

M Santini

Mme Askenazy-Gittard

Florence Pédopsychiatrie

M Barranger

Emmanuel Gynécologie Obstétrique

M Bérard

Étienne Pédiatrie

M Bongain

André Gynécologie-Obstétrique

Mme Breuil

Véronique Rhumatologie

) M Castillo

) M Chevallier

Patrick Radiologie

M Drici

Milou-Daniel Pharmacologie Clinique

M Ferrari

Émile Cardiologie

M Ferrero

Jean-Marc Cancérologie

M Pradier

Christian Épidémiologie

Économie

Mme Raynaud

Dominique Hématologie

M Rosenthal Éric

M Schneider

Mme Alunni Véronique

M Bahadoran

Philippe Cytologie

Histologie

Mme Baillif

Stéphanie Ophtalmologie

Mme Bannwarth

Sylvie Génétique

M Fournier

Jean-Paul Thérapeutique

Mlle Giordanengo

Valérie Bactériologie-Virologie

Mme Giovannini-Chami

Lisa Pédiatrie

Mme Sacconi

M Albertini

Marc M Gastaud

Pierre M Balas

Daniel M Gérard

Jean-Pierre M Batt

Michel M Gillet

Jean-Yves M Blaive

Bruno M Grellier

Patrick M Boquet

Patrice M Grimaud

Dominique M Bourgeon

André M Jourdan

Jacques M Boutté

Patrick M Lambert

Jean-Claude M Bruneton

Jean-Noël M Lazdunski

Michel Mme

Bussiere Françoise

M Lefebvre

Jean-Claude M Camous

Jean-Pierre M Le Fichoux

Yves M Canivet

Bertrand Mme Lebreton

Elisabeth M Cassuto

Jill-Patrice M Mariani

Roger M Chatel

Marcel M Masseyeff

René M Coussement

Alain M Mattei Mathieu

Mme Crenesse

Dominique M Mouiel

Jean M Darcourt

MYQUEL Guy Mme

Martine M Dellamonica

Pierre M Ortonne

Jean-Paul M Delmont

Jean M Pringuey

Dominique M Demard

François M Sautron

Jean Baptiste

M Desnuelle

Claude M Schneider

Maurice M Dolisi

Claude M Toubol

Jacques Mme

Euller-Ziegler Liana

M Tran

Dinh Khiem

M Franco

Alain M Van Obberghen

Emmanuel M Freychet

Pierre M Ziegler

Gérard M C U Honoraires

M Arnold

Jacques M Giudicelli

Jean M Basteris

Bernard M Magné

Jacques Mlle Chichmanian

Rose-Marie Mme

Memran Nadine

Mme Donzeau

Michèle M Mengual

Raymond M Emiliozzi

Roméo M Philip

Patrick M Franken

Philippe M Poirée

Jean-Claude M Gastaud

Marcel Mme

Roure Marie-Claire

Discipline : Hépato-Gastro-Entérologie Composition du jury de thèse

MAITRES DE CONFÉRENCES DES UNIVERSITÉS -PRATICIENS HOSPITALIERS

Vous me faites l'honneur de présider mon jury de thèse et de juger mon travail. Merci d'avoir cru en moi dès notre première rencontre. Au-delà de la médecine, vous m'avez coaché pendant les quatre années d'internat et avez éveillé mon intérêt pour la recherche clinique. Merci de m'avoir poussé à atteindre mes objectifs. Soyez assuré de ma profonde gratitude.

A monsieur le Docteur Emmanuel CHAMOREY,

Merci de me faire l'honneur de siéger dans mon jury de thèse. Merci pour l'implication de votre équipe qui a participé à l'aboutissement de ce travail, en espérant qu'il ne soit que le premier d'une solide collaboration. Avec tout mon respect.

A monsieur le Professeur Patrick CHEVALLIER,

Merci de me faire l'honneur de siéger dans mon jury de thèse. Merci de toujours rester disponible pour nous donner conseils et explications, pour les relectures d'examens, et ce même à minuit, un soir de réveillon. Merci de votre implication auprès des patients. Soyez assuré de mon plus grand respect.

A monsieur le Professeur Xavier HEBUTERNE,

Merci de me faire l'honneur de siéger dans mon jury de thèse. Vous êtes à mes yeux un exemple de médecin qui est resté proche des patients malgré les compétences et le statut. J'admire votre façon de vous asseoir au lit des patients pour prendre le temps nécessaire. Merci de prendre le temps également avec tous ceux qui sont disposés à apprendre (étudiants, médecins et mêmes patients). Votre empathie force le respect et est un modèle pour moi. Je vous remercie pour tout ce que vous m'avez enseigné.

A monsieur le Professeur Rodolphe ANTY,

Merci de m'avoir fait l'honneur de diriger mon travail de thèse. Merci de m'avoir pris sous ton aile et de continuer à me transmettre chaque jour tes innombrables compétences cliniques (de l'examen endobuccal au TR). Merci de t'être positionné en tant que maître en médecine mais également d'endosser le rôle de grand frère quand j'en ai besoin. En plus du savoir médical, tu m'as enseigné la grandeur d'esprit.

INTRODUCTION

Hepatocellular carcinoma (HCC) accounts for 7% of all cancers worldwide. With about 800.00 cases per year it is the sixth most common tumor, while with 780.000 death per year it is the fourth most frequent cause of death from cancer in 2019 [START_REF]Estimated number worldwide[END_REF] . In France, the most recent data show a net survival at 1, 3 and 5 years respectively of 46%, 23% and 15% 2 . Despite the implementation of surveillance programs, many patients are detected at an intermediate or advanced stage of HCC [START_REF] Sangiovanni | Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance[END_REF] , and only 23% of diagnosed patients have access to curative treatment [START_REF] Goutté | Geographical variations in incidence, management and survival of hepatocellular carcinoma in a Western country[END_REF] .

Percutaneous thermoablation (PT) is recommended by French, American and Asian societies as curative treatment for HCC ≤ 30 mm [START_REF] Blanc | Carcinome hépatocellulaire[END_REF][START_REF] Bruix | American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update[END_REF][START_REF] Omata | Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma[END_REF][START_REF] Cucchetti | Cost-effectiveness of hepatic resection versus percutaneous radiofrequency ablation for early hepatocellular carcinoma[END_REF] . During radiofrequency ablation (RFA), the heat propagates in a centrifugal direction from the energy source (electrode tip) in the center of the tumor to the periphery of the tumor (« centrifugal » ablation) and the temperature decreases, together with the distance from the electrodes and when the blood flow is present in the vicinity.

This phenomenon explains the decrease in local control of a tumor larger than 20 to 30 mm, as well as the decrease in efficacy of the technique when the tumor is localized near a major vessel (the so-called « heat sink effect ») [START_REF] Nault | Percutaneous treatment of hepatocellular carcinoma: State of the art and innovations[END_REF] . Surgical resection is recommended for HCC between 30 and 50 mm or for HCC with 2 to 3 nodules located in the same segment [START_REF] Blanc | Carcinome hépatocellulaire[END_REF][START_REF] Cucchetti | Cost-effectiveness of hepatic resection versus percutaneous radiofrequency ablation for early hepatocellular carcinoma[END_REF] . Only 5 to 40% of HCCs are candidates for surgical treatment because of inappropriate localization, presence of portal hypertension, inappropriate hepatic function or excessive comorbidity [START_REF] Blanc | Carcinome hépatocellulaire[END_REF][START_REF] Bruix | Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma[END_REF] .

HCCs between 30 and 50 mm and oligonodular (n≤3) are at higher risk of recurrence. PT for these nodules leads to a complete necrotic rate of 29 to 70% [START_REF] Livraghi | Hepatocellular carcinoma: radio-frequency ablation of medium and large lesions[END_REF] . This population of HCC, in case of the absence of accessibility to a surgical treatment, benefits from non-curative treatment by transcatheter arterial chemotherapy infusion with or without embolization (TAC).

Preliminary studies suggest that the association of TAC with PT leads to better overall survival and recurrence-free survival [START_REF] Chevallier | Treatment of hepatocellular carcinomas by thermal ablation and hepatic transarterial chemoembolization[END_REF] . The combination in a single session has been introduced as a method to increase the size of the ablative zone because TAC can decrease perfusionmediated heat loss during RFA [START_REF] Sugimori | Radiofrequency ablation in a pig liver model: effect of transcatheter arterial embolization on coagulation diameter and histologic characteristics[END_REF] if TAC is performed first. If PT is performed first a physiologic hyperhemia rim created around the hyperthermia zone increases the effect of the TAC by leading an accumulation of drug and embolic material within this rim. Furthermore, the association of a TAC can treat satellites micronodules which can be far away the primitive tumor. This method has been studied mainly in Asian populations. It has been shown to be effective for HCCs greater than 50 mm [START_REF] Yuan | Angio-CT-Guided Transarterial Chemoembolization Immediately in Combination with Radiofrequency Ablation for Large Hepatocellular Carcinoma[END_REF] and for HCCs less than 30 mm infeasible for ultrasound-guided RFA [START_REF] Hyun | Combined transarterial chemoembolization and radiofrequency ablation for small treatment-naïve hepatocellular carcinoma infeasible for ultrasound-guided radiofrequency ablation: long-term outcomes[END_REF] .

The objective of our study was to evaluate the efficacy and safety of TAC and PT performed in a single session for a European population with treatment-naïve HCC between 30 and 50 mm or oligo-nodular up to 30 mm compared to uninodular HCC up to 30 mm without any poor prognostic criteria treated with PT alone.

PATIENTS AND METHODS

Selection of patients

This was a retrospective cohort study based on information collected prospectively from the medical records at the University Hospital of Nice, France. Between January 2009 and December 2014, we identified patients with histologically proven HCC who received, in firstline treatment, a combination of TAC and PT in a single session. Among them, we selected those with one nodule between 30 and 50 mm or 2 to 3 nodules up to 30 mm for the "PT+TAC group". Patients with a discordant arteriography and extra-hepatic metastasis were excluded.

A "control" group of uninodular HCCs up to 30 mm without any poor prognostic criteria (infiltrating character, satellite micronodules, endoportal tumor extension) was identified and treated by PT alone. For the "PT group" patients with histologically proven HCC who received PT in first-line treatment and without extra-hepatic metastasis were selected. The study complied with the provisions of the Declaration of Helsinki and was approved by the Ethics Committee of our institution (Authorization reference no. 319).

Methods

All procedures were performed under general anesthesia under conditions of surgical asepsis.

For the PT+TAC group, pre-ultrasound and arteriography were performed, followed by PT and TAC in a single session.

PT procedure: A radiofrequency (Boston scientific) or microwave (Amica) needle was deployed percutaneously under sonographic guidance. Several applications were carried out if necessary (mean of 1.8 applications).

TAC procedure: TAC was performed immediately after PT in the same session. A 4-French introducer was inserted in the femoral artery using the Seldinger technique. A coeliomesenteric arteriography was performed to investigate the site and size of the HCCs and to confirm patency of the portal vein. A selective or hyper-selective catheterization of a branch of the hepatic artery was then followed by injection of a solution of chemotherapy (1mg/kg doxorubicine or adriamycin) mixed with 10 ml of iodized oil (Lipiodol ultrafluide, Guerbet, France), with or without a complementary embolization (embozenes 250 μ, Boston scientific).

The selectivity of the TAC was chosen during the procedure on the basis of the tumoral burden.

The technical goal was to obtain blood stasis in the treated liver for 3 to 5 heart beats during the final arteriography.

Assessment and follow-up

The primary endpoint was the cumulative overall survival (OS) rate from initial treatment until the last follow-up or death. The secondary endpoints were the relapse free survival (RFS) rate from initial treatment until first relapse or death, and complications as described in the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. We also assessed the technical feasibility and therapeutic response on the first follow-up imagery.

Computed tomography or magnetic resonance imaging of the liver was performed in a mean of 5.2 weeks after the therapeutic session. The morphological follow-up was left to the discretion of the practitioners, but usually every 3 to 4 months the first year and every 6 months thereafter. In case of tumoral recurrence, the most appropriate therapy was given according to clinical guidelines.

Statistical analysis

Distribution of continuous and categorical variables were summarized as mean (standard deviation) or median values (min and max), and frequencies (percentage), respectively.

Medians and proportions were compared using the Wilcoxon test and χ2 test (or Fisher's exact test, if appropriate), respectively. OS and RFS curves were estimated with the Kaplan-Meier method and compared between the PT and PT+TAC groups using the log-rank test. Cox proportional hazard models were performed to estimate the hazard ratio (HR) and the 95% confidence interval (IC95) for factors associated with OS or RFS. The association of parameters with OS or RFS was first assessed using univariate Cox analyses and then those with p < 0.1 were entered into a final multivariable Cox regression model including the treatment group. The collinearity between variables entered into the model was evaluated using the 'r' Pearson correlation coefficient. If r > 0.40, one of the two variables was considered as redundant and was removed from the model. Finally, a stepwise selection was performed, forcing the treatment group variable in the final model. Complications were assessed in both groups and compared using the χ 2 test or Fisher's exact test, if appropriate. All analyses were performed using R version 3.5.1. Values of p < 0.05 were considered statistically significant and all tests were two-sided.

RESULTS

Among the 151 patients who received a combination of TAC and PT in a single session in the period considered, 61 had previous treatment for HCC (surgery, transplantation, TAC, PT or systemic chemotherapy), 40 had nodules outside the size criteria, 11 did not have HCCs, 5 had no histological evidence, 3 had a discordant arteriography and 1 was metastatic. Finally, patients who received PT alone in the period considered, 94 had a HCC without any prior treatment. Among them, 41 had nodules outside the size criteria, 12 had no histological evidence, 6 had poor prognostic criteria (4 had endoportal tumor extension and 2 had satellite micronodules) and 1 was metastatic. Finally, 34 consecutive patients were included in the PT group (Figure 1b).

Baseline characteristics

There was no significant difference between the mean age in both groups: 65.1 years vs 66.2 years, respectively for the PT+TAC and PT groups (p=0.724), nor in the sex ratio (p=0.381), see Table 1. The histological differentiation was similar in both groups: HCC was welldifferentiated for 53.3% vs 55.9%, respectively (p=1). Ninety percent of the population was cirrhotic without a significant difference between the two groups (p=1), and 63.0% and 64.5%, respectively were Child-Pugh A5 (p=1). Eighty percent of the population had a Performans Status (PS) score of 0, without a significant difference between the two groups (p=1). There was no significant difference in etiology between the two groups: alcoholic for 40.0% vs 50.0%, respectively (p=0.582), hepatitis C virus for 70.0% vs 47.1%, respectively (p=0.109), hepatitis B virus for 3.3% vs 11.8%, respectively (p=0.431), and non-alcoholic steatohepatitis for 6.7% vs 8.8%, respectively (p=1). Portal hypertension, endoscopically or imaging highlighted, was significantly less present in the PT+TAC group (46.7%) vs the PT group (76.5%, p=0.028).

There was no significant difference between the two groups for the median alpha-foetoprotein level: 15.0 vs 9.3 μg/l, respectively in the PT+TAC vs PT group (p=0.393). There was no significant difference between the two groups for the patient's major comorbidity (p=0.471).

Major comorbidities were principally other neoplasia or cardiopulmonary conditions, which precluded surgical management.

In the PT+TAC group, the thermoablation was performed by RFA for 66.7% and by microwave ablation (MWA) for 33.3%. In the PT group, the distribution was equal in the two groups (p=0.274). There was no difference in the proportion of patients transplanted in both groups: 20% in the PT+TAC group vs 12% in the PT group (p=0.58).

Relapse free survival

The 1-, 3-, and 5-year RFS was 59.3%, 18.5% and 5.6% in the PT+TAC group, which was significantly lower than in the PT group: 89.3%, 46.4% and 24.5% (p=0.02, Figure 3). In a univariate analysis, the only factor with a negative impact on the RFS was the PT+TAC treatment (HR = 1.9; IC95: [1.1 to 3.4]; p=0.023), see Table 3. In a multivariate analysis, this result was not significant (Table 3).

There was significantly more uninodular relapse in the PT+TAC group than in the PT group: 66% vs 50% respectively (p=0.029), see Table 4. The maximal tumor size on relapse was significantly identical in both groups: mean of 22.4 mm vs 18.6 mm, respectively in the PT+TAC and PT group (p=0.467).

Patients of the PT+TAC group were significantly more re-treated than in the PT group (Table 5). One and 3 years after initial treatment 56.7% and 63.3% of the PT+TAC group was treated again, vs 14.7% and 32.3 of the PT group (p=0.003 and p=0.001, respectively). There was no significant difference at 5 years. There is not significant difference on overall survival between the two groups.

DISCUSSION

The association of TAC with PT in a single session for treatment of uninodular HCCs between 30 to 50 mm and oligonodular HCCs (up to 3 nodules, up to 30 mm) seems to catch up to the OS of uninodular HCCs less than 30 mm treated by PT alone. The 1-, 3-, and 5-year OS in the studied group was 100%, 82% and 48.5% vs 94.1%, 72.7% and 65.2% in the PT group (p=0.88). However, these more advanced HCCs recurred faster and required more treatment sessions. The 1-, 3-, and 5-year RFS in the studied group was 59.3%, 18.5% and 5.6% vs 89.3%, 46.4% and 24.5% in the PT group (p=0.02). Fifty-seven percent of patients was treated again one year after the initial treatment versus fifteen percent in the PT group (p=0.003).

There was no significant difference in the grade 3 complication rate between the two groups.

To our knowledge there are only a few articles evaluating TAC following PT in a single session, and our study is the first to be done on a Western population.

More and more resources are being deployed to widen the range of curative treatments for where the delay between the two treatments was 1 week [START_REF] Okamoto | Efficacy of combination therapy with transcatheter arterial chemoembolization and radiofrequency ablation for intermediate-stage hepatocellular carcinoma. ILC 2019, Abstract FRI-493[END_REF] . The 1-, 3-, and 5-year OS in the combination treatment group was 97%, 70% and 60%, significantly higher than in TAC alone group. The association of TAC with PT in a single session has been very little studied. Saviano A. et al. compared this association in a single session for treatment of single HCC ≥ 30 mm (range 30-68 mm) versus liver resection [START_REF] Saviano | Liver resection versus radiofrequency ablation plus trancatheter arterial chemoembolization in cirrhotic patients with solitary large hepatocellular carcinoma[END_REF] . The 1-and 3-year OS in the TAC+PT group was 89.4% and 48.2%, which was lower than the OS in our study. However, the HCC was not "naïve-treatment" and many HCC were larger than in our study. There was no significant 3year OS difference between TAC+PT and liver resection. Huyn D. et al. tested the combination TAC+PT in a single time on HCC < 30 mm infeasible for ultrasound-guided RFA [START_REF] Hyun | Combined transarterial chemoembolization and radiofrequency ablation for small treatment-naïve hepatocellular carcinoma infeasible for ultrasound-guided radiofrequency ablation: long-term outcomes[END_REF] . The 1-and 3-year OS in the TAC+PT group was 100% and 89%, as for our results (100% and 82%)

although the HCC of our studied group were larger. Finally, Yuan H. et al. compared the combination treatment in a single session for HCC ≥ 50 mm versus sequential treatment of TAC and RFA (RFA at 2-4 weeks after TAC). The 1-and 3-year OS of the combination treatment group was 95.8% and 58.3% vs 83.3% and 43.8% for the sequential group. The difference was significant at 1 year (p=0.045) but not at 3 years (p=0.153). Our work was designed to evaluate the association of TAC with PT in a single session for HCC of intermediate size, a size lying between that of the two above studies. We chose the size criteria according to the "Milan criteria", the benchmark for the selection of patients with HCC for liver transplantation. In the case of a long-anticipated waiting time, patients may be offered treatment to minimize the risk of tumor progression. The association of TAC with PT could be proposed to offer a "bridge" to transplantation. To obtain the purest possible results, we decided to include only treatment-naïve patients with histologically proven HCC, and concordant arteriography.

Early stage HCC patients can be complex to manage. All guidelines recommend a liver transplantation for HCC according to Milan criteria [START_REF] Blanc | Carcinome hépatocellulaire[END_REF][START_REF] Study | EASL clinical practice guidelines: management of hepatocellular carcinoma[END_REF][START_REF] Heimbach | AASLD guidelines for the treatment of hepatocellular carcinoma[END_REF][START_REF] Vogel | Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[END_REF] . There is interest in a "bridging treatment", but the modality of this treatment is not clear. Liver resection, PT or TAC are proposed in turn, favoring resection for large single HCC. But few HCC are candidates for liver resection due to portal hypertension or major comorbidity. In addition, single HCC between 30 to 50 mm or oligonodular HCC up to 30 mm may be treated by TAC, which is a palliative treatment. Most guidelines mention the association of TAC with PT especially for these nodules, reporting that further studies are needed [START_REF] Blanc | Carcinome hépatocellulaire[END_REF][START_REF] Study | EASL clinical practice guidelines: management of hepatocellular carcinoma[END_REF][START_REF] Heimbach | AASLD guidelines for the treatment of hepatocellular carcinoma[END_REF] . Likewise, new ablation techniques are mentioned, including multipolar RFA and irreversible electroporation. So, the current challenge is to better treat HCCs that are borderlines between BCLC-A and BCLC-B. Multipolar RFA, cryoablation and irreversible electroporation are performed by only a few expert centers.

Potential interest in association of TAC with PT lies in the availability of these techniques in most centers. Our study shows the usefulness of this association for selected HCCs. It should be noted that all of our patients had major comorbidities and/or portal hypertension, so they were rejected for resection. Moreover, only 20% of patients in the studied group (in Milan criteria) were finally transplanted within the considered period. An increase in this proportion would have probably increased the OS.

The main weakness of our study is the relatively small size of our population, but the results are encouraging and require confirmation in larger cohorts. Moreover, this study is retrospective and done according a non-randomized schema. However, an objective strong primary endpoint, the OS and strict inclusion criteria were obtained. The strengths of our study include the pilot character of the association that has never been studied in a Western population, the long follow-up (up to 5 years) and the rigorous inclusion criteria (histologically proven, naïve-treatment, arteriography concordant).

To conclude, the association of TAC with PT in a single session for treatment of HCC according to Milan criteria is an interesting solution in the current state of knowledge. The OS for this association was equal to unique HCC up to 30 mm treated by PT alone. However, the occurrence of relapse was more frequent, requiring more intensive monitoring and treatment.

These results need to be confirmed in randomized clinical trials. It might be interesting to compare this association with other radiological techniques currently evaluated. Finally, it may be interesting to evaluate the impact of this association on the time to relapse after liver transplantation to validate this treatment as "bridging therapy".

Figure 2 :

 2 Figure 2: Kaplan-Meier curves of overall survival comparing PT+TAC group and PT group

Figure 3 :

 3 Figure 3: Kaplan-Meier curves of relapse free survival comparing PT+TAC group and PT group

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	PROFESSEUR DES UNIVERSITÉS	REMERCIEMENTS
	M.	AMBROSETTI Damien HOFLIGER Philippe	Cytologie et Histologie (42.02) Médecine Générale (53.03) Aux Membres du Jury,
	M. A monsieur le Professeur Thierry PICHE, BENOLIEL José	Biophysique et Médecine Nucléaire (43.01)
	Mme MAITRE DE CONFÉRENCES DES UNIVERSITÉS BERNARD-POMIER Ghislaine Immunologie (47.03)
	M.	BRONSARD Nicolas		Anatomie Chirurgie Orthopédique et Traumatologique (42.01)
	Mme M.	BUREL-VANDENBOS Fanny DARMON David	Anatomie et Cytologie pathologiques (42.03) Médecine Générale (53.03)
	M.	DOGLIO Alain		Bactériologie-Virologie (45.01)
	M PROFESSEURS AGRÉGÉS DOYEN Jérôme		Radiothérapie (47.02)
	M	FAVRE Guillaume		Néphrologie (52.03)
	M. Mme LANDI Rebecca FOSSE Thierry		Bactériologie-Virologie-Hygiène (45.01) Anglais
	M.	GARRAFFO Rodolphe		Pharmacologie Fondamentale (48.03)
	Mme	HINAULT Charlotte		Biochimie et biologie moléculaire (44.01)
	M. Mme PRATICIEN HOSPITALIER UNIVERSITAIRE HUMBERT Olivier LAMY Brigitte	Biophysique et Médecine Nucléaire (43.01) Bactérilogie-virologie (45.01)
	Mme M.	LONG-MIRA Elodie DURAND Matthieu		Cytologie et Histologie (42.02) Urologie (52.04)
	Mme	MAGNIÉ Marie-Noëlle		Physiologie (44.02)
	Mme	MOCERI Pamela		Cardiologie (51.02)
	M. PROFESSEURS ASSOCIÉS MONTAUDIE Henri		Dermatologie (50.03)
	Mme	MUSSO-LASSALLE Sandra	Anatomie et Cytologie pathologiques (42.03)
	M. M.	NAÏMI Mourad GARDON Gilles		Biochimie et Biologie moléculaire (44.01) Médecine Générale (53.03)
	Mme Mme MONNIER Brigitte POMARES Christelle		Parasitologie et mycologie (45.02) Médecine Générale (53.03)
	M.	SAVOLDELLI Charles		Chirurgie maxillo-faciale et stomatologie (55.03)
	Mme MAITRES DE CONFÉRENCES ASSOCIÉS SEITZ-POLSKI barbara	Immunologie (47.03)
	M.	TESTA Jean		Épidémiologie Économie de la Santé et Prévention (46.01)
	M. Mme CASTA Céline TOULON Pierre		Hématologie et Transfusion (47.01) Médecine Générale (53.03)
	M.	GASPERINI Fabrice		Médecine Générale (53.03)
	M.	HOGU Nicolas		Médecine Générale (53.03)

monsieur le Professeur Jean-Claude TRINCHET, Merci

  Ton dévouement fait de toi un modèle. Je te remercie pour ton soutien indéfectible et ta disponibilité. Merci d'avoir été à mes côtés ces quatre dernières années et d'avoir respecté mes volontés. Merci pour les longues heures de discussion parfois à des horaires pas possibles. Je ne trouve pas les mots pour exprimer tout ce que je te dois. Merci infiniment.Merci de nous pousser dans nos retranchements afin de nous mener toujours plus haut. Merci de nous enseigner l'esprit de synthèse et de précision. J'admire votre façon de gérer les équipes avec pragmatisme, tel un entrepreneur. Merci de m'avoir accueilli dans le service avec bienveillance et de continuer à me transmettre vos compétences en Hépatologie.Je n'ai pas eu la chance de faire un semestre complet à l'USN, cependant tu m'as énormément appris. Merci d'avoir réussi à débloquer ce fameux 3 e poste d'interne qui m'a permis d'accéder à la si belle ville de Nice. En plus d'être un maître en nutrition, tu as des connaissances sur de nombreux sujets, que tu sais nous enseigner avec une pointe d'humour toujours bien dosée. Sois assuré de tout mon respect. Kamel, Kamel, Kamel… Tu m'as toujours fait confiance et m'as énormément appris (que ce soit GPE, endoscopie ou des blagues un peu douteuses). Tu m'as permis de passer des heures en salle d'endoscopie et toujours dans la bonne humeur. Ta gentillesse est légendaire et digne du respect de tous. Merci pour tous tes conseils sur la vie en général. Tu es pour moi bien plus qu'un chef.A Eve GELSI et Cécile GOMERCIC, j'ai énormément apprécié mon passage aux SMC. Eve, merci pour ta rigueur, ta franchise et pour les urgences endoscopiques toujours improbables que l'on rencontre quand tu es d'astreinte. Cécile, merci de ta patience qui permet à chaque interne d'apprendre à poser une voie centrale (même si je ne suis pas ta plus grande réussite...). Et merci pour tes qualités humaines. Merci à vous deux de nous faire partager vos compétences cliniques et endoscopiques.A Régine TRUCHI, pour ta gentillesse et ton engagement auprès des patients. Tu es un exemple de volonté et tu parviens à faire de grandes choses par ton implication, dans toutes les unités où tu exerces. Je suis heureux que l'on puisse travailler ensemble davantage.

	A mes Aînés,
	A monsieur le Professeur Albert TRAN,
	A monsieur le Professeur Stéphane SCHNEIDER,
	A Nadia ARAB, de répondre à toutes mes questions sur les MICI et les protocoles. Tu
	cherches toujours à aider les patients peu importe les problèmes, ton empathie est exemplaire.
	A Franck SOUSSI, merci de m'avoir reçu en consultation à plusieurs reprises et de m'avoir
	fait partager tes connaissances et ta bonne humeur.
	A Daniel BIANCHI, merci d'être aussi proche des internes et de toujours nous soutenir à fond
	(notamment au GastroQuizz !). Merci de nous faire confiance en endoscopie et de prendre le
	temps de discuter avec chacun de nous.
	A Laurianne DE GALLEANI, de m'avoir accueilli dans ton bloc pour m'apprendre l'utilisation
	des traitements instrumentaux en proctologie.
	A Dov BELHASSEN, de m'avoir permis d'assister à mes premières endoscopies et de m'avoir
	aiguillé sur la spécialité que j'aime tant aujourd'hui.
	A Eva AFFLALO, je devrais dire « Docteur Afflalo ». Plus qu'un pédiatre ou un médecin
	traitant, vous avez été un exemple pour moi. Je vous idéalise depuis toujours. Votre relation
	aux patients est la raison qui m'a donné envie de faire médecine. Votre façon de pratiquer la
	médecine donne un sens à chaque mot du serment d'Hippocrate. Votre contribution dans ma
	vie est majeure.
	A Chrystelle TREZIERE, mes quelques mois de stage avec vous m'ont fait découvrir une
	médecine générale de qualité.
	A l'

A monsieur le Professeur Geoffroy VANBIERVLIET,

Merci pour le temps passé ensemble en endoscopie. Merci pour ta droiture qui nous pousse à toujours tirer le meilleur de nous-même, tout en nous faisant confiance. Merci pour ton implication dans l'enseignement et milles mercis de m'avoir permis de participer aux universités d'endoscopie. Sois assuré de toute ma reconnaissance.

A monsieur le Professeur Robert BENAMOUZIG,

Merci pour votre gentillesse. Merci d'avoir pris le temps à plusieurs reprises de m'aiguiller dans les choix qui m'ont finalement mené où je suis aujourd'hui. Soyez assuré de toute ma gratitude.

A monsieur le Professeur Frédéric ADNET,

Merci de m'avoir accueilli dans votre service où j'ai tant appris.

A de m'avoir enseigné mes premières notions d'Hépatologie. Votre souvenir restera un monument dans la discipline.

A Jérôme FILIPPI et Ophélie ANTUNES, de m'avoir guidé dans mes premiers pas d'interne de gastroentérologie et en endoscopie.

A Anne-Claire FRIN et Delphine OUVRIER, de m'avoir fait fumer passivement tous les matins avant la visite. Plus sérieusement, merci de votre bonne humeur qui a rendu agréable mon stage en cancérologie.

A Marie-Lise MONTOYA, ma maman du CHU. Je t'ai appréciée au-delà de notre relation professionnelle. Tu es une personne exceptionnellement humaine, et les patients le ressentent (les seuls que j'ai vus attendre 3 mois de délai avant la consultation juste pour te dire merci !). Merci pour tes petites attentions au retour de voyage. J'espère que ta retraite dans les îles sera aussi belle que ta carrière.

A Kamel ARAB,

A Julie BENARD-LAME, pour ta sympathie et ton efficacité dans le service.

équipe de Médecine Nucléaire de l'Archet : Micheline RAZZOUK, Philippe VIAU, Guillaume NIVAGGIONI, de

	m'avoir accueilli et présenté votre spécialité (les scanners avec
	les couleurs...).
	A l'

équipe des Urgences d'Avicenne : Birol, Charlotte, Hayatte, Lilia, Louis-Etienne, Lydia, Maguy, Paul-Georges, Pranesh, Roxana, Sabine, Sheila, et les autres … A mes co-internes, A Clémence CANIVET, d

  'avoir été mon exemple en tant qu'interne. J'espère pouvoir assurer autant que tu ne l'as fait dans le service. Merci pour tout ce que tu m'as appris.

	A Léa LOMBARDI, merci pour tous tes conseils bébé.
	A Thibaut DELASALLE, notre semestre ensemble en cancérologie a été une incroyable
	rencontre humaine. J'espère que notre route se recroisera rapidement.
	A Grégoire BESSI, d'avoir pris le temps de me présenter le service quand j'étais en stage à
	l'Archet 1.
	A Audrey HASTIER-DE CHELLES, pour ta gentillesse, ta solidarité et ta force d'organisation
	qui font de toi un excellent médecin et une personne formidable.
	A Clément FORTIER-BEAULIEU, pour ton sérieux et tes conseils avisés en endoscopie.
	A Edouard LARREY et Maude DESCHAMPS DE BOISHEBERT, j'ai adoré faire équipe avec
	vous. Entre les crises existentielles de Maude et la zen-attitude d'Edouard, on a quand même
	passé quatre belles années ensemble. J'espère qu'on ne se perdra pas de vu.
	A Juliette LAVEISSIERE, avec qui j'ai été le plus souvent binôme. Ça a été un plaisir. Ton
	dynamisme et ta force de caractère sont capables de te mener très loin.
	A Adrien NICOLAU, qui est toujours de bonne humeur. Tu apportes une stabilité à l'équipe
	tout en envoyant des punchlines assassines.

A Morgane SALLETTE, Léa MARIE, et Marie DE MATHAREL, bon

	courage pour la suite de
	votre internat dans notre belle spécialité.
	A mes co-internes non gastro : Marion (the first-one), Théo, Margaux, Angélique, Perrine,
	Wulfran, Imane et Al-Aydin.

A mes co-internes des urgences d'Avicenne : Sujeewa et

	Yasmine (quel trio
	mémorable !!!), Sylvie, Morgane, Cecilia et Rhyzlene.
	Aux autres spécialités,
	Aux Anesthésistes Réanimateurs : Rémi, Mathilde, Romain, Olivier, Andrea, et tous les
	autres, de nous sauver chaque nuit quand ça part en vrille dans les services et d'avoir la
	patience de nous assister en endoscopie.
	Aux Chirurgiens : Pr IANNELLI pour ta confiance et ta bonne humeur, Pr GUGENHEIM, Pr
	BENIZRI, Dr RAHILI, Manuela, Alexandre, Clémentine, Lionel, Benjamin, et tous les autres.

A Magalie HAMM-ORLOWSKI et Dr CHERIKH, pour

  votre gentillesse et votre patience.

	Aux radiologues : Julien, Madleen, Fabrice et Dr TRAN, pour le temps que vous nous
	accordez.

Aux équipes soignantes, Du 4°B : Alexia

  , Arielle, Asma, Aude, Carole, Céline, Franck, Julie, Maeva, Paolo, Rémi, Roukia, Stéphanie, … ceux et celles qui me connaissent depuis le plus longtemps. Aurélie, Blandine, Claire, Eva, Gelissa, Ingrid, Jenny, Jocelyne, Johanna, Laurence, Lorène, Marylou, Maud, Nolwenn, Romane, Safia, Sandrine, Sandy, Sophie, Tiffany … d'avoir réalisé mon dernier jour de stage le plus mémorable.

D'Hépatologie : Alain, Anaïs, Audrey, Cécile et ses tortues, Gourette, Juliette, Laurence, Madely, Magalie, Marie, Marilyne, Martine, Nadège, Olivier, Ridha, Sabino, Sandrine, Vanessa, Véronique G, Véronique L (la faucheuse), …, pour l'équipe formidable que vous formez, toujours motivée pour améliorer les choses.

A Marie-Pierre GILLY, pour ton travail et ton implication extraordinaire.

De Cancérologie :

De l'HDS : Audrey, Brigeou, Cyrielle, Isabelle, Laure, Lucilia, Marie, Marlène, Sylvie, pour l'incroyable bonne humeur qui règne dans le service.

De l'EFD : l'infatigable

Paupau et Marie-Hélène. Du SMC : Carine, Céline, Claude, Elisabeth et ses éventails designs, Éric, Fafa, Floriane, Juju, Jocelyne qui est bien plus jeune que mon père, Laurent, Océ, Olivier, Sarah, Stéph, Valentina, Valérie, Véro, Séverine, … seulement 4 mois de stage mais des relations fortes créés avec chacun d'entre vous. De l'USN : Christine, Claire, Eva, Jessica, Najouah, Nathalie pour ton implication exemplaire, Laura, Nadège, Rabeb, Sab, … De l'Endoscopie : Alexandra, Bernard, Emilie, Elodie, Franck, Jean-Pierre, Georgiana, Gérard, Jean-Yves, Marc, Marion, Mathilde, Micka, Stefania,… De l'HDJ : Alicia, Christophe, Éric, Isabelle, Jean, Marie-Pierre, Noëlle, Siam … Du Pôle : Emmanuelle, Elise, Céline, … pour le travail formidable que vous effectuez. Du CSAPA : Cécile et Nathalie pour l'ambiance, les compétences et l'implication. De l'URC : Aaron, Hélène, Jessica, Joris, Virginie Des services de chirurgie De Médecine Nucléaire et des Urgences d'Avicenne Aux secrétaires, Annie, Brigitte, Céline, Christine, Chrystelle, Colette, Corinne, Diane, Dominique, Florence, Graziella, Laetitia, Megan, Roselyne, Sandrine, Sylvie, Virginie, … d'avoir passé de longues heures à écouter ma douce voix qui ne parle pas du tout trop vite. Aux diététiciennes, Delphine, Evelyne, Isabelle, Katia et Mégane. Aux assistantes sociales, Johanna et Marina.

Aux cadres infirmiers, Chrystelle, Elodie, Eya, Jean-Jacques, Khanika, Magalie, Marcelle, Nathalie, Séverine, Victor, mais aussi aux cadres secrétaires Mme Liberatore et Mme Noble.

Un remerciement tout particulier

aux équipes de nuit… A ma famille, A mes parents Patrick et Sonia, de

  m'avoir transmis les bases qui m'ont permis d'évoluer dans la vie. Merci d'avoir cru en moi et de m'avoir transmis la valeur de la famille et de l'effort. Papa, tu es mon exemple de courage et de persévérance. Maman, tu m'as soutenu, poussée et même tenu par la main pendant ma scolarité (et même pendant la p1). Je vous aime. mon bébé qui est maintenant un homme, chaque moment passé avec toi me remplit de bonheur. Tu me manques énormément. Je suis tellement fier de toi. mon frère d'adoption. Merci pour ton aide constante, tes conseils avisés et nos conversations nocturnes du vendredi soir jusqu'à pas d'heures. de nous recevoir à chaque voyage à Paris. Merci pour toutes nos rigolades et toutes les pizzas partagées. A mes neveux Lok d'amour.Voilà maintenant plus de dix ans que l'on se tient la main… ces quelques mots ne suffiront donc jamais à exprimer les remerciements que je te dois et l'amour que je te porte. Nous sommes tellement complices que je pourrais te faire rentrer dans quasiment toutes les cases de ces remerciements : bien sûr la famille, mais aussi les collègues, et encore plus les amis. Toi, ma moitié, avec qui dix ans après, je ne me lasse pas de rester à discuter pendant des heures comme si on ne s'était pas vu pendant des mois. Notre relation est volcanique, un bouillonnement d'émotions qui mélange l'amour, l'amitié, le respect, la franchise et des valeurs communes. Tu as contribué à tout ce que j'ai touché ces dix dernières années, tu m'as aidé dès la première année de médecine puis tu as continué jour après jour à m'encourager, m'entraîner, me pousser toujours plus haut. Pendant l'externat tu as appris chaque mot, chaque cours, chaque mnémotechnique avec moi parfois jusqu'à des horaires pas possibles.Tu n'es pas encore mais nous t'attendons avec impatience. Nous pensons à toi chaque jour (surtout ta mère quand tu tapes dans sa vessie) et t'aimons déjà très fort. La thermoablation percutanée (TAP) pour les patients porteurs de carcinomes hépatocellulaires (CHC) oligonodulaires ou uninodulaires entre 30 et 50 mm peut être insuffisante. Son association synchrone à un traitement endoartériel (TE) lipiodolé avec ou sans embolisation complémentaire a été proposée pour potentialiser son efficacité. Le but de cette étude était d'évaluer l'efficacité et la tolérance d'un traitement combiné par TAP et TE réalisé en une seule séance pour des patients porteurs de CHC dans les critères de Milan.Patients et Méthodes : Analyse rétrospective monocentrique d'un groupe de 30 patients consécutifs ayant eu un premier traitement combiné entre janvier 2009 et décembre 2014 pour un CHC histologiquement prouvé, uninodulaire, entre 30 et 50 mm ou oligonodulaire (n ≤ 3) de moins de 30 mm (« groupe TAP+TE »). Un groupe témoin était constitué de 34 patients consécutifs avec un CHC uninodulaire de moins de 30 mm sans aucun critère de mauvais pronostic en imagerie (caractère infiltrant, micronodules satellites, extension tumorale endoportale) traités par TAP seule (« groupe TAP »). L'objectif principal était l'étude de la survie globale (SG).Conclusion : L'association d'un traitement TAP+TE, chez des patients ayant un CHC entre 30 et 50 mm ou oligonodulaires (n ≤ 3) de moins de 30 mm, permettrait d'avoir une survie globale similaire à celle de patients ayant un CHC uninodulaire de moins de 30 mm sans critère de mauvais pronostic traités par TAP, sans plus de complications mais avec une récidive tumorale plus précoce.

	A mon noyau familial, Endoarterial treatment in combination with percutaneous thermoablation
	A Dorine, for medium-sized and oligonodular hepatocellular carcinomas
	Dann Joseph Ouizeman 1 , Antoine Falcoz 2 , Emmanuel Chamorey 2 , Yann Chateau 2 , Jocelyn
	Gal 2 , Edouard Larrey 1 , Thierry Piche 1,3 , Albert Tran 1,3,4 , Patrick Chevallier 3,5 , Rodolphe Anty 1,3,4
	A tata Clémence et tonton Daniel (tu ne pourras pas y échapper), de nous avoir reçus chez 1. University Hospital of Nice, Digestive Center, Nice, France
	vous sans oublier que vous étiez chez nous. Merci pour tout et merci encore d'embellir notre
	vie niçoise. Merci aussi à Amiel, Daphné, Youval, Batsheva, David, Eyal, sans oublier mon 2. Centre Antoine Lacassagne, Department of Epidemiology and Biostatistics, Nice, France
	cousin Robert et Jeannine. 3. University Côte d'Azur, Faculty of Medicine, Nice, France
	4. National Institute of Health and Medical Research (INSERM), U1065, C3M, Team 8 « Chronic
	liver diseases associated with obesity and alcohol », Nice, France
	Aucun échec de procédure n'a été observé. Une réponse complète était observée en
	imagerie dans 93 % vs 97 % respectivement dans les groupes TAP+TE vs TAP (p = 0,91).
	La SG à 1, 3 et 5 ans était significativement identique dans les 2 groupes : 100 %, 82 % et
	48,5 % dans le groupe TAP+TE et 94,1 %, 72,7 % et 65,2 % dans le groupe TAP (p = 0,88).
	La survie sans récidive à 1, 3 et 5 ans était significativement plus basse dans le groupe
	TAP+TE : 59,3 %, 18,5 % et 5,6 %, contre 89,3 %, 46,4 % et 24,5 % dans le groupe TAP (p
	= 0,02). Des complications sont survenues chez respectivement 27 % et 15 % des patients
	(p = 0,38) dans les groupes TAP+TE et TAP, majoritairement des douleurs grade I/II (13 %
	et 9 %, p = 0,75), et uniquement 2 complications grade III dans chaque groupe (p = 0,47). Il
	n'y avait pas de différence sur la proportion de patients transplantés dans les 2 groupes (20
	% vs 12 %, p = 0,58).
	A mes beaux-parents Jean-Jacques et Nicole, d'être aussi extraordinaires, on ne pourrait
	rêver meilleurs beaux-parents. Votre abnégation force l'exemple. Merci pour votre soutien
	permanent. Soyez assurés de tout mon respect et ma gratitude.

A David, pour tous les bons moments partagés pendant notre enfance. Merci à Julia et toi pour mon neveu à venir.

A Keren, pour tes petits plats attentionnés et tes gratouilles dans le dos. Je te souhaite une carrière pleine d'épanouissement. A Dov, A Samuel, mon cousin/frère farfelu, merci d'être toi et d'égayer ma vie. Merci pour tes colorations capillaires incroyables et tout le reste. A mes grands-parents Paul et Jacqueline, pour votre soutien inconditionnel et votre présence permanente. Merci pour tous les moments passés ensemble. A mes grands-parents David et Margotte, pour l'amour que vous m'avez transmis et d'avoir grandement contribué à mon éducation. A Franck, pour ta bonne humeur, tes blagues incroyables et tes multiples attentions. A Carole, de m'avoir considéré comme un fils. A Jacky, mon deuxième père, tu as toujours été présent dans les bons et les mauvais moments. Tu me manques au quotidien. Merci de nous avoir amené Mélisa qui a exactement les mêmes qualités que toi. A Didier et Schelly, pour votre gentillesse et votre générosité. A Avi et Corinne, pour nos discussions interminables. Merci d'être présent et de nous faire partager de super moments. Au-delà des mathématiques, je vous dois une bonne partie de ma culture générale. A Franck et Linda, d'être toujours là pour nous. A Jennifer, Mickael, Kevin, Samuel, Kevin, Sacha, Ilona, Julien, Shana, Gabou, Nathan, Nina, David, Shanaelle, Léane et Lola A ceux qui nous ont quittés et qui nous manquent tant. A la famille Bensimon, et mes plus vieux neveux pour ces merveilleux moments passés au Canada. A Michael, A madame le Docteur Audrey Sultan, soyez assuré de tout mon respect. A Maxime et Audrey, A Claude et Audrey Micallef, de nous avoir reçu comme leur famille. A mes amis, A mes amis de longue date : Mélanie et Isaac, Keren, Cynthia, Déborah, Yohann, Benjamin, Laurent, Jonathan et Dana, Michael et Sarah, Johanna et Yohan R, Johanna et Yohann D, Johanna et Kevin, Abigaeuuullle, Anaëlle et Ilann... A mes potes de promo : Bob mon duo de sous-colle, Simon, Mike, Aude et Alex, Chimon, Lionel, Elie (pour notre stage fantôme en MPR), Anaïs mon binôme de garde, Sam Co, Idir, Vincent Jerem et Adrien pour les ambiances en stage. A mes amis niçois : Jacob et Manue de nous avoir fait découvrir le reste de la liste, Anthony, Gab et Rachel, Judicael et Judith, Israël et Léa, David et Jordan, Anthony A mes cousins niçois Alex et Ilana, vous formez un couple magnifique. A ceux non encore cités, A la cellule de programmation mais surtout à Yamina, pour ton efficacité. A l'équipe de Biostatistiques du CAL, Antoine, Jocelyn et Yann, pour votre motivation et votre efficacité. Ce travail n'aurait pu exister sans votre aide. A Eugénia MARINE-BARJOAN, qui a pris le temps de m'expliquer les statistiques, de faire et refaire mes analyses.

Aux patients qui rendent notre métier passionnant.

Aux étudiants exigeants de la faculté de Nice qui me poussent à m'améliorer chaque jour. Tu as travaillé pendant mes études pour que l'on puisse se marier et tu as assumé les revenus de la famille. Puis tu as tout quitté, famille, amis et travail, pour me suivre loin de chez nous, afin que je puisse exercer la spécialité que j'avais choisi. Pendant l'internat tu as continué à me motiver malgré les horaires incroyables que je faisais, tu me poussais à aller au bout de ma passion. Tu as partagé mes joies et mes peines comme si c'était les tiennes. Tu t'es occupée de tout ce que j'aurais pu faire pour que je puisse me concentrer sur mon travail. Tu as d'ailleurs aussi contribué à celui que je présente ce soir. Aujourd'hui je pense que tu mérites de recevoir mes remerciements, mais que tu peux également prendre pour toi tous les compliments qui me sont adressés… A Emmy, Ma fille, mon ainée, mon bébé, il est trop tôt pour que tu comprennes ce que je t'écris aujourd'hui, mais tu le liras surement un jour. Merci d'être ma motivation chaque jour. Merci pour l'amour que tu nous portes à ta mère et moi. Nous sommes déjà très fiers de toi alors que tu n'as que trois ans, et j'ai toute confiance pour que tu continues à nous étonner. Tu es et tu resteras ce que j'ai de plus cher dans ma vie. Reste toujours pleine de vie comme tu l'es. Je te promets que ta mère et moi ferons tout pour t'élever afin que tu deviennes une femme épanouie et responsable.

A ma deuxième fille,

RESUME Introduction :

Résultats : La majorité des patients étaient cirrhotiques (90 % vs 91 % respectivement dans les groupes TAP+TE vs TAP), avaient un score Performans Status à 0 (80 % vs 79 %) et une tumeur bien différenciée (53 % vs 56 %). Parmi les patients cirrhotiques la majorité étaient CHILD A (83 % vs 85 %). Les patients du groupe TAP+TE présentaient moins fréquemment une hypertension portale (47 % vs 76 %, p = 0,03). Il n'y avait pas de différence significative du taux médian d'alpha-foeto-protéine entre les 2 groupes (15 vs 9,3 μg/l, p = 0,39). 5. University Hospital of Nice, Department of Diagnostic and Interventional Imaging, Nice, France Word count of main body of manuscript: 3288 Total number of figures and tables: 9 List of abbreviations (in order of appearance): HCC, Hepatocellular carcinoma; PT, Percutaneous thermoablation; RFA, Radiofrequency ablation; TAC, Transarterial chemotherapy; OS, Overall survival; RFS, Relapse free survival; CTCAE, Common Terminology Criteria for Adverse Events; HR, Hazard ratio; IC95, 95% confidence interval; PS, Performans status; MWA, Microwave ablation; DC-BEADS, Drugeluting beads; BCLC, Barcelona Clinic Liver Cancer None of the authors have any commercial association or other conflicts of interest regarding the manuscript. No financial support was received for the study.

Table 1 :

 1 Patient and tumor characteristicsNo procedural failure was identified. Complete response evaluated on the first follow-up imaging was noted in 93% vs 97%, respectively for the PT+TAC and PT groups (p=0.91).

		N †	PT+TAC	%	N †	PT	%	p-value
	Total population	30	100	34	100
	Mean age (SD ‡ ), years		65.1 (13.5)			66.2 (11.5)		0.724
	Sex							0.381
	Male	22	73.3	29	85.3
	Female	8	26.7	5	14.7
	Tumor number							-
	1	21	70.0	34	100
	2	8	26.7	0		0
	3	1	3.3	0		0
	Pejorative factors							-
	Micronodules	9	30.0	0		0
	Infiltrating	4	13.3	0		0
	Portal extension	1	3.3	0		0
	Differentiation							1
	High	16	53.3	19	55.9
	Medium/Low	14	46.7	15	44.1
	Performans Status							1
	0	24	80.0	27	79.4
	1	6	20.0	7	20.6
	Comorbidity	16	53.3	14	41.2	0.471
	Cirrhosis	27	90.0	31	91.2	1
	Child-Pugh grade							1
	A5	17	63.0	20	64.5
	≥ A6	10	37.0	11	35.5
	Etiology
	Alcoholic	12	40.0	17	50.0	0.582
	Hepatitis C virus	21	70.0	16	47.1	0.109
	Hepatitis B virus	1	3.3	4	11.8	0.431
	NASH	2	6.7	3	8.8	1
	Portal hypertension	14	46.7	26	76.5	0.028
	AlphaFoetoProtein, μg/l
	Median [min-max]	15 [2.1-2677.7]	9.3 [1.3-68335.8]	0.393
	≤ 100 > 100	20 5	80.0 20.0	27 4	87.1 12.9	0.724
	Ablation type							0.274
	RFA	20	66.7	17	50.0
	MWA	10	33.3	17	50.0
	† Number of patients, ‡ Standard derivation

Table 2 :

 2 Univariate and multivariate overall survival analysis

	Univariate analysis	Multivariate analysis
	HR †	IC95% ‡	p	HR †	IC95% ‡	p
	Group
	PT	Reference			Reference
	PT+TAC 1.1 0.5-2.4	0.880 0.9	0.4-2.3	0.833
	Age, years
	<70	Reference
	≥70 0.7 0.3-1.6	0.356
	Differentiation
	High	Reference
	Medium/Low 1.1 0.5-2.4	0.896
	Performans Status
	0	Reference			Reference
	1 3.0 1.3-7.1	0.011 4.7 1.8-12.6	0.002
	Comorbidity
	No	Reference
	Yes 1.9 0.9-4.4	0.114
	CHILD score
	A5	Reference			Reference
	≥A6 2.8 1.2-6.4	0.017 3.0	1.2-7.6	0.023
	Portal hypertension
	No	Reference
	Yes 1.9 0.8-4.8	0.170
	AlphaFoetoProtein, μg/l
	≤ 100	Reference
	> 100 1.9 0.6-5.8	0.249
	Ablation type
	RFA	Reference
	MWA 0.8 0.4-1.9	0.648
	† Hazard Ratio, ‡ 95% confidence interval

Table 3 :

 3 Univariate and multivariate relapse free survival analysis

	Univariate analysis	Multivariate analysis
	HR †	IC95% ‡	p	HR †	IC95% ‡	p
	Group
	PT	Reference			Reference
	PT+TAC 1.9 1.1-3.4	0.023 1.5	0.8-2.9	0.185
	Age, years
	<70	Reference
	≥70 0.8 0.5-1.5	0.509
	Differentiation
	High	Reference
	Medium/Low 1.1 0.6-1.9	0.841
	Performans Status
	0	Reference
	1 1.0 0.5-2.1	0.904
	Comorbidity
	No	Reference
	Yes 0.8 0.4-1.4	0.418
	CHILD score
	A5	Reference
	≥A6 1.4 0.8-2.7	0.271
	Portal hypertension
	No	Reference
	Yes 0.9 0.5-1.6	0.673
	AlphaFoetoProtein, μg/l
	≤ 100	Reference
	> 100 1.7 0.8-4.0	0.190
	Ablation type
	RFA	Reference
	MWA 1.0 0.5-1.7	0.854
	† Hazard Ratio, ‡ 95% confidence interval

Table 5 :

 5 Number of treatments after the initial treatment, classed by delay from initial treatment for alive patients

	Delay from initial treatment	N †	PT+TAC	%	N †	PT	%	p-value
	1 year							0.003
	0	13		43.3	27		79.4
	1	11		36.7	3		8.8
	≥2	6		20	2		5.9
	3 years							0.001
	0	2		6.7	12		35.3
	1	6		20	8		23.5
	≥2	13		43.3	3		8.8
	5 years							0.164
	0	0		0	5		14.7
	1	2		6.7	2		5.9
	≥2	5		16.7	6		17.7

  HCC. Validated curative treatments of HCC include liver transplantation, liver resection and PT by RFA or MWA. The curative radiological treatments under development are multipolar radiofrequency, cryoablation and irreversible electroporation[START_REF] Hocquelet | Comparison of no-touch multi-bipolar vs. monopolar radiofrequency ablation for small HCC[END_REF] . Looking for innovative technical ways to increase the possibility of curing patients with HCC of more than 2 cm of diameter is an important challenge. The association of TAC with RFA for the treatment of intermediate HCC, according to Barcelona Clinic Liver Cancer (BCLC) classification, is known to obtain higher tumor response rates and to improve survival rates than TACE alone[START_REF] Yang | Meta-analysis of transcatheter arterial chemoembolization plus radiofrequency ablation versus transcatheter arterial chemoembolization alone for hepatocellular carcinoma[END_REF] . However, most studies perform TAC and PT in two steps, TAC being performed first. The delay between TAC and PT is increasingly being shortened. Okamoto T. et al. presented to the European Hepatology Congress a study into the association of TAC with RFA for intermediate stage HCC

†Number of patients

SERMENT D'HIPPOCRATE

Au moment d'être admis(e) 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 les demandera. Je ne me laisserai pas influencer par la soif du gain ou la recherche de la gloire.

Admis(e) dans l'intimité des personnes, je tairai les secrets qui me seront confiés. Reçu(e) 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 ne provoquerai jamais la mort délibérément.

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 déshonoré(e) et méprisé(e) si j'y manque.

ABSTRACT

Background & Aims: The association of transcatheter arterial chemotherapy infusion (TAC) with percutaneous ablation (PT) has been introduced as a method to increase the size of the ablative zone and treat satellites micronodules. The aim of this study was to evaluate the efficacy of PT and TAC performed in a single session for hepatocellular carcinomas (HCCs) between 30 and 50 mm or oligonodular HCC up to 30 mm. Methods: Thirty patients with a histologically proven HCC, uninodular between 30 and 50 mm or oligonodular (n≤3) up to 30 mm, treatment-naïve and non-metastatic, received the combination treatment ("PT+TAC group"). A "control" group consisted of 34 patients with uninodular HCC up to 30 mm without any poor prognostic criteria treated with PT alone ("PT group").

Results:

The majority of patients were cirrhotic (90% vs 91%, respectively for the PT+TAC and PT groups), Child-Pugh A (83% vs 85%), with a Performans Status of 0 (80% vs 79%).

There was no significant difference in the median alpha-fetoprotein level (15 vs 9.3 μg/l, p=0.39). The 1-, 3-, and 5-year OS was no significantly different in both groups: 100%, 82% and 48.5% in the PT+TAC group vs 94.1%, 72.7% and 65.2% in the PT group (p=0.88). The 1-, 3-, and 5-year relapse-free survival was significantly lower in the PT+TAC group: 59.3%, 18.5% and 5.6% vs 89.3%, 46.4% and 24.5%, in the PT group (p=0.02).

Conclusion:

The combination treatment for HCC between 30 and 50 mm or oligonodular up to 30 mm, showed a similar OS, compared to uninodular HCC up to 30 mm without poor prognostic criteria, treated with PT alone, at the price of earlier tumor recurrence.

Keywords: Hepatocellular carcinoma; Transarterial chemoembolization; Radiofrequency ablation; Microwave ablation

Lay Summary: New curative treatments for liver cancer are under development. The combination of thermal ablation and arterial chemotherapy infusion is a promising therapeutic avenue. The combination of these treatments performed in a single session shows survival equal to that of smaller liver cancers, without more complications. However, these initially larger cancers recur more often and require more additional treatment.

The chemotherapy product used for TAC was Adriamycin for 60% and Doxorubicin for 40%.

Drug-eluting beads (DC-BEADS) were used for 13.3% of patients.

Complications

Complications occurred in 27% and 15% of patients (p=0.38), respectively for the PT+TAC and PT groups; including mostly pain grade I/II according to CTCAE (50% and 60%, respectively, p=0.75, Table 6). Other complications in the PT+TAC group included: 2 liver bleedings, none requiring transfusion (1 grade I not requiring any treatment and 1 grade II requiring an evacuating puncture), 1 cholecystitis grade III requiring a radiological drainage, 1 inhalation grade III causing a pulmonary infection and 2 fever grade I. In the PT group, 2 patients had complications grade III: 1 liver bleeding requiring transfusion of 2 pouches of red blood cells but without specific treatment, and 1 local abscess of 100 mm, with favorable evolution after antibiotic therapy and radiological drainage. There was significantly more cytolysis, evaluated with a blood test at J+1, in the PT+TAC group than in the PT group: the mean AST level was 394 U/l vs 180 U/l, respectively in the PT+TAC and PT group (p=0.003). Liver International <onbehalfof@manuscriptcentral.com> 18 août 2019 à 22:45 Répondre à : LIVeditorialoffice@wiley.com À : dann.ouizeman@gmail.com Cc : dann.ouizeman@gmail.com, afalcoz@chu-besancon.fr, emmanuel.chamorey@nice.unicancer.fr, Yann.CHATEAU@nice.unicancer.fr, Jocelyn.GAL@nice.unicancer.fr, larrey.e@chu-nice.fr, piche.t@chu-nice.fr, tran.a@chu-nice.fr, Albert.Tran@unice.fr, chevallier.p@chu-nice.fr, anty.r@chu-nice.fr 18-Aug-2019 LIVint-19-01157 "Endoarterial treatment in combination with percutaneous thermoablation for medium-sized and oligonodular hepatocellular carcinomas" Dear Dr. Ouizeman, The editorial office of Liver International has received your recently submitted manuscript, entitled "Endoarterial treatment in combination with percutaneous thermoablation for medium-sized and oligonodular hepatocellular carcinomas".

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Elio Mansour
email: elio.mansour@univ-pau.fr

Richard Chbeir
email: richard.chbeir@univ-pau.fr

Philippe Arnould
email: philippe.arnould@univ-pau.fr

EQL-CE: An Event Query Language for Connected Environment Management

Keywords: General and reference → General conference proceedings, • Information systems → Query representation, • Theory of computation → Grammars and context-free languages, • Computer systems organization → Sensor networks Event Query Language, Internet of Things, Sensor Networks

Recent technological advances have fueled the rise of connected environments (e.g., smart buildings and cities). Event Query Languages (EQL) have been used to define (and later detect) events in these environments. However, existing languages are limited to the definition of event patterns. They share the following limitations: (i) lack of consideration of the environment, sensor network, and application domain in their queries; (ii) lack of provided query types for the definition/handling of components/component instances; (iii) lack of considered data and datatypes (e.g., scalar, multimedia) needed for the definition of specific events; and (iv) difficulty in coping with the dynamicity of the environments. To address the aforementioned limitations, we propose here an EQL specifically designed for connected environments, denoted EQL-CE. We describe its framework, detail the used language, syntax, and queries. Finally, we illustrate the usage of EQL-CE in a smart mall example.

the energy footprint of smart buildings, helping drivers avoid traffic congestion in smart cities). The aforementioned applications have different objectives. However, in order to achieve their goals, they all need to define and detect specific key events (e.g., machinery faults, traffic congestion, energy wastes). Event Query Languages (EQL) have been proposed in many works [START_REF] Amato | Querying moving events in wireless sensor networks[END_REF][START_REF] Nicholas | Distributed complex event processing with query rewriting[END_REF] as a means for event definition prior to detection. EQL allow users to express how the targeted events are defined (i.e., event describing features, patterns). However, existing works [START_REF] Anicic | EP-SPARQL: a unified language for event processing and stream reasoning[END_REF][START_REF] Anicic | Etalis: Rule-based reasoning in event processing[END_REF][START_REF] Roger | Event correlation and pattern detection in CEDR[END_REF][START_REF] Bry | Rule-based composite event queries: the language XChange EQ and its semantics[END_REF][START_REF] Chakravarthy | Snoop: An expressive event specification language for active databases[END_REF][9][START_REF] Gyllstrom | SASE: Complex Event Processing over Streams[END_REF] suffer from various limitations:

(1) Lack of considered components. In addition to events, one might need to handle other components in a connected environment (these works heavily focus on defining events).

For instance, managing the infrastructure (e.g., locations, spatial ties), the sensor network (e.g., sensors, observations), and additional descriptions related to the application domain (e.g., industrial, environmental). (2) Lack of considered query types. In addition to defining components, one should be able to modify previously defined components (e.g., altering, renaming, or dropping), and manipulating component instances (e.g., selecting, inserting). (3) Lack of considered datatypes. It is important to integrate the diverse data and datatypes needed for the definition of specific events (e.g., for scalar, multimedia sensor observations). (4) Handling environment dynamicity. In a dynamic environment, mobile sensors can enter/leave the network or change locations at any time. Since events rely on sensors and their observations, event queries need to cope with the changes. In addition, some works [START_REF] Arasu | The CQL continuous query language: semantic foundations and query execution[END_REF][START_REF] Francesco | C-SPARQL: SPARQL for continuous querying[END_REF] are not re-usable in different setups due to their reliance on a specific data model-based syntax. In this paper, we propose an Event Query Language specifically designed for Connected Environments. Our proposal, denoted EQL-CE, considers the entire connected environment components. This entails defining the infrastructure, its sensor network, the targeted events, and the application domain. Our proposal provides the common query types needed for the definition of components and the management of their instances. Also, EQL-CE integrates various datatypes, and copes with the dynamicity of the environment by re-writing/updating queries that became obsolete due to sensor mobility (to be detailed in a separate work). Finally, EQL-CE uses EBNF (Extended Backus-Naur Form), a generic and easy to parse language in order to allow re-usability in various contexts. In the following, we present our motivating scenario in Section 2, and present some background on EBNF in Section 3. Then, we briefly describe the framework of EQL-CE and detail its syntax in Section 4. An illustration example, and the experimental protocol are provided in Section 5. We compare related work on EQL in Section 6. Finally, Section 7 concludes the paper and discusses future research directions.

MOTIVATING SCENARIO

Consider the following scenario that illustrates a smart mall. Please note that this example does not summarize all needs found in a connected environment/event detection application scenario. It is only used to highlight the main needs and challenges related to this work. Figure 1 details the infrastructure's location map, and individual locations (e.g., shops). The mall is equipped with a sensor network having static/mobile sensors that produce various observations (e.g., temperature, video). A mall manager would like to adopt an existing EQL capable of: This entails defining connected environment components (e.g., environment, sensor network, events, and application domain). This also includes interrogating the connected environment (e.g., selecting sensors, retrieving sensor observations, detecting events). • Need 2: Coping with the connected environment changes.

For instance, integrating a newly added shop into the mall's location map and detecting events in the new area. Similarly, adding more sensor instances in the mall in order to detect new events or better detect previously defined events (e.g., average values for indoor temperature). Adding components related to the environment/sensor network is needed. • Need 3: Handling various datatypes. This entails covering scalar and multimedia sensor observations (e.g., textual temperature values, video surveillance footage). The mall manager needs to define different events (e.g., intrusion detection, indoor overheating). To do so, the EQL should be able to manipulate different data and their respective datatypes. • Need 4: Coping with the dynamicity of the environment.

The mall manager relies on clients' mobile phones as mobile sensors in the network. This allows dynamic sensing, and improves coverage without adding many static sensors and increasing the costs. However, mobile sensors change locations and enter/exit the network. Since the defined events rely on sensed data, some event definitions might become obsolete over time. The EQL should be capable of coping with this issue. Existing EQL mainly focus on event definition, and do not handle other connected environment components. To address needs 1 and 2, one might use another language that integrates different functionality and handles the environment/sensor network changes. However, in this case, the manager will have to use various languages with different syntax. A more appropriate solution might be to extend the capabilities of the EQL to provide a means for defining the structure of various components related to the environment, sensor network, targeted events, and application domain (cf. Need 1-2). The EQL should also handle scalar/multimedia observable properties and sensor observations (cf. Need 3). In addition, the EQL should be capable of re-writing/re-defining obsolete event definitions (i.e., replacing sensors/observations that are missing due to sensor mobility) in order to cope with the dynamicity of the environment (cf. Need 4). Finally, this should be done using a generic, technology independent syntax that could be parsed into various data model-based languages to ensure re-usability. However, when considering all of the above, the following challenges emerge:

• Challenge 1: How to consider various query types to cover all the required functionality? • Challenge 2: How to consider different components (i.e., environment, sensor network, events, and application domain) in the queries? • Challenge 3: How to define the structure of both scalar and multimedia data? • Challenge 4: How to detect obsolete event definitions? How to redefine these events by replacing missing sensors/data? • Challenge 5: How to establish a generic/re-usable syntax that is independent from the underlying infrastructure?

In the following section, we provide some background on the EBNF syntax used in our proposal EQL-CE.

BACKGROUND & PRELIMINARIES

A syntactic metalanguage is useful whenever a clear formal description and definition is required. EBNF is defined by the International Organization for Standardization (ISO 14977 1 ). It proposes a notation for defining the syntax of a language using rules. Each rule names part of the language (called a non-terminal symbol) and then defines its possible forms. A terminal symbol is an atom that cannot be split into smaller components of the language. EBNF extends the original BNF to avoid lengthier rules by adding notations for options and repetitions. Furthermore, EBNF includes mechanisms for enhancements, defining the number of repetitions, excluding alternatives, and adding comments. The following resumes the main characteristics of EBNF:

• Terminal symbols of the language are quoted so that any character, including one used in EBNF, can be defined as a terminal symbol of the language being defined

EQL-CE PROPOSAL

Here, we describe our EQL-CE [START_REF] Mansour | EQL-CE: an event query language for connected environments[END_REF] framework and briefly discuss its two layers. Then, we focus more on the syntax, and detail the structure of various connected environment components.

EQL-CE Framework

EQL-CE has two layers: (i) the logical layer allows the construction of generic queries; and (ii) the physical layer parses the queries into a data model-specific language (e.g., SQL, SPARQL) and executes the parsed queries. Figure 2 shows an overview of EQL-CE. In the following, we discuss each layer. ). Also, one could define the structure of scalar/multimedia data using EQL-CE (cf. Criterion 3 -Section 6). Finally, a query optimizer discovers/re-writes obsolete queries to cope with the dynamicity of the environment (cf. Criterion 4 -Section 6). This module is not detailed here, will leave it for a dedicated separate work.

EQL-CE Syntax

Here, we detail the syntax that describes the structure of the various connected environment components. To avoid redundancies, we state here that each component has a unique identifier. We define two types of platforms: (i) infrastructures; and (ii) devices. Infrastructures represent physical, real world environments (e.g., office, building, forest). Each infrastructure has a location map to describe spatial features, and a set of hosted platforms such as other infrastructures or devices (cf. Syntax 2). A location map has a set of distinct locations (cf. Syntax 3), and each location has a description that details its geometric shape, coordinates in space, and a set of spatial relations with other locations (cf. Syntax 4). We also allow users to define external spatial relations (from the application domain) and use them for inter-location ties.

CREATE LOCATION ( [ ID ] <location_id> [ , [ DESCRIPTION ] <description_id> ] [ , { ( [ RELATION ] <relation> , [ LOCATION ] <location_id> ) } ] ) ; <relation> = 'contains' | 'covers' | 'crosses' | 'equals' |'includes' | 'isAbove' | 'isBelow' | 'isCloseTo' | 'isDisjointWith' | 'isFraFrom' | 'isLeftOf' | 'isRightOf' | 'overlaps' | 'touches' | <spatial_relation_id> ;
Devices (cf. Syntax 5) are also considered platforms since they are capable of hosting sensors. We describe their hardware, software, and provided services in Syntax 6. The descriptions for hardware might include information about the device's power supply, memory, processor, network interface, and expansion cards where sensors are embedded. The description of software might include details about the operating system. And finally, the services descriptions might specify the provided functionality, and input/output. 4.2.2 Sensor Network Component Syntax. When considering the sensor network, many components can be defined. For the sake of brevity, we choose here to detail the structure of observable properties in the environment (cf. Syntax 7), sensor observations (cf. Syntax 8), and sensors (cf. Syntax 9). Various properties can be monitored in a connected environment (e.g., temperature, noise, humidity). Some are scalar (i.e., textual) and others multimedia (i.e., audio, video, images). And each property is linked to a set of sensor observations. Each observation, has a description (e.g., unit of measurement), data value (if scalar) or a data object/file (if multimedia) alongside a datatype. Finally, each observation is mapped to a set of metadata tag/value pairs. Finally, we define static or mobile sensors. Each having (i) a description; (ii) a location history record containing a set of location/time interval pairs; (iii) a coverage area history record containing a set of coverage area/time interval pairs; (iv) a set of sensed properties/produced observations; and (v) the platform in which the sensor is embedded/hosted. We should mention that the location/coverage area records must contain at all times a current value for the sensor location and coverage area (i.e., a location/coverage area with an ongoing time interval).

CREATE SENSOR ( [ ID ] <sensor_id> [ , [ TYPE ] <type> = 'static' | 'mobile' ] ( [ , WITH [ , { [ DESCRIPTION ] <description_id> } ] [ , [ LOCATION HISTORY ] <location_history> = { ( [ LOCATION ] <location_id> , [ TIME INTERVAL ] <ti> ) } ] [ , [ COVERAGE HISTORY ] <coverage_history> = { ( [ COVERAGE AREA ] <coverage_area_id> , [ TIME INTERVAL ] <ti> ) } ] ] ) ( [ , SENSING { [ PROPERTY ] <property_id> } ] ) ( [ , PRODUCING { [ OBSERVATION ] <observation_id> } ] ) ( [ , HOSTED ON [ PLATFORM ] <platform_id> ] ) ) ;

Event Component Syntax.

We define an event (cf. Syntax 10) by assigning to it what we called an event space, an n-dimensional space where each dimension represents an event describing feature. In addition, since the events are detected based on sensor data, we map a set of contributing sensors to each event definition. When defining the event, one might choose a specific set of sensors, or any available ones that fit the event needs.

CREATE EVENT ( [ ID ] <event_id> [ , [ EVENT SPACE ] <event_space_id> ] [ , USING { [ SENSOR ] <sensor_id> } ] ) ;

The event space (cf. Syntax 11) contains a set of features each having some related conditions (e.g., temperature feature with a condition greater than 35 • C). Finally, all observations belonging to an event are found within its space.

Syntax 11: Defining the structure of an Event Space

CREATE EVENT SPACE ( [ ID ] <event_space_id> [ , { ( [ FEATURE ] <feature_id> [ , [ CONDITION ] <condition_id> ] ) } ] [ , { [ OBSERVATION ] <observation_id> } ] ) ;
4.2.4 Application Domain Component Syntax. Since event features are better defined by an expert. We leave the feature syntax (cf. Syntax 12) to the application domain part. A feature is represented as a dimension in the event space. Therefore, each feature has a specific datatype for its values, a function that measures the distance between two instances belonging to the same feature, a default value, and a description. We provide a set of basic features, and leave the definition of advanced/complex features to domain experts.

Syntax 12: Defining the structure of a Feature

CREATE FEATURE ( [ ID ] <feature_id> [ , [ DATATYPE ] <datatype> = 'integer' | 'float' | 'boolean' | 'date' | 'time' | 'date time' | 'character' | 'string' ] [ , [ DISTANCE MEASURE ] <distance_measure_id> ] [ , [ DEFAULT VALUE ] <value> ] [ , [ DESCRIPTION ] <description_id> ] ) ;

The application domain experts also define the constraints related to each feature. Syntax 13 defines a condition as a set of statements each having operands and an operator. We provide various operators and allow users to import external operators/functions. Finally, since the application domain description differs from one context to another, one needs a generic definition of application domain components and relationships that could be instantiated in any context. Therefore, we define a component named Concept (cf. Syntax 14), and an inter-concept relationship, denoted Relation (cf. Syntax 15). Relations can also be used between environment, sensor network, or event components. To conclude, one can define the structure of various connected environment components (cf. Criterion 2 -Section 6). Also users can rename, drop, or even alter the structure of a previously defined component 2 .

ILLUSTRATION & EXPERIMENTAL SETUP

In this section, we rely on the component definitions provided in Section 4 to illustrate the usage of EQL-CE in the Smart Mall (cf. Figure 1). Then, we discuss the evaluation of the language. 2 Syntax details for all definition queries is provided on the following link https:// github.com/eliomansour/EQL-CE/blob/master/EQL-CESyntax.pdf 5.1 EQL-CE Queries 5.1.1 Environment Queries. The mall is a platform of type infrastructure. It has a location map containing five locations (the Hallway, Movie Theater, Grocery Store, Coffee Shop, and Shop 1). The locations and location map are instantiated in queries 1 and 2 respectively. Each location instance specifies the relation between the location and its neighbours. The smart mall infrastructure hosts a mobile device dev 1 . The device instance is shown in Query 3. We do not detail the representation of the hardware, software, or services. We only specify that a temperature sensor ('s_6') is embedded on the device. The mall infrastructure and mobile device host sensors. Therefore, they are also considered platforms. Queries 5 and 6 insert the two platform instances. 1). In [START_REF] Chakravarthy | Snoop: An expressive event specification language for active databases[END_REF], the authors propose an intuitive event query language denoted SNOOP. They define three event attributes: (i) a name; (ii) a set of conditions (the pattern); and (iii) a set of actions to be triggered once the event is detected. SNOOP integrates operators for inter-condition relations (e.g., conjunction, dis-junction, and sequence) and represents repetitive events through the usage of the periodic/aperiodic operators. In [START_REF] Roger | Event correlation and pattern detection in CEDR[END_REF], the authors propose a language denoted CeDR. In comparison with SNOOP, CeDR adds a WHERE clause for filtering statements and has a wider range of operators. Therefore, CeDR is considered more expressive in terms of event pattern description. CeDR also includes an event lifetime operator and a detection window operator. CQL [START_REF] Arasu | The CQL continuous query language: semantic foundations and query execution[END_REF] is another language that can be used for event definition/retrieval. CQL extends SQL by emphasizing on continuous data streams/queries. The authors add temporal operators, sliding windows, and window parameters to better handle continuous data.

Discussion: The aforementioned works are intuitive, practical, and allow various composition operators for event definition. However, [START_REF] Roger | Event correlation and pattern detection in CEDR[END_REF][START_REF] Chakravarthy | Snoop: An expressive event specification language for active databases[END_REF] mainly focus on the definition and retrieval of events and neglect other tasks such as updating definitions or inserting data (cf. Criterion 1). CQL provides various query types and covers different functionality since it extends SQL.

Component Coverage

Here we evaluate some works' capability to cover various connected environment components (cf. Need 2). The authors in [START_REF] Gyllstrom | SASE: Complex Event Processing over Streams[END_REF] propose an event query language for data streams called SaSE. They include the WITHIN and RETURN statements to respectively declare sliding time windows and the required output. SaSE also allows event pattern operators (similar to CeDR) in a WHERE clause. ETALIS [START_REF] Anicic | Etalis: Rule-based reasoning in event processing[END_REF] is an EQL that describes events as rules. Its syntax is based on logic style formulas. The authors propose a set of temporal relations and composition operators to define the event patterns. The syntax of the rules is independent of any underlying data model. EP-SPARQL [START_REF] Anicic | EP-SPARQL: a unified language for event processing and stream reasoning[END_REF] extends SPARQL to provide an EQL for linked data management systems. It integrates event processing operators (e.g., sequence) into the SPARQL syntax. This work allows the definition of simple and complex event patterns.

Discussion: The aforementioned works cover the majority of temporal and composition operators. ETALIS and SASE provide a re-usable syntax, however EP-SPARQL is restricted to semantic data models since it extends SPARQL. In terms of component coverage, SASE and ETALIS heavily focus on events and do not consider other connected environment components (cf. Criterion 2). EP-SPARQL has the ability to define structures for various components (e.g., related to the environment, sensor network).

Data Diversity

Here we evaluate some works' capability to integrate different data and datatypes in their syntax (cf. Need 3). SPARQL-ST [START_REF] Perry | Sparql-st: Extending sparql to support spatiotemporal queries[END_REF] extends SPARQL by adding operators for spatial/temporal queries. This covers the definition and manipulation of spatial shapes and temporal entities. [START_REF] Kurz | SPARQL-MM-extending SPARQL to media fragments[END_REF] also extends SPARQL. It considers multimedia data, and media fragments. This language aims to improve semantic multimedia data retrieval. XChangeEQ [START_REF] Bry | Rule-based composite event queries: the language XChange EQ and its semantics[END_REF] is a logic style based language. It allows: (i) data-related operations such as variable bindings and conditions containing arithmetic operations; (ii) event composition operators such as conjunction, dis-junction, and order; (iii) temporal and causal relations between events in the queries; and (iv) event accumulation, for instance aggregating data from previous events to discover new ones.

Discussion: All the aforementioned works provide expressive tools for event definition. Languages extending SPARQL [START_REF] Kurz | SPARQL-MM-extending SPARQL to media fragments[END_REF][START_REF] Perry | Sparql-st: Extending sparql to support spatiotemporal queries[END_REF] are all user friendly since they are based on a known language. Even though, these works handle various datatypes for scalar data (e.g., integer, float, string, date), SPARQL-MM [START_REF] Kurz | SPARQL-MM-extending SPARQL to media fragments[END_REF] is the only one that integrates multimedia data as well.

Handling Environment Dynamicity

Here we evaluate some works' capability to cope with the dynamicity of a connected environment (cf. Need 4). ESPER [9] is an implementation for event detection in database systems. The authors proposed an SQL-like syntax for event processing. Therefore, known operators such as CREATE, SELECT, INSERT, UPDATE, and DELETE are available for event definition and detection. ESPER also includes temporal operators and a specific statement for event definition (i.e., the pattern). In addition to the aforementioned advantages, this language has a fast learning curve since it is highly similar to traditional SQL. In [START_REF] Grandi | T-SPARQL: A TSQL2-like Temporal Query Language for RDF[END_REF], the authors present an extension of SPARQL to integrate temporal features (e.g., annotating triples with time stamps) for better querying of RDF triples over time. C-SPARQL [START_REF] Francesco | C-SPARQL: SPARQL for continuous querying[END_REF] extends SPARQL to consider stream data in the queries. To do so, the authors integrate sliding time windows.

Discussion: The aforementioned works integrate temporal operators, and some of them consider data streams. Also, some provide users with update queries to modify the data over time. However, none provides the means to automatically discover and re-write queries that have become obsolete due to sensor mobility. This entails measuring sensor/data similarities in order to replace missing the elements with correct alternatives.

Since none of the mentioned works fully considers our entire list of criteria, we examine next the Extended Backus-Naur Form metalanguage (EBNF). We provide some background and preliminaries, discuss its usage, syntax, and notations.

CONCLUSION & FUTURE WORK

Many challenges emerge when considering an EQL for connected environments. Here, we addressed the issues of covering various components, query types, datatypes, and coping with the environment's dynamicity. Our proposal provides a generic and re-usable syntax. EQL-CE considers various connected environment components (e.g., environment, sensor network, events, and application domain), offers common query types (e.g., for definition and manipulation of components/instances), and allows the definition of scalar/multimedia data structures. As future work, our first priority is to finish the implementation and evaluation of EQL-CE. Then, we would like to address the following issues. First, we aim to define the security/privacy related query types (e.g., access control). Then, we would like to develop the query optimizer by integrating advanced spatial/temporal elements to the queries for specific event definitions. Moreover, we would like to evaluate our query re-writing engine and test it in various scenarios. Furthermore, we still need to consider composite events in EQL-CE by integrating event composition operators. Finally, we would like to test the language in a real connected environment setup.

Figure 1 :

 1 Figure 1: The Smart Mall

Figure 2 :

 2 Figure 2: EQL-CE Overview

Syntax 2 :

 2 Defining the structure of an Infrastructure CREATE INFRASTRUCTURE ( [ ID ] <infrastructure_id> [ , [ LOCATION MAP ] <location_map_id> ] [ , { [ PLATFORM ] <platform_id> }]) ; Syntax 3: Defining the structure of a Location Map CREATE LOCATION MAP ( [ ID ] <location_map_id> [ , { [ LOCATION ] <location_id> } ] ) ; Syntax 4: Defining the structure of a Location

Syntax 5 :

 5 Defining the structure of a Device CREATE DEVICE ( [ ID ] <device_id> [ , { [ HARDWARE ] <hw_id> } ] [ , { [ SOFTWARE ] <sw_id> } ] [ , { [ SERVICE ] <service_id> } ] ) ; Syntax 6: Defining the structure of a device's Hardware, Software, and Services CREATE HARDWARE ( [ ID ] <hw_id> [ , [ DESCRIPTION ] <description_id> ] ) ; CREATE SOFTWARE ( [ ID ] <sw_id> [ , [ DESCRIPTION ] <description_id> ] ) ; CREATE SERVICE ( [ ID ] <service_id> [ , [ DESCRIPTION ] <description_id> ] ) ;

Syntax 7 :

 7 Defining the structure of a Property CREATE PROPERTY ( [ ID ] <property_id> [ , [ TYPE ] <type> = 'scalar' | 'audio' | 'image' | 'video' ] [ , { [ [ SCALAR | MEDIA ] OBSERVATION ] <observation_id> } ] ) ; Syntax 8: Defining the structure of an Observation CREATE [ SCALAR | MEDIA ] OBSERVATION ( [ ID ] <observation_id> [ , [ DESCRIPTION ] <description_id> ] [ , ( [ DATA VALUE ] <data_value_id> | [ DATA OBJECT ] <data_object_id> , [ DATATYPE ] <datatype_id> ) ] [ , { ( [ METADATA TAG ] <metadata_tag> : [ METADATA VALUE ] <metadata_value> ) } ] ) ;

Syntax 9 :

 9 Defining the structure of a Sensor

Syntax 10 :

 10 Defining the structure of an Event

Syntax 13 :

 13 Defining the structure of a Condition CREATE CONDITION ( [ ID ] <condition_id> [ , { STATEMENT <statement_id> } ] ) ; CREATE STATEMENT ( [ ID ] <statement_id> , ( [ OPERAND ] <operand_id>, [ OPERATOR ] <op> [ , [ OPERAND ] <operand_id> ] )); CREATE OPERAND ( [ ID ] <operand_id> , ( [ TYPE ] <type> = 'Temporal' | 'Spatial' | 'Other' , [ VALUE ] <val> ) ) ; <val> = <string> | [ LOCATION ] <location_id> | [ TIMESTAMP ] <ts> | [ TIME INTERVAL ] <ti> ; <op> = [ COMPARISON ] <cop> | [ TEMPORAL ] <top> | [ SPATIAL ] <sop> | FUNCTION <function_id> <cop> = '=' | '<=' | '>=' | '<' | '>' | 'not' ; <top> = 'hasBegining' | 'hasEnd' | 'inside' | 'intervalAfter' | 'intervalBefore' | 'intervalContains' | 'intervalDisjoint' | 'intervalDuring' | 'intervalEquals' | 'intervalFinishedBy' | 'intervalFinishes' | 'intervalIn' | 'intervalMeets' | 'intervalMetBy' | 'intervalOverlappedBy' | 'intervalOverlaps' | 'intervalStartedBy' | 'intervalStarts' | [ TEMPORAL RELATION ] <temporal_relation_id> ; <sop> = 'contains' | 'covers' | 'crosses' | 'equals' | 'includes' | 'isAbove' | 'isBelow' | 'isCloseTo' | 'isDisjointWith' | 'isFraFrom' | 'isLeftOf' | 'isRightOf' | 'overlaps' | 'touches' | [ SPATIAL RELATION ] <spatial_relation_id> ; [ FUNCTION ] <function_id> ;

Syntax 14 :

 14 Defining the structure of a Concept CREATE CONCEPT ( [ ID ] <concept_id> [ , { ELEMENT <element_id> } ] ) ; ELEMENT [ ID ] <element_id> = COMPONENT <component_id> | ATTRIBUTE ( <name>, <datatype> ) ; Syntax 15: Defining the structure of a Relation CREATE [ <name> ] RELATION ( [ ID ] <relation_id> [ , { ( CONCEPT SOURCE <concept_id> , CONCEPT TARGET <concept_id> ) } ] [ , { ( COMPONENT SOURCE <component_id> , COMPONENT TARGET <component_id> ) } ] ) ;

Query 1 :

 1 Inserting the Locations INSERT LOCATION ( 'Movie_Theater' , { ( 'touches' , 'Hallway' ) , ( 'isRightOf' , 'Coffee_Shop' ) , ( 'touches' , 'Coffee_Shop' ) } ) ; INSERT LOCATION ( 'Coffee_Shop' , { ( 'touches' , 'Hallway' ) , ( 'isLeftOf' , 'Movie_Theater' ) , ( 'touches' , 'Movie_Theater' ) } ) ; INSERT LOCATION ( 'Shop_1' , { ( 'touches' , 'Hallway' ) , ( 'isLeftOf' , 'Grocery_Store' ) , ( 'touches' , 'Grocery_Store' ) } ) ; INSERT LOCATION ( 'Grocery_Store' , { ( 'touches' , 'Hallway' ) , ( 'isRightOf' , 'Shop_1' ) , ( 'touches' , 'Shop_1' ) , ( 'isAcrossOf', 'Movie_Theater') } ) ; INSERT LOCATION ( 'Hallway' ) ; Query 2: Inserting the Location Map INSERT LOCATION MAP ( 'Mall_Location_Map' , { 'Movie_Theater', 'Coffee_Shop', 'Shop_1', 'Grocery_Store', 'Hallway' } ) ;

Query 3 :

 3 Inserting the Device, its hardware, software, and provided services INSERT DEVICE ( 'dev_1' , { 'dev_1_Hardware' } , { 'dev_1_Software' } , { 'dev_1_Service' } ) ; INSERT HARDWARE ( 'dev_1_Hardware' , { 's_6' } ) ; INSERT SOFTWARE ( 'dev_1_Software' ) ; INSERT SERVICE ( 'dev_1_Service' ) ;Since all infrastructure elements have been instantiated, one can now insert the infrastructure instance (cf. Query 4).

Query 4 :

 4 Inserting the Mall Infrastructure INSERT INFRASTRUCTURE ( 'Mall_Infrastructure' , 'Mall_Location_Map' , { 'dev_1' } ) ;

Query 5 :

 5 Inserting the Mall PlatformINSERT PLATFORM ( 'Mall_Platform' , <type> = 'infrastructure' ) ;

Table 1 :

 1 • The [] symbols indicate optional rules/statements • The {} symbols indicate repetition • Each rule has an explicit final character so that there is never any ambiguity about where a rule ends • Brackets group items together. It is an obvious convenience EBNF Notations

	Usage	Notation	Usage	Notation
	Definition	=	Grouping	( ... )
	Concatenation	,	Terminal String	...
	Termination	;	Terminal String	' ... '
	Alternation	|	Comment	(* ... *)
	Option	[ ... ]	Special Sequence	? ... ?
	Repetition	{ ... }	Exception	-

to use the ( ) symbols in their ordinary mathematical sense Table

1

details the main EBNF notations and their usage.

1 https://www.cl.cam.ac.uk/~mgk25/iso-14977.pdf

  4.2.1 Environment Component Syntax. Sensors and sensor networks are hosted on platforms. Each platform has a unique identifier and a type (cf. Syntax 1).

	Syntax 1: Defining the structure of a Platform
	CREATE PLATFORM ( [ ID ] <platform_id>
	[ , [ TYPE ] <type> = 'infrastructure' | 'device' ] ) ;

5.1.2 Sensor Network Queries. In regards to the sensor network related queries, we begin by instantiating the two properties that are currently monitored in the example: (i) the scalar property temperature; and (ii) the multimedia property video. This is shown in queries 7 and 8 respectively. These properties are monitored by various sensors. Six temperature sensors exist in the smart mall. s 1 , s 2 , ands 3 are deployed in the movie theater, s 4 in the grocery store, s 5 in Shop 1, and s 6 is the only mobile sensor deployed on dev 1 which is currently located in the Coffee Shop. A surveillance camera cam 1 is deployed in Shop 1. Query 9 instantiates all the aforementioned sensors. Note that the mobile sensor s 6 has a previous/current location/coverage area. When the network becomes operational, sensors will start producing observations. The latter are sent to a middle-ware that will generate an insert query in order to push the observations into the data model according to the observation syntax (cf. Section 4). Then, the middle-ware will update both sensors and properties by mapping them to their related observations. Query 10 shows an insert query generated by the middle-ware for a temperature observation having a float value of '20.3' and two associated metadata for time and location of capture. Similarly Query 11 shows another temperature observation taken from the Coffee Shop. Query 12 instantiates a video observation taken from the surveillance camera in Shop 1. This observation includes the video recording file, temporal, location, and video length related metadata. 5.1.3 Event Queries. In order to give an example of how an event can be instantiated we define next an intrusion event in Shop 1. The mall manager relies on video sensor cam 1 for the detection of this event. He/She defines the event as a face detected by cam 1 in the Shop after 8 PM. Three features define this event: (i) time with a condition after 8 PM; (ii) location with a restriction to Shop 1; and (iii) a detected face with a Boolean value equals true. In this example, the manager uses our provided basic features for time, location, and detected face (cf. Query 13) where we only define the feature as an identifier assigned to a datatype. The manager also creates the required conditions for each feature (cf. Query 14). However, one can use the application domain queries to define more complex/advanced features/conditions if needed. Finally, query 15 details the event space, and query 16 instantiates the event. Query 18: ALTER Query -Infrastructure example

In regards to the data manipulation language, one could also select, update, or delete component instances. Examples are shown in queries 19, 20, and 21 respectively.

Experimental Setup

We are currently implementing the EQL-CE query run engine that executes the queries. It is part of an online platform for event detection in connected environments. Since the development is still ongoing, we propose here the experimental protocol that we will use to evaluate the query language. We propose the following experiments:

• Query Cost Evaluation: Providing the user with the ability to define the entire connected environment allows him/her to manage all its components from scratch. However, this might be costly in terms of the number of 'steps' (i.e., queries) required to achieve a specific task/objective. In this experiment, we set a list of objectives (e.g., defining a platform, a sensor, a location map) and quantify the required query batch size and the total cost of achieving the task. ing if the EQL provides the means to modify the structure of previously defined components (e.g., events) in order to cope with the environment's dynamicity. This is useful in a dynamic setup, where sensor mobility causes gain/loss of data in certain areas of the environment (cf. Need 4). In the following, we evaluate some works for each criterion (we do not detail here every existing EQL for the sake of brevity).