Clinical Research

Pour l'honneur qu'il m'a fait pour sa participation à mon jury de thèse en qualité de rapporteur de mon travail, pour le temps consacré à la lecture de cette thèse. Je suis particulièrement honorée de sa présence dans ce jury de soutenance. Je lui exprime ici ma plus haute considération. Monsieur le Professeur Frédéric Farizon Pour avoir accepté d'être rapporteur et membre de jury de cette thèse. Je le remercie pour l'intérêt et la considération qu'il a porté à ces travaux. Je lui adresse mes sincères remerciements ainsi que ma profonde gratitude. Monsieur le Professeur Philippe Neyret, Je tenais à vous remercier de l'accueil que vous m'avez réservé et du temps que vous m'avez consacré lors de mon parcours professionnel. Cette expérience sera très importante pour ma carrière et les tâches auxquelles vous m'avez associée m'ont vraiment permis de consolider mes connaissances et d'en développer de nouvelles. Monsieur le Professeur Sébastien Lustig, Sans vous, cette thèse n'aurait pas été possible. Je vous remercie pour votre patience et vos encouragements qui m'ont portée dans les moments difficiles, pour vos idées et suggestions PLAN ABSTRACT CHAPTER I. INTRODUCTION Hill, Iwaki and coworkers [10] applied MRI scans to 13 unloaded knees and 7 loaded knees for the description of the surface geometry and relative movements of the femur and the tibia. According to this study, during flexion in the unloaded knee, medially, the mean AP position of the femoral condyle did not change from 110° to-5°. Laterally, the femoral condyle rolled

Background: Clubfeet and constriction band syndrome is a very rare non-idiopathic condition. Treatment is often difficult and the recurrence deformity rate is high. The purpose of this study was to assess the effectiveness of Ponseti method in the treatment of congenital constriction band syndrome accompanied by clubfoot deformity and lymphedema. Case presentation: We are presenting an interesting case of bilateral clubfeet and congenital circumferential constriction band syndrome in the lower limb. Ponseti method of correcting the congenital clubfoot deformity was applied. Constriction band release is accomplished by two stages completely excising the fibrous band and multiple two-stage Z-plasties on the right calf. Conclusion: The results of this study indicate that the Ponseti method of gentle, systematic manipulation and weekly cast changes is an effective treatment of non idiopathic clubfoot distal to congenital amniotic constriction band.

Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case–control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.

Context and Objective: Predicting pituitary tumor behavior remains a challenge. This multiparameter
investigation aimed to identify markers for recurrence and progression in prolactin tumors.
Design: From a cohort of patients treated for prolactin tumors by surgery, we retrospectively
studied clinical data, tumor characteristics, clinical outcome, and the expression of nine genes by
quantitative RT-PCR.
Results: This study included 94 patients (62 females and 32 men), with long postoperative follow-up
periods (mean, 138
46 months); 54.3% of patients had a macro or giant adenoma. Tumors were
classified into three pathological groups based on their radiological and histological characteristics
(noninvasive, 61; invasive, 22; and aggressive-invasive, 11). Immediately after surgery, 60 patients
(63.8%) went into remission (prolactin level normalization). Persistently elevated prolactin levels
(36.2%) were associated with increasing age, male sex, high preoperative prolactin levels, large tumor
size on univariate analysis, and invasion and pathological classification on univariate and multivariate
(P  8  1010 and 3  108) analysis. During follow-up, 19 patients (20%) had tumors that recurred
or progressed under dopamine agonist treatment. Invasion and pathological classification were associated
with recurrence or progression on univariate analysis. Seven genes (ADAMTS6, CRMP1, PTTG,
ASK, CCNB1, AURKB, and CENPE) were associated with tumor recurrence or progression and five of
these (ADAMTS6, CRMP1, ASK, CCNB1, and CENPE) were associated with the pathological classification.
Conclusion: This study identifies both the clinical and histological factors that relate to prolactin
tumor recurrence or progression. Molecular markers give additional information for prognosis of
such tumors. Altogether, our results could influence the management of patients with pituitary
tumors.

Objective:  In recent years, therapeutic approaches including cytoreductive surgery followed by intraperitoneal chemotherapy have proven effective in peritoneal carcinomatosis of colorectal origin. If cytology is to be used to include patients in aggressive treatment regimens, it is necessary to evaluate its performance, particularly in terms of specificity. The aim of this study was to assess interobserver agreement for the detection of intraperitoneal free cancer cells (IFCCs) in patients with non-gynaecological adenocarcinomas.

Methods:  Over a 5-year period, 1223 patients were recruited in 19 French surgery departments. Peritoneal samples were examined in 14 dispersed pathology laboratories. Giemsa-stained slides were sent to a control reader blind to the previous diagnosis. Discordant cases, concordant positive results and a random selection of negative concordant cases were reviewed by a panel of seven cytopathologists. The ‘final diagnosis’ was that of the consensus meetings but took into account locally-processed slides.

Results:  Gathering dubious cases with negative results, a 95.6% concordance was achieved between local readers and the control reader. IFCCs were ascertained by the panel in 85 cases (7.0%). Eight of 873 colorectal cancers cases viewed locally were falsely positive (0.9%). Radiotherapy and neoadjuvant therapy had no impact on the false-positive rate as assessed by final validation by the panel (P > 0.05). Samples initially considered as dubious were reclassified as negative by the panel in 24 of 25 cases (96.0%).

Conclusions:  The panel consensus allowed reclassification of most dubious/equivocal peritoneal cytology cases, whereas clearcut distinction between benign and malignant cases was correctly achieved in almost all cases.

As part of the national 2009–2013 Cancer Plan, and with the support of the National cancer Institute and the French ministry of health, the National network for the treatment of rare peritoneal malignancies (RENAPE) has been organized. Its main objective is to optimize the framework for the healthcare management and treatment of rare peritoneal malignancies. This specific organization covers the whole national territory including clinical expert and specialized structures and should lead to an appropriate treatment based on expertise and proximity. Within the RENAPE network, the RENA-PATH group gathers the pathologists actively involved in the management of rare peritoneal malignancies. The actions of RENA-PATH are focused primarily on the harmonization of pathological diagnostic criteria, reporting of new cases in the RENAPE registry and histology reviewing.

Water sonolysis leads to the formation of hydroxyl radicals (OH*). Various techniques are used to detect the OH* production and thus to assess the level of ultrasound-mediated cavitation generated in vitro. In this study, we used terephthalic acid (TA) as an OH* trap. This method is based on the fluorescent properties of hydroxyterephthalic acid (HTA) formed by the reaction of TA with OH* and used as an indicator of the degree of inertial cavitation caused. The experimental system is comprised mainly of a focused piezoelectric ultrasound transmitter and a measurement cell containing 1X PBS/TA diluted solution. In the first part, we aimed to characterize the most appropriate experimental conditions (TA dosimeter solution, irradiation time) in order to optimize the resulting HTA fluorescence values. Then, we could determine that the HTA production increased with the level of the cavitation phenomenon caused by the acoustic power from which OH* production may be estimated.

Background: In Europe, gastric cancer remains diagnosed at advanced stage (serosal and/or lymph node involvement).
Despite curative management combining perioperative systemic chemotherapy and gastrectomy with D1-D2 lymph
node dissection, 5-year survival rates of T3 and/or N + patients remain under 30%. More than 50% of recurrences are
peritoneal and/or locoregional. The use of adjuvant hyperthermic intraperitoneal chemotherapy that eliminates free
cancer cells that can be released into peritoneal cavity during the gastrectomy and prevents peritoneal carcinomatosis
recurrences, was extensively evaluated by several randomized trials conducted in Asia. Two meta-analysis reported that
adjuvant hyperthermic intraperitoneal chemotherapy significantly reduces the peritoneal recurrences and significantly
improves the overall survival. As it was previously done for the evaluation of the extension of lymph node dissection, it
seems very important to validate on European or caucasian patients the results observed in trials performed in Asia.
Methods/design: GASTRICHIP is a prospective, open, randomized multicenter phase III clinical study with two arms
that aims to evaluate the effects of hyperthermic intraperitoneal chemotherapy with oxaliplatin on patients with gastric
cancer involving the serosa and/or lymph node involvement and/or with positive cytology at peritoneal washing,
treated with perioperative systemic chemotherapy and D1-D2 curative gastrectomy. Peroperatively, at the end of
curative surgery, patients will be randomized after preoperatively written consent has been given for participation. Primary
endpoint will be overall survival from the date of surgery to the date of death or to the end of follow-up (5 years).
Secondary endpoint will be 3- and 5-year recurrence-free survival, site of recurrence, morbidity, and quality of life. An
ancillary study will compare the incidence of positive peritoneal cytology pre- and post-gastrectomy in two arms of the
study, and assess its impact on 5-year survival. The number of patients to be randomized was calculated to be 306.
Trial registration: EudraCT number: 2012-005748-12, ClinicalTrials.gov identifier: NCT01882933.

Background
A majority of patients with rectal cancer and metastasis are not eligible to curative treatment because of an extensive and unresectable metastatic disease. Primary tumor resection is still debated in this situation. Rectal surgery treats or prevents the symptoms and avoids the risk of acute complications related to the primary tumor. Several studies on colorectal cancers seem to show interesting results in terms of survival in favor to the resection of the primary tumor. To date, no randomized trial or even a prospective study has assessed the impact of primary tumor resection on overall survival in patients with colorectal cancer with unresectable metastasis. All published studies were retrospective and included colon and rectal cancers. Rectal cancer is associated with specific problems related to the rectal surgery. Surgery is more complex, and may be source of more morbidity and postoperative functional dysfunctions (stoma, digestive, sexual, urinary) than colic surgery. On the other hand, symptoms related to the progression of rectal tumor are often very disabling: pain, rectal syndrome.

Methods/Design
GRECCAR 8 is a multicentre randomized open-label controlled trial aimed to evaluate the impact on survival of the primary tumor resection in rectal cancer with unresectable synchronous metastasis. Patients must undergo upfront systemic chemotherapy for at least 4 courses before inclusion. Patients with progressive metastatic disease during upfront chemotherapy will be excluded from the study. Patients will be randomly assigned in a 1:1 ratio to Arm A: primary tumor resection followed by systemic chemotherapy versus Arm B: systemic chemotherapy alone. Primary endpoint will be overall survival measured from the date of randomization to the date of death or to the end of follow-up (2 years). Secondary endpoints will include progression-free survival, quality of life, toxicity of chemotherapy, response of the primary tumor and metastatic disease to chemotherapy, postoperative morbidity and mortality, rate of patient not eligible for postoperative chemotherapy (arm A), primary tumor related complications and rate of emergency surgery (arm B). The number of patients needed is 290.

Peritoneal malignant mesothelioma is a rare tumor, less common than its pleural counterpart. It develops from the mesothelial cells overlying peritoneum and preferentially occurs in male, with an average age ranging from 47 to 60.5 years. Asbestos whose impact is less strong than in pleural mesothelioma, SV 40 virus, chronic peritonitis could be implicated as factors favoring the development of peritoneal mesothelioma. Clinical symptoms are not specific, and the imagery remains little or not contributive. The 2004 WHO classification recognizes 3 different types, which differ in terms of presentation and prognosis: diffuse epithelioid mesothelioma (the most common), sarcomatoid mesothelioma and biphasic mesothelioma. Many variants are described within these groups. Immunohistochemistry is mandatory to affirm or disprove peritoneal malignant mesothelioma diagnosis, based on a panel of antibodies divided in positive markers and negative markers. Indeed an accurate diagnosis is necessary to define a therapeutic strategy more and more frequently based on the combination of radical surgery and hyperthermic intra peritoneal chemotherapy. Such an approach significantly improves the prognosis of these aggressive diseases.

Pseudomyxoma peritonei is a clinical entity characterized by a gelatinous ascite associated with mucinous tumor deposits spreading on peritoneal surface and potentially invading abdominal organs. It is considered as a tumor process linked, in most of cases, to a mucinous appendiceal neoplasm. Pseudomyxoma peritonei may benefit from a therapeutic strategy combining cytoreductive surgery and intra-peritoneal chemotherapy, which has led to a major prognosis improvement. Different classifications are available and the last one corresponds to the WHO 2010 version, which individualizes pseudomyxoma peritonei in two classes: low grade and high grade mucinous carcinoma. The very low frequency of this entity and its specific therapeutic strategy need specific health care centres, as well as physicians and pathologists collaborating through dedicated networks. The aim of this article is to summarize the pathology, causes, mechanisms and therapeutic approaches of pseudomyxoma peritonei, as well as their interfaces with dedicated networks.

Access to good quality biological samples is a prerequisite for highlevel
translational research. The BIG-RENAPE Biobank has been established
by the French hyperthermic intraperitoneal chemotherapy centers
involved in the management of peritoneal surface malignancies.
The Biobank is a core facility aiming to support researchers who conduct
studies with sample collections, both within and outside the Big-
RENAPE Network.
The Biobank is certified according to NFS 96-900 and has been
launched in February 2016 as a service of processing, storage and transfer of high quality biological (plasma, serum, buffy coat) and tissue
(formalin-fixed-paraffin-embedded) samples from patients with
digestive peritoneal carcinomatosis. Biospecimens are collected at
each stage of diagnostic and therapeutic care. The patient and his
derivates are anonymized and registered in a web database reporting
disease status, treatments, surgical procedures, pathological diagnosis,
quality of life’s assessment and long term follow-up. All participants
have given their informed consent before any sample. The
Biobank was approved by the local Ethical Committee, based on the
assessed compliance to French regulatory rules. The Biobank is located
in the Centre Hospitalier Lyon (SudBioTech), which is known to be
an expert center in the management of the peritoneal carcinomatosis.
Research projects that require material stored in the Biobank are
submitted by specific form and evaluated by the BIG-RENAPE
Scientific Committee. A material transfer agreement is agreed with
the recipient before samples are allowed to be sent from the Biobank.

L'organisation de la prise en charge des patients atteints de cancers rares du péritoine s'appuie sur un réseau national (RENAPE) dont l'objectif est de garantir à chaque patient l'accès à l'expertise médicale quel que soit son lieu de traitement, à la fois par la mise en place d'une relecture de ses prélèvements tumoraux par des experts pathologistes pour un diagnostic certain, et par la discussion systématique de son dossier médical par des experts cliniciens pour guider la prise en charge thérapeutique. Le réseau RENAPE participe à l'actualisation de recommandations de bonnes pratiques cliniques et contribue à promouvoir la recherche sur ces cancers rares à travers des études fondamentales, translationnelles et cliniques qui peuvent s'appuyer sur une base de don-nées nationale et une tumorothèque virtuelle associée. Abstract The French health care organization for rare peritoneal malignancies has been structured with a national network (RENAPE). The RENAPE network is responsible for arranging double reading of tumour specimens, structur-ing referral multidisciplinary consultative meetings, sponsoring multicentre studies in basic, translational and clinical research on these rare cancers, drafting and updating recommendations for good practice, establishing a national database to contribute to the epidemiological observation of these cancers, organizing training for all health professionals involved, working in collaboration with the patient association (AMARAPE), and providing relevant information to general public.

Background: Over the last two decades, many surgical teams have developed programs to treat peritoneal carcinomatosis with extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Currently, there are no specific recommendations for HI-PEC procedures concerning environmental contamination risk management, personal protective equipment (PPE), or occupational health supervision. Methods: A survey of the institutional practices among all French teams currently performing HIPEC procedures was carried out via the French network for the treatment of rare peritoneal malignancies (RENAPE). Results: Thirty three surgical teams responded, 14 (42.4%) which reported more than 10 years of HIPEC experience. Some practices were widespread, such as using HIPEC machine approved by the European Community (100%), individualized or centralized smoke evacuation (81.8%), " open " abdominal coverage during perfusion (75.8%), and maintaining the same surgeon throughout the procedure (69.7%). Others were more heterogeneous, including laminar flow air circulation (54.5%) and the provision of safety protocols in the event of perfusate spills (51.5%). The use of specialized personal protective equipment is ubiquitous (93.9%) but widely variable between programs. Conclusion: Protocols regarding cytoreductive surgery/HIPEC and the associated professional risks in France lack standardization and should be established.

Based on the importance of assessing the true extent of peritoneal disease, PeRitOneal MalIgnancy Stage Evaluation (PROMISE) internet application (www.e-promise.org) has been developed to facilitate tabulation and automatically calculate surgically validated peri-toneal cancer index (PCI), and other surgically validated scores as Gilly score, simplified peritoneal cancer index (SPCI), Fagotti and Fagotti-modified scores. This application offers computer-assistance to produce simple, quick but precise and standardized pre, intra and postoperative reports of the extent of peritoneal metastases and may help specialized and non-specialized institutions in their current practice but also facilitate research and multicentre studies on peritoneal surface malignancies. Please cite this article in press as: Villeneuve L, et al., A new internet tool to report peritoneal malignancy extent. PeRitOneal MalIgnancy Stage Evaluation (PROMISE) application, Eur J Surg Oncol (2016), http://dx.