A carcinomatose peritoneal (CP), secundária ao avanço neoplásico maligno na cavidade abdominal, causa grande morbidade e tem como recomendação terapêutica atual um tratamento multimodal, que consiste na combinação de cirurgia citorredutora (CCR) agressiva e quimioterapia hipertérmica intraperitoneal (HIPEC). O objetivo do presente estudo é caracterizar a função respiratória desse grupo de pacientes, potencialmente candidatos à abordagem de tratamento multimodal e a relação da função respiratória com a capacidade de exercício e qualidade de vida relacionada à saúde (QVRS). Nesse estudo transversal, 25 pacientes com CP candidatos à abordagem de tratamento multimodal, foram avaliados em um centro terciário de saúde, entre maio de 2013 e abril de 2014. Foram avaliados o performance status (PS), espirometria, pressões respiratórias máximas, capacidade de exercício pelo teste de caminhada de seis minutos (TC6m) e um questionário de QVRS (QQVRS) específico para portadores de câncer. Os valores médios da avaliação de força muscular respiratória e da espirometria estavam dentro dos limites de normalidade. Todavia, foram encontrados valores reduzidos na pressão inspiratória máxima (PImax), na pressão expiratória máxima (PEmax) e na distância percorrida no TC6m em 6/25 (24%), 4/25 (16%), e 9/20 (45%), respectivamente. A PImax se associou com o PS, enquanto que a PEmax se associou com a capacidade de exercício, escala funcional do QQVRS e PS. Em conclusão, uma significativa proporção de pacientes apresentava fraqueza muscular respiratória e redução da capacidade de exercício. A força muscular respiratória mostrou associação significativa com PS, enquanto que a PEmax se relacionou com a capacidade de exercício e escala funcional do questionário de QVRS. / Peritoneal carcinomatosis (PC), secondary to advanced abdominal malignancies, causes great morbidity and is currently treated using multimodal approaches combining aggressive cytoreductive surgery (CRS) and intraperitoneal hyperthermic chemotherapy (HIPEC). The aim of the present study is to characterize the respiratory functional status of patients with PC potentially candidates to multimodal treatment approaches and the relationship of respiratory function with exercise capacity and health related quality of life (HRQL). In a cross-sectional study, 25 patients with PC referred for CRS plus HIPEC treatment approach at a tertiary care center between May 2013 and April 2014 were evaluated. Performance status, spirometry, maximal respiratory pressure measures,6-minute walk test (6MWT) and cancer specific HRQL questionnaire were assessed. Mean values of spirometry and respiratory muscle strength were above normal limits. However, reduced maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP) and 6MWT distance was found in 6/25 (24%), 4/25 (16%), and 9/20 (45%), respectively. MIP was associated with performance status while MEP was associated with exercise capacity, functional scale of HRQL questionnaire and performance status. A significant proportion of patients presented respiratory muscle weakness and impaired exercise capacity. MEP and MIP were related with performance status while MEP was additionally associated with exercise capacity and functional scale of HRQL.

A carcinomatose peritoneal (CP), secundária ao avanço neoplásico maligno na cavidade abdominal, causa grande morbidade e tem como recomendação terapêutica atual um tratamento multimodal, que consiste na combinação de cirurgia citorredutora (CCR) agressiva e quimioterapia hipertérmica intraperitoneal (HIPEC). O objetivo do presente estudo é caracterizar a função respiratória desse grupo de pacientes, potencialmente candidatos à abordagem de tratamento multimodal e a relação da função respiratória com a capacidade de exercício e qualidade de vida relacionada à saúde (QVRS). Nesse estudo transversal, 25 pacientes com CP candidatos à abordagem de tratamento multimodal, foram avaliados em um centro terciário de saúde, entre maio de 2013 e abril de 2014. Foram avaliados o performance status (PS), espirometria, pressões respiratórias máximas, capacidade de exercício pelo teste de caminhada de seis minutos (TC6m) e um questionário de QVRS (QQVRS) específico para portadores de câncer. Os valores médios da avaliação de força muscular respiratória e da espirometria estavam dentro dos limites de normalidade. Todavia, foram encontrados valores reduzidos na pressão inspiratória máxima (PImax), na pressão expiratória máxima (PEmax) e na distância percorrida no TC6m em 6/25 (24%), 4/25 (16%), e 9/20 (45%), respectivamente. A PImax se associou com o PS, enquanto que a PEmax se associou com a capacidade de exercício, escala funcional do QQVRS e PS. Em conclusão, uma significativa proporção de pacientes apresentava fraqueza muscular respiratória e redução da capacidade de exercício. A força muscular respiratória mostrou associação significativa com PS, enquanto que a PEmax se relacionou com a capacidade de exercício e escala funcional do questionário de QVRS. / Peritoneal carcinomatosis (PC), secondary to advanced abdominal malignancies, causes great morbidity and is currently treated using multimodal approaches combining aggressive cytoreductive surgery (CRS) and intraperitoneal hyperthermic chemotherapy (HIPEC). The aim of the present study is to characterize the respiratory functional status of patients with PC potentially candidates to multimodal treatment approaches and the relationship of respiratory function with exercise capacity and health related quality of life (HRQL). In a cross-sectional study, 25 patients with PC referred for CRS plus HIPEC treatment approach at a tertiary care center between May 2013 and April 2014 were evaluated. Performance status, spirometry, maximal respiratory pressure measures,6-minute walk test (6MWT) and cancer specific HRQL questionnaire were assessed. Mean values of spirometry and respiratory muscle strength were above normal limits. However, reduced maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP) and 6MWT distance was found in 6/25 (24%), 4/25 (16%), and 9/20 (45%), respectively. MIP was associated with performance status while MEP was associated with exercise capacity, functional scale of HRQL questionnaire and performance status. A significant proportion of patients presented respiratory muscle weakness and impaired exercise capacity. MEP and MIP were related with performance status while MEP was additionally associated with exercise capacity and functional scale of HRQL.

A carcinomatose peritoneal (CP), secundária ao avanço neoplásico maligno na cavidade abdominal, causa grande morbidade e tem como recomendação terapêutica atual um tratamento multimodal, que consiste na combinação de cirurgia citorredutora (CCR) agressiva e quimioterapia hipertérmica intraperitoneal (HIPEC). O objetivo do presente estudo é caracterizar a função respiratória desse grupo de pacientes, potencialmente candidatos à abordagem de tratamento multimodal e a relação da função respiratória com a capacidade de exercício e qualidade de vida relacionada à saúde (QVRS). Nesse estudo transversal, 25 pacientes com CP candidatos à abordagem de tratamento multimodal, foram avaliados em um centro terciário de saúde, entre maio de 2013 e abril de 2014. Foram avaliados o performance status (PS), espirometria, pressões respiratórias máximas, capacidade de exercício pelo teste de caminhada de seis minutos (TC6m) e um questionário de QVRS (QQVRS) específico para portadores de câncer. Os valores médios da avaliação de força muscular respiratória e da espirometria estavam dentro dos limites de normalidade. Todavia, foram encontrados valores reduzidos na pressão inspiratória máxima (PImax), na pressão expiratória máxima (PEmax) e na distância percorrida no TC6m em 6/25 (24%), 4/25 (16%), e 9/20 (45%), respectivamente. A PImax se associou com o PS, enquanto que a PEmax se associou com a capacidade de exercício, escala funcional do QQVRS e PS. Em conclusão, uma significativa proporção de pacientes apresentava fraqueza muscular respiratória e redução da capacidade de exercício. A força muscular respiratória mostrou associação significativa com PS, enquanto que a PEmax se relacionou com a capacidade de exercício e escala funcional do questionário de QVRS. / Peritoneal carcinomatosis (PC), secondary to advanced abdominal malignancies, causes great morbidity and is currently treated using multimodal approaches combining aggressive cytoreductive surgery (CRS) and intraperitoneal hyperthermic chemotherapy (HIPEC). The aim of the present study is to characterize the respiratory functional status of patients with PC potentially candidates to multimodal treatment approaches and the relationship of respiratory function with exercise capacity and health related quality of life (HRQL). In a cross-sectional study, 25 patients with PC referred for CRS plus HIPEC treatment approach at a tertiary care center between May 2013 and April 2014 were evaluated. Performance status, spirometry, maximal respiratory pressure measures,6-minute walk test (6MWT) and cancer specific HRQL questionnaire were assessed. Mean values of spirometry and respiratory muscle strength were above normal limits. However, reduced maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP) and 6MWT distance was found in 6/25 (24%), 4/25 (16%), and 9/20 (45%), respectively. MIP was associated with performance status while MEP was associated with exercise capacity, functional scale of HRQL questionnaire and performance status. A significant proportion of patients presented respiratory muscle weakness and impaired exercise capacity. MEP and MIP were related with performance status while MEP was additionally associated with exercise capacity and functional scale of HRQL.

La chimiothérapie systémique par voie intraveineuse, essentiellement réservée aux cancers avancés, n'est pas ciblée sur la tumeur, il est très difficile d’atteindre des niveaux thérapeutiques en intra tumoral, et ses effets secondaires et sa toxicité sont doses-limitantes.La chimiothérapie localisée pourrait permettre :1) la stabilisation des molécules médicamenteuses incorporées une seule administration médicamenteuse,2) une libération prolongée et contrôlée du médicament pour assurer une diffusion adéquate et l'absorption par les cellules cancéreuses sur plusieurs cycles de division cellulaire 3) le chargement de molécules de chimiothérapie insolubles dans l’eau, 4) l’apport direct au site de la maladie, 6) des effets secondaires diminués en évitant la circulation systémique,7) des résections chirurgicales moindres en traitant les marges de la tumeur. Nous nous sommes plus particulièrement intéressés aux cancers gynécologiques. Nous avons étudié les effets pharmacologiques et cliniques de microsphères chargées en doxorubicine (Doxo) sur un modèle de carcinose péritonéale et de tumeur de glande mammaire, et étudié le profil de diffusion ganglionnaire de divers implants non chargés. 12 jours après injection laparoscopique de tumeurs VX2 sur les ligaments larges droits et gauches de lapines WNZ 12 une injection laparoscopique de 0,5 ml de microsphères chargées ou non de Doxo (respectivement DM, groupe 1 et BM, groupe 2) a été réalisée de façon aléatoire d’un côté ou de l’autre, en sous péritonéal, au site tumoral. 7 jours après les ligaments larges, l’utérus, les ovaires, les orifices de trocarts, les intestins, la vessie, le foie et les poumons ont été examinés en macroscopie et microscopie. Le volume tumoral était plus faible dans le groupe 1 (3,6 ± 3,2 cm) par rapport au groupe 2 (8,9 ± 5,4 cm) (MW, p = 0,0179). La nécrose a été observée autour de toutes les DM, sans nécrose autour des BM. La concentration de Doxo était de 2,1 ± 2,7 uM aux limites tumorales, au-dessus du niveau thérapeutique de 1,0 uM. Sur un autre modèle, 19 jours après injection locale de suspensions tumorales de VX2 sur la deuxième glande mammaire de lapines WNZ chaque glande a été aléatoirement traitée par injection locale de 0,5 ml de microsphères chargées ou non de Doxo (HSDOXO, Groupe1, et HS, groupe 2).Pour les tumeurs de moins de 5 cm3 ou 2 cm de diamètre avant traitement, le volume final était plus faible dans le groupe 1 par rapport à groupe2 (respectivement p<0.008 et p<0.3, MW)et la croissance tumorale a été diminuée après injection de HSDOXO par rapport à HS. En microscopie une nécrose tissulaire a été observée autour des HSDOXO en extratumoral, sans nécrose autour des HS.Nous avons enfin étudié la diffusion de particules de diverses tailles, non chargées, au ganglion sentinelle d’une tumeur de glande mammaire . Les animaux ont été répartis en trois groupes de trois, chacun d'eux recevant des particules de 100 nM, 1 uM ou 10 uM. Cinq jours après traitement, l'intensité de fluorescence a été évaluée par lampe UV. Le ganglion sentinelle a été disséqué selon la technique du bleu, avant curage complet. Les premiers résultats montrent la capture de particules de 1 et 100µm par les ganglions tumoraux mais aussi dans les ganglions sains, ce qui permettrait d’envisager un traitement ganglionnaire préventif et curatif.De plus en plus de tumeurs seront décelées au stade local. Par ailleurs l'identification des phénotypes génomiques permettra un traitement personnalisé « à la carte ». On pourrait envisager un dispositif de délivrance programmable traitant tous les aspects de la maladie, de l'inhibition de la croissance tumorale et de l'angiogenèse à la promotion de la cicatrisation des tissus normaux. / Systemic chemotherapy is mainly reserved for advanced cancers, is not targeted to the tumor, it is very difficult to achieve intratumoral therapeutic levels and its side effects and toxicity are dose-limiting.Local chemotherapy may have several advantages:1) stabilization of embedded drug molecules and preservation of anticancer activity,2) controlled and prolonged drug release to ensure adequate diffusion and uptake into cancer cells over many cycles of tumor cell division, 3) loading and release of water-insoluble chemotherapeutics, 4) direct delivery to the site of disease, 5) one-time administration of the drug, 6) diminished side effects due to the avoidance of systemic circulation of chemotherapeutic drugs.We were particularly interested in gynecological cancers. We studied the pharmacological and clinical effects of doxorubicin-loaded microspheres (Doxo) in a model of peritoneal carcinomatosis,a model of mammary gland tumor, and studied the diffusion profile of various micro and nanoparticles in tumoral and non tumoral lymph nodes.12 days after laparoscopic injection of VX2 tumors on the right and left broad ligament of WNZ rabbits laparoscopic injection of 0.5 ml of microspheres loaded or not with Doxo (DM or Group 1, BM Group 2 respectively) was conducted randomly to one side or another, at the sub peritoneal tumor site. 7 days after the broad ligaments, uterus, ovaries, trocars, bowels, bladder, liver and lungs were examined macroscopically and microscopically. The tumor volume was lower in group 1 (3.6 ± 3.2 cm) compared with group 2 (8.9 ± 5.4 cm) (MW, p = 0.0179). Necrosis was observed around all DM without necrosis around the BM. Doxo concentration was 2.1 ± 2.7 µM at the tumor margins, above the therapeutic level of 1.0 uM.On another model, 19 days after local injection of VX2 tumor suspensions in the second mammary gland of WNZ rabbits each gland was randomly treated by local injection of 0.5 ml of microspheres loaded or not with Doxo (HSDOXO, Group1, and HS Group 2).For tumors less than 5 cm3 or 2 cm in diameter before treatment, the final volume was lower in group 1 compared to Group 2 (p <0.008 and p <0.3, MW) and tumor growth was reduced after HSDOXO injection compared to HS. Microscopic tissue necrosis was observed around extratumoral HSDOXO without necrosis around the HS.We finally studied the diffusion of unloaded particles of various sizes on the lymph nodes of a mammary gland tumor. The animals were divided into three groups of three, each receiving particles of 100 nm, 1 µm or 10 µm. Five days after treatment, the fluorescence intensity was measured by UV lamp. The sentinel lymph node was dissected according to the technique of blue dye.The first results show the capture of 1 μm and 100μm particles by the tumoral and non tumoral lymph nodes, which would consider a preventive and curative treatment of the nodes.Since more and more tumors are detected at the local stage and with the identification of genomic phenotypes, a personalized local chemotherapy could be the next step of cancer therapy. One could imagine a programmable controlled drug delivery device dealing with all aspects of the disease, inhibition of tumor growth and angiogenesis, while promoting the healing of normal tissues.

Les cancers ovariens se distinguent par leur faible incidence, associée à une mortalité élevée, et représente la cinquième cause de mortalité par cancer pour la population féminine. Cette mortalité est due principalement à l’absence de symptômes aux stades précoces des cancers ovariens, retardant leur diagnostic, majoritairement posé lorsqu’une carcinomatose péritonéale est installée. La cavité abdominale est alors envahie par de nombreuses métastases. Le traitement de référence est la chirurgie de cytoréduction complète et la chimiothérapie par voie intraveineuse. Lors de la chirurgie, le chirurgien doit inspecter la totalité de la surface de la cavité péritonéale, et éliminer des tumeurs de toutes tailles, mêmes submillimétriques. Faute de pouvoir détecter toutes les métastases, la cytoréduction est souvent partielle, avec pour conséquence une diminution des chances de guérison. Afin de guider le chirurgien et améliorer le pourcentage de cytoréduction complète, des sondes fluorescentes, conçues pour marquer spécifiquement les tumeurs, ont été développées. Malgré des résultats encourageants, ces sondes souffrent de nombreuses limitations en termes de brillance, de stabilité, et de modularité. Dans ce contexte, de nombreuses nanoparticules, capables de passer outre ces limitations, suscitent un grand intérêt. Parmi celles-ci, des nanocristaux semi-conducteurs, appelés quantum dots, se distinguent par une brillance exceptionnelle. Notre étude s’est basée sur ces quantum dots, associés à un agent de ciblage de référence pour les cancers ovariens, le folate. D’abord testées sur modèles cellulaires et tumoraux in vitro, ces nanoparticules ont démontré de bonnes capacités d’imagerie. Ces propriétés ont ensuite été expérimentées sur modèle murin de carcinomatose péritonéale. Enfin, la bioaccumulation des quantum dots restant un obstacle à leur application clinique, différentes alternatives ont été appliquées pour tenter d’obtenir leur excrétion / Ovarian cancers have a low incidence but a high mortality rate, making them the fifth cause of death by cancer for female population. This high mortality rate is associated with the absence of symptom at the early stage of ovarian cancer, often delaying the diagnosis to advanced stages, mainly peritoneal carcinomatosis. At this stage, metastases have already invaded the abdominal cavity. The reference treatment combines a complete cytoreduction surgery and intravenous chemotherapy. During the cytoreduction, the surgeon must inspect the whole peritoneal surface, and remove all of all sizes, even sub-millimetric. Because of the difficulty to detect and to remove every cancerous tissue, cytoreduction is frequently incomplete, thus reducing the recovery rate. To guide the surgeon and to increase the percentage of complete cytoreduction, fluorescent probes have been developed to target tumors specifically. Despite encouraging results, these probes suffer from many limitations such as low brightness, weak stability and cumbersome modularity. In this context, nanoparticles, that are able to outpass these limitations, have generated a growing interest. Among these nanoparticles, semiconductor nanocristals, called quantum dots, display an exceptional brightness. We investigated these quantum dots, associated with folate, a reference targeting agent for ovarian cancers. Firstly investigated on in vitro cellular and tumor model, folate targeted nanoparticles show encouraging imaging capabilities. These capabilites were also experimented on peritoneal carcinomatosis murine model. Finally, the main obstacle to quantum dot clinical application remains their bioaccumulation, therefore, different alternatives were explored to achieve excretion

La carcinose péritonéale est une atteinte néoplasique métastatique de la séreuse péritonéale caractérisée par la diffusion de multiples nodules tumoraux. Son pronostic est sombre, marqué par une chimiorésistance. Les traitements intrapéritonéaux, développés pour délivrer des drogues de chimiothérapie anti-cancéreuse directement au contact de ces nodules, ont permis d’améliorer en partie les résultats oncologiques de cette pathologie. Le principe est de mettre à profit la barrière péritonéo-plasmatique pour administrer des posologies plus élevées de drogues, directement au contact des nodules, et ainsi majorer leur cytotoxicité. En stratégie curative, la chimiothérapie intrapéritonéale est associée à une chirurgie de cytoréduction (CRS) complète et son efficacité est majorée par l’adjonction d’une hyperthermie (ChimioHyperthermie IntraPéritonéale - CHIP). Si ce traitement combiné a transformé le pronostic de patients sélectionnés, les résultats restent insatisfaisants. Par exemple les patients atteints de carcinose d’origine colorectale présentent un taux de survie globale à 5 ans de 40% lorsqu’ils sont éligibles à la CRS-CHIP et une médiane de survie de l’ordre de 16 mois quand le traitement se cantonne à de la chimiothérapie systémique.Une meilleure compréhension des mécanismes cellulaires impliqués dans cette chimiorésistance est donc nécessaire pour déterminer de nouvelles cibles thérapeutiques. Les protéines de choc thermique jouent un rôle fondamental dans l’homéostasie protéique intracellulaire en agissant comme protéines chaperonnes et en régulant l’architecture du cytosquelette. L’Hsp27 (ou HspB1) en particulier est impliquée dans la réponse à différents stress cellulaires comme le choc thermique, le stress oxydatif et l’exposition aux drogues de chimiothérapie. Via des mécanismes finement régulés, Hsp27 exerce une protection garantissant la survie cellulaire, en adaptant ses niveaux d’expression, d’oligomérisation et de phosphorylation. Le taux d’Hsp27 est dès lors augmenté dans la plupart des cancers et apparaît comme marqueur fort de mauvais pronostic. Cela en fait un acteur clé de la chimiorésistance et une cible thérapeutique potentielle.Parmi les thérapeutiques ciblées basées sur l’ARN, les oligonucléotides antisens (ASO) sont des molécules issues du génie génétique capables de bloquer spécifiquement la traduction d’un ARN messager cible en protéine. L’apatorsen, un ASO anti-Hsp27 de deuxième génération, a été développé pour bloquer la synthèse d’Hsp27 au sein de la cellule cancéreuse et ainsi rétablir la chimiosensibilité. Après avoir mis en place un modèle de carcinose péritonéale colorectale traitée par CRS et CHIP chez le rat, nous avons étudié in vitro et in vivo, l’effet de l’adjonction de l’apatorsen au traitement standard de cette maladie. Nos résultats ne montrent pas de gain significatif de survie et donnent lieu à une discussion sur cette stratégie de traitement / Peritoneal carcinomatosis is a neoplasic metastatic process of the peritoneal serous lining characterized by the spread of multiple tumoral nodules. The prognosis of such attempt is very poor, characterized by a global chemoresistance. Intraperitoneal treatments were developed to improve drug’s cytoxicity by delivering them directly on nodules. The principle is to take advantage of the peritoneal-plasma barrier that allows to deliver higher drug’s concentration directly onto nodules and so to improve cytotoxicity. In curative intent strategy intraperitoneal chemotherapy is combined to a complete surgical cytoreduction (CRS) and to hyperthermia to enhance efficiency (Hyperthermic Intraperitoneal Chemotherapy - HIPEC). Thanks to this strategy overall survival improved in selected patients but still be flawed. For example, patients with colorectale peritoneal carcinomatosis present a 40% five-year overall survival, whereas those not eligible to that aggressive treatment present a 16 months median survival. So a better understanding of cellular molecular mechanisms responsible for this chemoresistance that will allow identifying new therapeutic targets is needed. Heat shock proteins play a fundamental role in intracellular protein homeostasis by acting as chaperone and regulating cytoskeleton architecture. In particular, Hsp27 acts as a regulator of the cellular response to various stress, such as thermic choc, oxidative stress, exposition to antineoplasic drugs. Through finely regulated process, Hsp27 exerts a cytoprotective role to guaranty cell survival, by adapting its level of expression, oligomerization and phosphorylation. As so Hsp27 is a key actor of chemoresistance and a designated therapeutic target.Antisens oligonucleotides are a new class of molecular targeted treatment able to specifically block the traduction into protein of a messenger RNA. Apatorsen, a second generation anti-Hsp27 ASO, has been developed to decrease Hsp27 levels in neoplastic cells and so restore chemosensitivity.After establishing a colorectal peritoneal carcinomatosis rat model with CRS and HIPEC, we studied in vitro and in vivo the effect of the apatorsen adjunction to this standard treatment. Our results did not show a significant survival improvement and give rise to a discussion upon this treatment strategy

Depuis 20 ans, certains patients porteurs d’une carcinose péritonéale sont traités par une chirurgie de cytoréduction combinée avec une chimiohyperthermie intrapéritonéale (CHIP). Bien que l’oxaliplatine (OX) soit couramment utilisée lors de CHIP, une telle utilisation chez l’humain n’est supportée que par des études de phase II et il n’y a pas d’études précliniques caractérisant les propriétés de l’OX dans le contexte d’administration intrapéritonéale. L’objectif de ce projet de maîtrise est d’étudier l’effet de la température sur l’absorption tissulaire et systémique de l’OX administrée par voie intrapéritonéale chez le rat. Nous avons procédé à une perfusion intrapéritonéale de 3 différentes doses d’OX à 3 différentes températures pendant 25 minutes chez une total 35 rats Sprague-Dawley, puis effectué le dosage des concentrations d’OX dans différents compartiments. Nous avons observé une augmentation linéaire (p<0,05) entre la dose d’OX administrée et sa concentration dans tous les compartiments (péritoine, mésentère, sang portal et systémique). De plus, avec l’augmentation de la température de perfusion, nous avons observé une augmentation de la concentration d’OX dans le péritoine mais une diminution de sa concentration dans les compartiments systémique et portal (p<0,05). Ces résultats démontrent donc que la dose et l’hyperthermie augmentent indépendamment la pénétration tissulaire de l’OX et que l’hyperthermie limite son absorption systémique. Ces observations suggèrent que l’hyperthermie pourrait réduire la toxicité systémique de l’OX. Pour connaître la cinétique de l’OX, des études subséquentes doivent être faites. / Over the last twenty years, certain patients afflicted with peritoneal carcinomatosis have been treated with a combination of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion. Supported by phase II studies only, Oxaliplatin (OX) is commonly used in this context. However, pre-clinical studies to characterize its properties in such conditions are lacking. The purpose of this project is to study the effect of temperature on tissue and systemic absorption of OX when administered by intraperitoneal route in the rat. By intraperitoneal route, we administered 3 different doses of OX at 3 different temperatures for 25 minutes on 35 Sprague-Dawley rats. Samples from selected compartments were harvested and OX concentration was measured using high performance liquid chromatography. We obtained a linear correlation (p<0.05) between OX dose and tissue concentration in every compartments analyzed (peritoneum, mesentery, systemic and portal blood). With hyperthermia, we observed an increase in peritoneum and mesentery concentration of OX, but a decrease it its systemic and portal concentration (p<0.05). Intraperitoneal administration of OX leads to high concentration of drug in local tissues. Hyperthermia enhances tissue absorption and minimizes systemic absorption suggesting it could reduce systemic toxicity. Additional studies are needed to further define the pharmacokinetics of OX administered by intraperitoneal route.

Le cancer de l’ovaire est la première cause de décès par cancer gynécologique en France et il présente un fort taux de récidive justifiant la recherche de nouvelles thérapeutiques. Notre projet consiste à développer et à explorer sur des modèles expérimentaux précliniques de carcinose péritonéale de nouveaux agents thérapeutiques radiopharmaceutiques et des voies d’administration innovantes ciblant plus particulièrement la maladie résiduelle micro-métastatique présente après chirurgie de cytoréduction. Nous utilisons des anticorps monoclonaux internalisants spécifiques d’un récepteur membranaire surexprimé dans le cancer de l’ovaire et d’autres cancers gynécologiques, le récepteur de type 2 de l’hormone anti-müllerienne (AMHR2). Ces anticorps sont couplés à des radionucléides aux propriétés thérapeutiques : le Lutecium-177 (un émetteur de particules beta moins) et le Bismuth-213 (un émetteur de particules alpha) réalisant un traitement de radioimmunothérapie. Ils sont évalués après injection intrapéritonéale mais également en utilisant la technique RadioImmunoThérapie Intrapéritonéale Brève (BIP-RIT) consistant à instiller de fortes activités d’anticorps radiomarqués dans le péritoine avant d’en réaliser un rinçage abondant, à l’image de la chimiothérapie hyperthermique intrapéritonéale (CHIP). Sont étudiés sur différents modèles la biodistribution, la dosimétrie, la toxicité et l’efficacité thérapeutique des différentes combinaisons de radionucléides et de voies d’administration. La BIP-RIT présente un profil de biodistribution et de dosimétrie toujours favorable, quel que soit le radionucléide utilisé même si l’utilisation du Bismuth-213 apparait plus particulièrement adaptée à cette technique (bonne efficacité thérapeutique avec absence de toxicité). L’imagerie PET/CT de la biodistribution in-vivo de ces anticorps a été réalisée à l’aide de l’émetteur de positrons Zirconium-89 ouvrant la voie à une approche théragnostique du traitement des cancers gynécologiques AMHR2+ par (radio)immunothérapie. Les mécanismes d’action thérapeutique d’une version humanisée de l’anticorps anti-AMHR2 sont également étudiés. Ce travail ouvre des perspectives cliniques intéressantes dans la prise en charge du cancer de l’ovaire. / Ovarian cancer is the first cause of cancer death from gynaecologic malignancy in France and it has high rate of recurrence justifying the development of new therapeutic tools. Our project aims at developing new radiopharmaceuticals and innovative route of administration to target the small volume residual disease after complete cytoreductive surgery of peritoneal carcinomatosis on preclinical models. We use internalising monoclonal antibodies specific of the anti-müllerian hormone type 2 receptor (AMHR2), overexpressed in ovarian cancer and gynaecologic malignancies. Antibodies are radiolabelled with Lutecium-177, a beta minus emitter, and Bismuth-213, an alpha emitter, to perform radioimmunotherapy. Radiolabelled antibodies are injected intraperitoneally but also after Brief IntraPeritoneal RadioImmunoTherapy (BIP-RIT), a technique delivering high activities in the peritoneal cavity for a short time before washing, like Hyperthermic IntraPEritoneal Chemotherapy (HIPEC). We studied biodistribution, dosimetry, toxicity and therapeutic efficacy on various models and combinaison of radionuclides and route of administration. BIP-RIT appears to be always favourable in term of biodistribution and dosimetry (especially for the tumour-over-blood ratio) whatever the radionuclide used. Bismuth-213 is particularly adapted for radioimmunotherapy of small residual tumours, showing therapeutic efficacy with no toxicity. PET/CT imaging of radiolabelled antibodies with Zirconium-89 was performed and may be used as a theranostic tool for (radio)immunotherapy with anti-AMHR2 antibodies. The anti-tumour efficacy mechanisms of a humanized version of anti-AMHR2 antibody are also presented. This work may lead to realistic theranostic options in ovarian cancer in clinic.

Gastric cancer (GC) is one of leading causes of death in the world, and peritoneal metastases (PM) are a major site of recurrence. PM from GC implies a poor prognosis, with median overall survival (mOS) approximately 3 months and no survival at five years. The aims of this thesis were to explore the incidence and evaluate prognostic factors for mOS of PM from GC in a defined population; to investigate the outcome of a new multimodal treatment; to analyse the treatment costs, and to investigate differences in drug sensitivity between individual patient samples and between various tumours. The incidence of loco-regional advanced GC was 3.8 per 100,000 person-years. Synchronous loco-regional GC in combination with synchronous distant metastasis was a negative prognostic factor while chemotherapy and good performance status, and radiotherapy plus chemotherapy were positive prognostic factors . There were no significant differences in mOS for the group of patients included during the period 2000-2004 versus 2005-2009, and this lack of improvement in mOS during the past decade justifies new treatment approaches. In a Phase II study of patients treated with neoadjuvant systemic chemotherapy followed by cytoreductive surgery + hyperthermic intraperitoneal chemotherapy, mOS was 14.3 months and for patients with macroscopically radical surgery mOS was 19.1 months. The mean overall cost of the loco-regional treatment was $145,700 compared to $59,300 with systemic chemotherapy treatment. In an ex vivo chemo-sensitivity test, it was determined that GC samples were equivalent to colorectal cancer in chemo-sensitivity to standard drugs and targeted drugs, whereas ovarian cancer samples were more sensitive. The individual GC samples varied considerably in sensitivity to increasing concentrations of the drugs, arguing for individualized drug selection. The incidence of loco-regional advanced GC was more common than previously reported and there were no improvements in mOS over the past decade. The mOS for patients with neoadjuvant systemic chemotherapy followed by macroscopically radical cytoreductive surgery + hyperthermic intraperitoneal chemotherapy was better than in recent reports on treatment with systemic chemotherapy. Treatment of advanced GC patients is costly irrespective of treatment modality. The GC samples varied considerably between individuals in terms of sensitivity to increasing concentrations of the drugs and were comparable to colorectal cancer in chemo-sensitivity.

Depuis 20 ans, certains patients porteurs d’une carcinose péritonéale sont traités par une chirurgie de cytoréduction combinée avec une chimiohyperthermie intrapéritonéale (CHIP). Bien que l’oxaliplatine (OX) soit couramment utilisée lors de CHIP, une telle utilisation chez l’humain n’est supportée que par des études de phase II et il n’y a pas d’études précliniques caractérisant les propriétés de l’OX dans le contexte d’administration intrapéritonéale. L’objectif de ce projet de maîtrise est d’étudier l’effet de la température sur l’absorption tissulaire et systémique de l’OX administrée par voie intrapéritonéale chez le rat. Nous avons procédé à une perfusion intrapéritonéale de 3 différentes doses d’OX à 3 différentes températures pendant 25 minutes chez une total 35 rats Sprague-Dawley, puis effectué le dosage des concentrations d’OX dans différents compartiments. Nous avons observé une augmentation linéaire (p<0,05) entre la dose d’OX administrée et sa concentration dans tous les compartiments (péritoine, mésentère, sang portal et systémique). De plus, avec l’augmentation de la température de perfusion, nous avons observé une augmentation de la concentration d’OX dans le péritoine mais une diminution de sa concentration dans les compartiments systémique et portal (p<0,05). Ces résultats démontrent donc que la dose et l’hyperthermie augmentent indépendamment la pénétration tissulaire de l’OX et que l’hyperthermie limite son absorption systémique. Ces observations suggèrent que l’hyperthermie pourrait réduire la toxicité systémique de l’OX. Pour connaître la cinétique de l’OX, des études subséquentes doivent être faites. / Over the last twenty years, certain patients afflicted with peritoneal carcinomatosis have been treated with a combination of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion. Supported by phase II studies only, Oxaliplatin (OX) is commonly used in this context. However, pre-clinical studies to characterize its properties in such conditions are lacking. The purpose of this project is to study the effect of temperature on tissue and systemic absorption of OX when administered by intraperitoneal route in the rat. By intraperitoneal route, we administered 3 different doses of OX at 3 different temperatures for 25 minutes on 35 Sprague-Dawley rats. Samples from selected compartments were harvested and OX concentration was measured using high performance liquid chromatography. We obtained a linear correlation (p<0.05) between OX dose and tissue concentration in every compartments analyzed (peritoneum, mesentery, systemic and portal blood). With hyperthermia, we observed an increase in peritoneum and mesentery concentration of OX, but a decrease it its systemic and portal concentration (p<0.05). Intraperitoneal administration of OX leads to high concentration of drug in local tissues. Hyperthermia enhances tissue absorption and minimizes systemic absorption suggesting it could reduce systemic toxicity. Additional studies are needed to further define the pharmacokinetics of OX administered by intraperitoneal route.