Design and Development of a Surgical Robot for Needle-Based Medical Interventions

Lung cancer is the leading cause of cancer related deaths. If diagnosed in a timely manner, the treatment of choice is surgical resection of the cancerous lesions followed by radiotherapy. However, surgical resection may be too invasive for some patients due to old age or weakness. An alternative is minimally invasive needle-based interventions for cancer diagnosis and treatment. This project describes the design, analysis, development and experimental evaluation of a modular, compact, patient-mounted robotic manipulator for lung cancer diagnosis and treatment. In this regard, a novel parallel Remote Centre of Motion (RCM) mechanism is proposed for minimally invasive delivery of needle-based interventions. The proposed robot provides four degrees of freedom (DOFs) to orient and move a surgical needle within a spherical coordinate system. There is an analytical solution for the kinematics of the proposed parallel mechanism and the end-effectors motion is well-conditioned within the required workspace. The RCM is located beneath the skin surface to minimize the invasiveness of the surgical procedure while providing the required workspace to target the cancerous lesions. In addition, the proposed robot benefits from a design capable of measuring the interaction forces between the needle and the tissue. The experimental evaluation of the robot has proved its capability to accurately orient and move a surgical needle within the required workspace. Although this robotic system has been designed for the treatment of lung cancer, it is capable of performing other procedures in the thoracic or abdominal cavity such as liver cancer diagnosis and treatment

A minimally invasive multimodality image-guided (MIMIG) system for peripheral lung cancer intervention and diagnosis

Abstract. The once-promising computed tomography (CT) lung cancer screening appears to result in high false positive rates. To tackle the common difficulties in diagnosing small lung cancer at an early stage, we developed a minimally invasive multimodality image-guided (MIMIG) interventional system for early detection and treatment of peripheral lung cancer. The system consists of new CT image segmentation for surgical planning, intervention guidance for targeting, and molecular imaging for diagnosis. Using advanced image segmentation technique the pulmonary vessels, airways, as well as nodules can be better visualized for surgical planning. These segmented results are then transformed onto the intra-procedural CT for interventional guidance using electromagnetic (EM) tracking. Diagnosis can be achieved at microscopic resolution using a fiber-optic microendoscopy. The system can also be used for fine needle aspiration biopsy to improve the accuracy and efficiency. Confirmed cancer could then be treated on-the-spot using radio-frequency ablation (RFA). The experiments on rabbits with VX2 lung cancer model show both accuracy and efficiency in localization and detecting lung cancer, as well as promising molecular imaging tumor detection

Régulation de l'expression de ligands de l'immunité par la voie Rho/ROCK sur les mélanomes

Ma thèse porte sur l'étude des rôles régulateurs des GTPases Rho et de leurs effecteurs ROCK sur l'expression de ligands du système immunitaire, sur des cellules de mélanomes murins et humains ainsi que les conséquences sur le développement tumoral de modulateurs de la voie RhoA/ROCK. A l'heure actuelle, les traitements du mélanome métastatique ont une efficacité limitée, c'est pourquoi les nouvelles stratégies s'orientent vers l'immunothérapie notamment en recherchant de nouvelles molécules pharmacologiques capables d'amplifier les réponses immunes anti mélanome. Mon travail a porté sur l'étude de trois ligands de l'immunité modulés par la voie RhoA/ROCK : - Nous avons étudié la régulation du ligand MICA qui est exprimé sur des mélanomes humains, mais qui est reconnu par les cellules NK humaines et murines du système immun inné. En utilisant des statines, qui sont des inhibiteurs de l'activité des Rho, nous avons induit une surexpression membranaire de MICA sans toxicité cellulaire. Cette surexpression s'accompagne d'une sensibilisation des mélanomes à la lyse par les cellules NK. Elle induit également un ralentissement de leur croissance tumorale sous-cutanée en souris NMRI nu/nu et une diminution de l'implantation des métastases pulmonaires. Nous avons aussi montré que cette régulation de MICA induite par les statines ne dépendait pas de l'inhibition des GTPases Ras ou Rho mais de la voie de PPAR?. - Nous avons ensuite étudié la régulation de la molécule de costimulation CD70 par les GTPases Rho sur des mélanomes humains et son rôle dans ces tumeurs. Nous avons montré que les mélanomes primitifs expriment CD70, que cette expression diminue au cours de la maladie et que la GTPase RhoA et la voie des MAPK contrôlent positivement l'expression de CD70 sur nos lignées de mélanome humain. De façon surprenante, nous avons aussi montré que CD70 possède une fonction non immunologique dans ces tumeurs. En effet, la trimérisation de CD70 favorise l'invasion tumorale et l'apparition de métastases en activant la voie de signalisation BRAF/MEK/ERK/RhoE et en inhibant les fibres de stress d'actine et des points focaux d'adhésion. - Enfin, nous nous sommes intéressés aux conséquences de la modulation de FasL sur le développement tumoral du mélanome murin B16F10. Des travaux précédents de l'équipe ont montré que la protéine RhoA et ses effecteurs ROCK régulent de façon négative l'expression de FasL à la membrane des cellules B16F10. Nous avons étudié le rôle in vivo de la surexpression de FasL induite par l'inhibition de ROCK par le H1152. Nous avons mis en évidence un ralentissement de la croissance tumorale in vivo chez les souris immunocompétentes. Ce contrôle du développement tumoral est dépendant de la voie Fas/FasL et de l'activité des lymphocytes TCD8+ et de l'IFN-?. De plus, l'inhibition de ROCK réduit le nombre de métastases pulmonaires sans intervention de la réponse immune adaptative. L'ensemble de mes travaux montre que le ciblage de la voie des GTPases Rho et de leurs effecteurs ROCK constitue une approche nouvelle pour amplifier les réponses immunes protectrices innées et adaptatives anti mélanome, suggérant que des inhibiteurs de cette voie pourraient être envisagés dans de nouveaux protocoles d'immunothérapie du mélanomeMy thesis focuses on the study of the regulatory roles of Rho GTPases and their effectors ROCK on the expression of immune system ligands in murine and human melanoma cell lines and the impact on tumor development of modulators of the RhoA/ROCK pathway. Current therapies for metastatic melanoma have poor efficiency. It is the reason why new immunotherapeutic strategies are developed for to find new pharmacological molecules that could improve anti-melanoma immune responses. My work is based on the study of three immune ligands: - We studied the regulation by Rho GTPases of MICA ligand expression in human melanoma cell lines and their recognition by NK cells. Using statins, inhibitors of Rho GTPases activity, we have induced MICA over-expression without any cell toxicity. This MICA over-expression enhanced melanoma cells sensitivity to NK cells lysis, then reduced subcutaneous tumor growth in NMRI nu/nu mice and also decreased pulmonary metastases implantation. We also showed that statins-induced MICA over-expression was not linked to Ras or Rho GTPases inhibition but to PPAR? pathway. - Then, we studied the expression and the function of a co-stimulatory molecule, CD70, and its regulation by the Rho pathway in human melanomas. We demonstrated that the RhoA GTPase and MAPK pathway positively regulate CD70 expression in our melanoma cell lines. Surprisingly, we observed a non-immunological function of CD70 in melanoma. Indeed, CD70 trimerization enhanced melanomas invasion and metastatic capacities through an activation of BRAF/MEK/ERK/RhoE pathway, which inhibited stress fibers and focal adhesions. - Finally, we analyzed the consequences of FasL over-expression on B16F10 murine melanoma development in vivo. Our previous studies have showed that RhoA/ROCK pathway negatively regulates membrane FasL expression on B16F10 cells. We studied in vivo the role of this FasL over-expression induced by ROCK inhibitor H1152, on melanoma cells. We showed tumor growth shrinkage in immunocompetent mice, when B16F10 cells were pretreated with H1152. The Fas/FasL pathway and the activity of TCD8+ cells and IFN- ? induced this tumor slowing down. Moreover, ROCK inhibition induced a reduction of pulmonary metastases implantation independently of T lymphocytes response. Altogether, my work showed that targeting Rho GTPases/ROCK pathway could be interesting in order to improve innate and adaptative anti melanoma immune responses, suggesting that inhibitors of this pathway could be envisaged in new melanoma immunotherapy protocol