Space structures are inevitable while covering large spans. Space structures are skeletal structures, which are lighter for the same stiffness when compared with RCC roofs. Till now, space structures, like any other metal structures have been designed assuming the joints as rigid, although there have been several publications about semi rigid joints. Of course, the publications mostly deal with 2D structures and there are very few reports on 3D structures. Space structures, by their nature fall into the latter category. The joints in a space structure are popularly called as "nodes". Generally, nodes, which ensure concentricity of member axes, are either solid or hollow. These are either cast or forged. There are other proprietary types, which do not come under the above classification, and have not been considered in this thesis. Hollow nodes are obviously more economical than solid nodes, but also more flexible. While it is prudent to prefer hollow nodes, it is equally necessary to assess their flexibility, because of its influence on the behaviour of the structure. The hollow spherical node is very popular because of its simplicity and adaptability to various forms of space frames. Double layer grids, which are the most popular forms for roofing applications, are being increasingly implemented. While the hollow spherical node is well suited for double layer grids, an evolutionary development has been what is called as the hollow octahedral node (this node is simply referred to as the 'Octa ' node in this thesis). Chapter 1 introduces space frames and double layer grids in particular, with the advantages of using double-layer grids. Jointing systems available around the world are briefed and the node connector used in the present study is introduced with a brief write-up on its advantages and disadvantages. This chapter also explores the available literature and, the scope and objectives of the thesis are mentioned. Chapter 2 introduces 3D finite element models of the hollow spherical and octahedral nodes. The stiffness matrixes of these nodes have been derived by conducting analyses on the computer for six sizes each of the Octa and spherical nodes. Using the stiffness matrix of the node, a new method of incorporating this into the regular analysis of a space truss has been developed. The new method proposed yields realistic values for the forces in the members and takes into account the elastic deflections in the node under the action of member forces. Implementation of the proposed method has been carried out by writing a custom program using state-of-the-art object oriented programming techniques. A sample problem has been analyzed using this program to demonstrate the effect of including joint flexibility. The effect of flexibility of nodes on the effective length of compression members in double-layer grids has been evaluated. The effect of compliance on the dynamic characteristics of a space frame has also been evaluated for the sample space frame with flexible joints. The analysis program has been modified to evaluate the natural frequencies of the system using rigid or flexible nodes. The study of the Octanode and spherical node under the action of uniaxial compression and tension dominates the contents of Chapter 3. The two types of nodes have been analyzed using commercially available finite element software considering material nonlinearity. The stress patterns from the analyses have been examined thoroughly. Two consistent methods for fixing the load at yield in both uniaxial compression and tension have been proposed using the load-displacement curve. Yield loads for all the nodes have been evaluated using both the methods and the results agree well between the two methods. Three material yield values have been selected for each of the node size for evaluating the yield values viz. 240,320 and 415 MPa. The members of a double layer grid are connected to the nodes by bolts and holes are drilled in the nodes for this purpose. The bolthole patterns differ between two popular types of double-layer grids. Both these bolthole patterns have been modeled separately in the above exercise and the results for these two have been shown to be approximately the same. The effect of varying diameters of the boltholes on the response of the nodes has been examined. Relationships between the yield load, diameter, thickness and material yield have been developed using the method of least squares. The differences in the behaviour of the nodes under uniaxial compression and tension have been discussed. Ramberg Osgood type of relationships have been worked out for all the load-displacement curves obtained from the analyses. The simulation of non-linear behaviour of nodes with cracks with plastic crack closing forces have been carried out with useful insights into the behaviour of the two types of nodes in uniaxial compression and tension. Chapter 4 is devoted largely for studying the two types of nodes under the influence of biaxial load combinations. The combinations studied are dual compression, dual tension and compression-tension. In all cases equal loads are applied along two orthogonal; directions in the horizontal plane. Stress patterns have been examined for each type of load combination and yield values for each case have been obtained using one of the methods proposed in chapter 3. These have been compared with the corresponding uniaxial values in both compression and tension. Some useful inferences have been possible by studying the behaviour of the nodes under the various biaxial load combinations. In each case, relationships between the biaxial yield load, uniaxial yield load, diameter of node, thickness of node and material yield of node have been obtained using the method of least squares. The nodes have been analyzed under some selected Multi-axial loading and combinations of load which cause yield based on the second method proposed in Chapter 3 have been obtained and tabulated. However, a proper and thorough study of the nodes under multi-axial loading proved to be beyond the scope of this thesis. Chapter 5 contains the contributions made towards developing new methods and algorithms for obtaining the several results of chapters 2, 3 and 4, using object oriented programming (OOP) techniques. The contributions have been in Object Pascal, the underlying language of Delphi, a popular RAD tool developed by Borland/Inprise of USA. Several new modules have been developed to reliably handle the large amounts of data generated by the hundreds of analyses detailed in chapters 2,3 and 4. The ease with which new methods were possible to be incorporated into existing software using OOP has been demonstrated, with source code examples. Comparisons with other types of tools available and die advantages of using OOP have also been demonstrated using the experience during the preparation of this thesis. A strong case for OOP as an indispensable tool for the researcher has been made. Chapter 6: Several important conclusions and suggestions for future work have been made. Appendix 1 contains a brief note on the Method of Least Squares. Appendix 2 contains a small write-up on Delphi and OOP. Concepts of OOP have been briefly described and comparisons between three popular OOP languages have been attempted. A brief description of the features in Delphi's Object Pascal has also been provided. Appendix 3 contains the listing of Unit Arrays, which is a general purpose unit developed to make handling of large arrays easy. Several matrix calculations have been implemented which make the unit extremely useful for programmers. Appendix 4 contains the full listing of program FormK, which has been developed for chapter 2 to derive the fall stiffness matrix of a space frame node. The program picks up results from several analyses, forms a few columns of the stiffness matrix and then fills up the rest using the cyclic symmetry present in the space frame node. This program is given in full, with the intention that other researchers may find it useful to use it as-is or use after making small alterations to suit their circumstances. OOP is known for fast, reliable and easy ways of implementing modifications to existing code. Appendix 5 provides the full listing of the Object Pascal program for extracting Eigenvalues of a space truss with rigid joints or flexible joints. The incorporation of flexibility of the joints proposed in chapter 2 has been implemented. Descriptions of the program's implementations have been provided in chapter 5. Bibliography contains the alphabetical list of references.

1 ABSTRACT Background Breast cancer cell population characteristics are used in common clinical practice for estimation of prognosis of the malignant disease (prognostic factors) and for prediction of reactivity of the tumor to certain therapeutic modality (predictive factors). Also axillary lymph node status is an independent prognostic factor in women with early breast cancer. Therefore, surgical excision and following histopathological examination of the nodes is the obligatory part of primary breast cancer surgery. The extension of axillary surgery varies widely, although sentinel lymph node biopsy is considered to be the standard procedure. However, it must be admitted that this type of procedure need not be optimal for all the breast cancer patients. Aims of the study The aim of this study is the verify the hypothesis whether or not the axillary lymph node metastatic affection can be effectively estimated using non-surgical methods - i.e. by evaluation of the combination of prognostic and predictive factors of the primary breast tumor. Statistical model composed on the basis of data of early breast cancer patients is the basic tool for this prediction. Application of this model In everyday practice can enable to adjust the extent of axillary surgery for each individual patient. Patients and methods A...

INTRODUÇÃO: O status linfonodal da axila ainda permanece como importante fator prognóstico em pacientes com câncer de mama invasivo. Muitos estudos já relataram a importância da ultrassonografia axilar e da punção aspirativa por agulha fina (PAAF) na avaliação pré-operatória das pacientes com câncer de mama. Nossos objetivos foram avaliar as características ultrassonográficas dos linfonodos axilares relacionadas à metástase linfonodal e o papel da PAAF na avaliação pré-operatória de pacientes com câncer de mama. Nosso objetivo secundário foi avaliar se, dependendo das características dos tumores, linfonodos sem alterações na ultrassonografia poderiam ter comprometimento metastático. MÉTODOS: Este estudo foi realizado no Instituto de Radiologia e no Instituto do Câncer do HCFMUSP. Foram incluídas 182 pacientes com câncer de mama invasivo recém-diagnosticado, sendo que, destas, apenas 145 realizaram cirurgia - 74 prosseguiram direto para cirurgia e 71 realizaram tratamento neoadjuvante e após cirurgia. Foi realizada avaliação ultrassonográfica da axila ipsilateral ao tumor e punção aspirativa por agulha fina de um linfonodo selecionado pelo radiologista. Os dados ultrassonográficos dos linfonodos e os achados citológicos da PAAF foram correlacionados com os resultados anatomopatológicos da biópsia do linfonodo sentinela ou do esvaziamento axilar. RESULTADOS: Nas 74 pacientes (75 axilas) que não realizaram tratamento neoadjuvante, as características ultrassonográficas do linfonodo associadas à metástase na análise univariada foram espessamento cortical difuso e a obliteração parcial ou completa do hilo gorduroso. A sensibilidade, especificidade, acurácia, valor preditivo positivo (VPP) e valor preditivo negativo (VPN) da ultrassonografia foram, respectivamente, 72,7%, 57,1%, 64,0%, 57,1% e 72,7% (p=0,009), e da PAAF: 36,4%, 97,6%, 70,7%, 92,3% e 66,1% (p < 0,001). Incluindo apenas linfonodos alterados na ultrassonografia, obtivemos, respectivamente, sensibilidade, especificidade, acurácia, VPP e VPN de 50%, 94%, 69%, 92% 59% (p=0,001). Nenhuma PAAF de linfonodo classificado como normal na ultrassonografia teve resultado positivo. Obtivemos, nas análises das curvas ROC, um valor de corte da espessura da cortical de 2,65 mm (p < 0,001) e do tamanho do tumor pré-cirúrgico de 2,45 cm (p=0,042). Na análise multivariada, as seguintes características foram associadas à metástase linfonodal: espessura da cortical (p = 0,005), tamanho do tumor pré-cirúrgico (p = 0,030), status pré-menopausa (p = 0,017), tipo histológico não especial (p = 0,034) e localização do tumor no quadrante superolateral (p = 0,011). Construiu-se um modelo de predição de risco de metástase axilar usando estas características. Nas 71 pacientes que realizaram tratamento adjuvante, a única característica do linfonodo associada à metástase linfonodal foi a forma redonda ou irregular. Os demais resultados deste grupo não podem ser generalizados, pois não é possível separar o efeito do tratamento nesta população. CONCLUSÕES: Linfonodos axilares com espessamento cortical difuso e com obliteração parcial ou completa do hilo gorduroso estão associados à malignidade. A PAAF apresentou-se mais útil nos linfonodos alterados, com sensibilidade de 50%. Pacientes com PAAF positivas devem ser encaminhadas para esvaziamento axilar ou quimioterapia neoadjuvante. Não há benefício da realização da PAAF em linfonodos sem alterações na ultrassonografia / BACKGROUND: The lymph node status of the axilla remains an important prognostic factor in patients with invasive breast cancer. Many studies have already reported the importance of axillary ultrasonography and fine needle aspiration (FNA) in the preoperative evaluation of patients with breast cancer. Our objectives were to evaluate the ultrasound characteristics of axillary lymph nodes related to lymph node metastasis and the role of FNA in the preoperative evaluation of patients with breast cancer. Our secondary objective was to assess whether, depending on the tumor characteristics, lymph nodes that showed no change on ultrasonography could have metastatic involvement. METHODS: This study was conducted at the Institute of Radiology and the Institute of Cancer of HCFMUSP. A total of 182 patients with newly diagnosed invasive breast cancer were included, of whom only 145 had undergone surgery - 74 went straight to surgery and 71 underwent neoadjuvant treatment and after surgery. Ultrasound evaluation of the axilla ipsilateral to the tumor and fine needle aspiration of a lymph node selected by the radiologist were performed. The ultrasound data of the lymph nodes and the cytological findings of FNA were correlated with pathology results from sentinel lymph node biopsy or surgical dissection. RESULTS: In the 74 patients (75 axillae) who did not undergo neoadjuvant treatment, the ultrasound characteristics of the lymph nodes associated with metastasis in the univariate analysis were diffuse cortical thickening and partial or complete fatty hilum obliteration. The sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of ultrasound were respectively 72.7%, 57.1%, 64.0%, 57.1% and 72.7% (p = 0.009) and of the FNA 36.4%, 97.6%, 70.7%, 92.3% and 66.1% (p <0.001). Including only atypical lymph nodes on ultrasonography, we obtained respectively sensitivity, specificity, accuracy, PPV and NPV of 50%, 94%, 69% 92% and 59% (p = 0.001). No FNA of lymph node classified as normal on ultrasonography had a positive result. With ROC curves analysis we obtained a cut-off value of cortical thickness of 2.65 mm (p <0.001) and pre-surgical tumor size of 2.45 cm (p = 0.042). In the multivariate analysis, the following characteristics were associated with lymph node metastasis: cortical thickness (p = 0.005), preoperative tumor size (p = 0.030), premenopausal status (p = 0.017), non-special histological type and tumor location in the upper outer quadrant (p = 0.011). A predictive model of axillary metastasis risk was constructed using these characteristics. In the 71 patients who underwent adjuvant treatment the only feature of the lymph node associated with lymph node metastasis was the round or irregular shape. The other results of this group cannot be generalized since it is not possible to separate the treatment effect in this population. CONCLUSIONS: Axillary lymph nodes with diffuse cortical thickening and with partial or complete fatty hilum obliteration are associated with malignancy. FNA was more useful in atypical lymph nodes, with a sensitivity of 50%. Patients with positive FNA should be referred for axillary surgical dissection or neoadjuvant chemotherapy. There is no benefit of performing FNA in lymph nodes without changes in ultrasound

Introdução: O adenocarcinoma gástrico é uma doença de elevada incidência e alta mortalidade. A gastrectomia com linfadenectomia é tratamento potencialmente curativo, promovendo controle loco-regional da doença e fornecendo material para análise histopatológica. Para o adequado estadiamento dos pacientes é recomendado que pelo menos 16 linfonodos sejam examinados pela patologia, entretanto, espera-se maior sobrevida quando >= 30 linfonodos são avaliados, mesmo em pacientes com tumores precoces. A justificativa para este achado é o sub-estadiamento de pacientes com poucos linfonodos examinados. Linfonodos pequenos são particularmente difíceis de serem encontrados, mas podem conter metástases e impactar negativamente na sobrevida. Visando facilitar sua identificação, soluções clareadoras de gordura foram propostas, entretanto não há evidência clara de seu benefício clínico. Objetivos: Comparar as soluções de Carnoy e de formalina neutra tamponada em relação ao número absoluto de linfonodos encontrados na peça cirúrgica de pacientes submetidos a gastrectomia. Averiguar se linfonodos retirados cirurgicamente são perdidos com a fixação em formalina e, caso isso ocorra, se este fato é relevante para o estadiamento. Observar se o protocolo de pesquisa influenciou o número de linfonodos encontrados. Métodos: Cinquenta produtos de gastrectomia subtotal com linfadenectomia D2 por adenocarcinoma gástrico foram randomizados para fixação em Carnoy ou formalina com posterior dissecção da peça em busca de linfonodos. Após a dissecção do grupo Formalina, a gordura residual a ser desprezada foi imersa em Carnoy e reavaliada posteriormente. Os dados de 25 gastrectomias D2 operadas previamente ao estudo também foram avaliados. Resultados: A média de linfonodos encontrados nos grupos Carnoy e Formalina foi de 50,4 e 34,8; respectivamente (p < 0,001). Na gordura residual foram encontrados linfonodos em todos os casos (média 16,9 linfonodos), elevando a média do grupo Formalina para 51,7 (valor similar ao do grupo Carnoy, p=0,809). Com exceção de 1 linfonodo de 7mm, todos os demais encontrados na gordura residual mediram <= 3mm. Treze linfonodos metastáticos passaram despercebidos com a fixação em formalina e a revisão da gordura residual determinou a mudança de estadiamento de 2 (8%) pacientes. Os linfonodos encontrados no Carnoy possuíam tamanho significativamente menor quando comparados aos do grupo Formalina (p=0,01). A média de linfonodos encontrados no grupo retrospectivo foi similar ao do grupo Formalina prospectivo (p=0,802). Conclusões: Quando comparada à formalina, a solução de Carnoy permite encontrar número maior de linfonodos no espécime cirúrgico de gastrectomias com linfadenectomia. Linfonodos milimétricos foram perdidos após a fixação em formalina, estes foram identificados com o Carnoy e são clinicamente relevantes, pois podem conter metástases modificando assim, o estádio clínico e prognóstico do paciente. A implementação de protocolo de pesquisa não influenciou o número de linfonodos encontrados neste estudo / Background: Gastric adenocarcinoma is a frequent disease with high mortality ratio. Gastrectomy with lymphadenectomy is potentially curative, allows local control of the disease and provides material for TNM classification. While pathology examination of at least 16 lymph nodes is recommended following surgery, longer survival rates are expected when >=30 lymph nodes are examined, even for early gastric cancer. The understaging of patients with less examined lymph nodes justifies this findings. Small lymph nodes are particularly difficult to identify and fat clearing solutions have been proposed to improve this, but there is no evidence of their clinical benefit. Objectives: Compare Carnoy\'s solution (CS) and formalin in terms of the total number of examined lymph nodes following gastrectomy. Verify if surgically retrieved lymph nodes are lost with the formalin fixation and if this fact is clinically significant. Observe if a research protocol influences the number of examined lymph nodes. Methods: Fifty specimens of gastrectomy with D2 lymphadenectomy were randomized for fixation in CS or formalin with posterior dissection in search for lymph nodes. In the Formalin group, the residual fat to be discarded was immersed in CS and dissected again. Data from 25 D2 gastrectomies performed previously the present study were retrospectively analyzed. Results: The medium number of examined lymph nodes was 50.4 and 34.8 for CS and formalin, respectively (p < 0.001). Lost lymph nodes were found in all cases in the Residual Fat group (medium 16.9), this increased the Formalin group average to 51.7 (which is similar to the CS group, p=0.809). With one exception (7mm), all other examined lymph nodes in the Residual Fat group measured <= 3mm. Thirteen lymph nodes from this group were metastatic, this determined the upstaging of 2 (8%) patients. Lymph nodes from the CS group were smaller than those found in the formalin group (p=0.01). The medium number of retrieved lymph nodes in the retrospective group was similar to the formalin group (p=0.802). Conclusions: When compared to formalin, Carnoy\'s solution increases lymph node detection following gastrectomy with lymphadenectomy. CS identifies small lymph nodes lost with formalin fixation and that are clinically significant, since they may contain metastasis, modifying the TNM classification. No influence of the research protocol over the number of examined lymph nodes was observed in the present study.

Résumé:IntroductionLa chirurgie reste le seul traitement à visée curative pour les patients porteurs d’un cancer colorectal (CCR) primitif ou métastatique. L’établissement précis de l’extension de la maladie, au niveau de la tumeur primitive, des ganglions loco-régionaux et des métastases à distance représente un élément essentiel pour la prise en charge thérapeutique. Les ganglions locorégionaux et la technique du ganglion sentinellePour les patients présentant un CCR non métastatique, l’analyse pathologique des ganglions (pN) conditionne la décision d’administrer ou non une chimiothérapie adjuvante. Les patients présentant un envahissement ganglionnaire (pN+) recevront un traitement adjuvant, celui-ci n’étant le plus souvent pas indiqué chez les patients sans envahissement ganglionnaire (pN0). Près de 20 à 30% des patients classés pN0 vont cependant développer des récidives tumorales. Parmi ces patients, il est probable qu’une partie ait été sous-classée au moment du diagnostic. La technique du ganglion sentinelle (GS) permet d’identifier les ganglions les plus susceptibles d’être envahis et de réaliser des analyses anatomopathologiques plus approfondies sur un nombre plus limité d’échantillon. Cette technique est recommandée dans le cancer du sein et dans le mélanome, mais son rôle reste discuté dans le CCR. Le premier volet de cette thèse concerne les résultats d’études cliniques que nous avons menées pour évaluer le rôle de la technique du GS au bleu patenté (BP) et de l’imagerie en fluorescence (IF) au vert d’indocyanine ou indocyanine green (ICG) dans le staging ganglionnaire des patients présentant un CCR. Les principaux objectifs de ces travaux étaient d’évaluer la faisabilité de ces techniques et leur apport dans le staging des patients présentant un CCR.Notre première étude sur la technique du GS au BP, représentant la plus grande cohorte monocentrique européenne, a permis de démontrer la faisabilité de la technique. En outre, cette approche a modifié le geste chirurgical dans 12% des cas (technique in vivo) et a permis de reclasser 10% des patients initialement classés pN0 en pN+ par la réalisation de coupes sériées spécifiquement réalisées sur les ganglions démontrés comme GS. Dans une seconde étude sur la technique du GS comparant l’IF-ICG à la technique au BP, nous avons montré que ces 2 techniques étaient complémentaires, permettant d’augmenter la sensibilité globale pour la détection des métastases ganglionnaires. De plus, l’IF-ICG apparaît comme plus sensible chez les patients présentant une surcharge pondérale. En termes de sensibilité, la recherche du GS par IF est supérieure à la technique BP, ces résultats restant cependant limités, notamment en raison d’un taux élevé de faux négatifs (FN) pour les tumeurs localement avancées (pT3-4). Les métastases ganglionnaires et la carcinose péritonéaleDans le CCR, les patients métastatiques, présentant une carcinose péritonéale (CP) et/ou un envahissement ganglionnaire, ont un pronostic sombre. La chirurgie d’exérèse de la CP associée à une chimiothérapie hyperthermique intrapéritonéale (CHIP) et la réalisation de curages ganglionnaires chez les patients porteurs d’une maladie oligométastatique permettent toutefois d’obtenir des survies prolongées et parfois des guérisons, avec des résultats similaires à ceux observés chez les patients opérés pour métastases hépatiques isolées. Pour la CP, l’étendue de la maladie et la radicalité de la résection sont les principaux facteurs pronostiques de survie. La sensibilité des examens d’imagerie conventionnelle et métabolique reste cependant faible pour déterminer l’extension de la maladie péritonéale. L’évaluation de l’étendue de la CP et son exérèse sont donc essentiellement fondées sur la palpation et l’exploration visuelle réalisée durant l’intervention chirurgicale, représentant un facteur limitant pour la radicalité de la chirurgie. De façon similaire, chez les patients présentant une maladie métastatique ganglionnaire limitée, la détection peropératoire est souvent difficile, nécessitant la réalisation de curages étendus de principe, afin de s’assurer de l’exérèse des ganglions pathologiques.L’utilisation de l’IF après injection iv intra-opératoire d’ICG a été rapportée comme une technique permettant la détection de tissu tumoral tant visible que non visible (infraclinique), pouvant potentiellement aider le chirurgien et guider les gestes de résection. Aucune étude n’avait particulièrement analysé le rôle de l’IF-ICG dans la détection de CP et de métastases ganglionnaires de CCR. Le second volet de cette thèse concerne l’évaluation de l’apport de l’IF après injection iv d’ICG pour la détection de la CP et des métastases ganglionnaires dans le CCR. L’objectif primaire était de vérifier si les métastases péritonéales (MP) et ganglionnaires visibles par le chirurgien étaient effectivement détectées par l’IF-ICG peropératoire. En parallèle, nous avons évalué si l’IF-ICG permettait de détecter une maladie infraclinique, non détectée par le chirurgien dans les conditions habituelles. La première étude de cette seconde partie a permis de montrer que les MP étaient visualisées comme hyperfluorescentes à l’IF-ICG pour autant qu’elles ne soient pas d’origine mucineuse. De plus, l’IF-ICG a permis de détecter des MP non visualisées en lumière visible, permettant d’adapter le geste chirurgical et d’augmenter la radicalité de la résection dans près de 38% des cas. Dans une seconde étude, nous avons rapporté que la technique d’IF utilisée in vivo et ex vivo après injection iv d’ICG permettait d’identifier des ganglions métastatiques, détectés ou non par les imageries conventionnelles et métaboliques préopératoires. Les résultats de cette étude constituant une preuve de concept ont été ensuite confirmés dans une étude rétrospective réalisée sur l’analyse ex vivo des ganglions de patients ayant reçu une injection iv d’ICG. Dans ce travail, nous avons montré que les ganglions envahis étaient plus fluorescents que les ganglions non envahis. Toutefois, cette preuve de concept doit encore être confirmée et évaluée plus largement dans une étude prospective. Ces 2 travaux montrent donc le bénéfice potentiel de l’utilisation de l’IF après injection iv d’ICG à 2 niveaux, pour guider la chirurgie en améliorant la détection peropératoire des sites métastatiques infracliniques et pour guider l’analyse histologique, en identifiant des ganglions fluorescents sur la pièce de résection, permettant une étude anatomopathologique plus ciblée et plus approfondie. Conclusions et perspectivesNos travaux sur la recherche du GS dans le CCR par la technique au BP et à l’IF-ICG ont montré que ces techniques étaient faisables mais que leurs sensibilités restaient limitées, en particulier chez les patients porteurs de tumeurs localement avancées. Dans la CP d’origine colorectale, nous avons montré que l’IF-ICG permettait d’améliorer la stadification de la CP des patients opérés de métastases péritonéales non mucineuses, de révéler des lésions non visibles dans les conditions standards et d’améliorer la radicalité de la chirurgie. Pour la détection de ganglions métastatiques, nous avons montré que l’IF-ICG permettait, in vivo, de détecter des ganglions infracliniques durant l’intervention et ex vivo, de guider l’analyse anatomopathologique de la pièce de résection. Enfin, nous pensons que ces observations pourraient nous permettre d’élaborer un nouveau concept de GS systémique par opposition au GS classique correspondant aux ganglions de drainage anatomique de la tumeur. Nous proposons que les capacités particulières de rétention de l’ICG dans les tissus cancéreux après injection par voie systémique pourraient permettre d’identifier des sites ganglionnaires métastatiques en dehors des sites de drainage révélés par les injections de marqueurs au sein ou en périphérie de la tumeur elle-même. Pour vérifier cette hypothèse, nous avons élaboré un nouveau protocole d’une étude clinique prospective dans laquelle la détection du GS systémique après injection iv d’ICG sera comparée aux résultats obtenus suite à l’injection péritumorale de BP. Les ganglions révélés par ces 2 techniques seront recherchés ex vivo sur la pièce de résection et analysés en anatomopathologie. Outre la démonstration de métastases ganglionnaires extra-anatomiques, nous pensons que cette approche systémique pourrait permettre de réduire le taux de FN observé suite à une injection péritumorale, notamment pour les tumeurs localement avancées, celles-ci pouvant perturber le drainage lymphatique selon les voies anatomiques. Summary:This thesis reports several clinical research works on the role of indocyanine green (ICG) fluorescence imaging (FI) for the detection of colorectal tumoral tissue. We first evaluate and compare the role of ICG-FI in the detection of sentinel lymph node (SLN) in colorectal cancer (CRC) in view to upstage patients. We have reported that both techniques (blue dye and ICG-FI) are similar in term of sensitivity with a high rate of false negative results. Therefore, we think that new approaches for SLN detection should be developped in CRC. Secondarily, we evaluate the role of ICG-FI after IV ICG injection for the detection of peritoneal carcinomatosis (PC) from CRC origin. We have reported that ICG-FI is able to detect non-mucinous PM with a sensitivity of 86%. Moreover, ICG-FI was able to guide surgery modifying the surgical procedure in 38% of patients. Thirdly, we investigate the role of ICG-FI for the detection lymph node (LN) metastases. We have reported that ICG-FI performed after IV ICG injection is able to detect LN metastases both in vivo and ex vivo. These findings have been confirmed in a retrospective study. Fiinally, we propose a new protocol to evaluate a new approach for SLN detection. In comparison with the standard technique using peritumoral injection, we propose a new approach using systemic (intravenous) ICG injection. We have called this approach the 'systemic' SLN detetion. This approach will be compared with the standard one using peritumoral blue dye injection. Sensitivity, specificity of both technique will be compared. In conclusion, the results of these preliminary clinical studies using ICG-FI for tumoral staging and treatment are encouraging and further larger studies should be performed. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

The objective of this dissertation is to investigate the factors that influence the design of wide-area wavelength division multiplexing (WDM) optical networks. Wide-area networks are presented as communication networks capable of transporting voice and data communication over large geographical areas. These networks typically span a whole country, region or even continent.The rapid development and maturation of WDM technology over the last decade have been well-received commercially and warrants the development of skills in the field of optical network design.The fundamental purpose of all communication networks and technologies is to satisfy the demand of end-users through the provisioning of capacity over shared and limited physical infrastructure. Consideration of the business aspects related to communications traffic and the grooming thereof are crucial to developing an understanding of customer requirements in terms of the selection and quality of services and applications. Extensive communication networks require complex management techniques that aim to ensure high levels of reliability and revenue generation.An integrated methodology is presented for the design of wide-area WDM optical networks. The methodology harnesses physical, logical, and virtual topologies together with routing and channel assignment (RCA) and clustering processes to enhance objectivity of the design process. A novel approach, based on statistical clustering using the Ward linkage as similarity metric, is introduced for solving the problem of determining the number and positions of the backbone nodes of a wide-area network, otherwise defined as the top level hub nodes of the multi-level network model. The influence of the geographic distribution of network traffic, and the intra/inter-cluster traffic ratios are taken into consideration through utilisation of modified gravity models and novel network node weighting. / Dissertation (MEng)--University of Pretoria, 2005. / Electrical, Electronic and Computer Engineering / unrestricted

Dans un graphe non orienté, le problème du sous-graphe k-sommet connexe consiste à déterminer un sous-graphe de poids minimum tel que entre chaque paires de sommets, il existe k chemins sommet-disjoints. Ce modèle a été étudié dans la littérature en termes d'arête connexité. Cependant, le cas de la sommet connexité n'a pas été traité jusqu'à présent. Nous décrivons de nouvelles inégalités valides et nous présentons un algorithme de Coupes et Branchements ainsi qu'une large étude expérimentale qui montrent l'efficacité des contraintes utilisées. Nous proposons ensuite une formulation étendue pour le même problème pour une connexité k=2, suivi d'un algorithme de Génération de Colonnes et Branchements pour résoudre cette formulation.Nous étudions ensuite la version avec chemins bornés du problème. Le problème consiste à trouver un sous-graphe de poids minimum, tel que entre chaque paire d'origine-destination, il existe k chemins sommet-disjoints de longueur au plus L. Nous proposons une formulation linéaire en nombres entiers pour L=2,3. Nous présentons de nouvelles inégalités valides et nous proposons des algorithmes de séparation pour ces contraintes. Nous présentons ensuite un algorithme de Coupes et Branchements qu'on a testé sur des instances de la TSPLIB. / Given a weighted undirected graph and an integer k, the k-node-connected subgraph problem is to find a minimum weight subgraph which contains k-node-disjoint paths between every pair of nodes. We introduce new classes of valid inequalities and discuss their facial aspect. We also devise separation routines, investigate the structural properties of the linear relaxation and discuss some reduction operations that can be used in a preprocessing phase for the separation. Using these results, we devise a Branch-and-Cut algorithm and present some computational results. Then we present a new extended formulation for the the k-node-connected subgraph problem, along with a Branch-and-Cut-and-Price algorithm for solving the problem.Next, we investigate the hop-constrained version of the problem. The k node-disjoint hop-constrained network design problem is to find a minimum weight subgraph such that between every origin and destination there exist at least k node-disjoint paths of length at most L. We propose an integer linear programming formulation for L=2,3 and investigate the associated polytope. We introduce valid inequalities and devise separation algorithms. Then, we propose a B\&C algorithm for solving the problem along with some computational results.

Skin sensitization resulting for allergic contact dermatitis (ACD) is an occupational and environmental health issue. The allergic hazard for workers and consumers is a serious problem for individuals, employers and marketing certain products. Consequently, it is necessary to accurately identify chemicals skin sensitization potential. According to the new EU chemical regulation REACH (Registration, Evaluation, Authorization and Restriction of Chemicals), information of skin sensitization of chemicals manufactured or imported at or above 1 ton/year should be available. Currently, valid approaches assessing skin sensitization rely on animal testing, such as local lymph node assay (LLNA). However, it now ultimately eliminates using animals for this purpose. Based on the fact that a key step in the skin sensitization process is formatting a covalent adduct between allergic sensitizers and proteins and/or peptides in skin, a lot of additional approaches are proposed and developed for replacing or reducing animal used. In this research, three bioassays, 24 h growth inhibition toward Tetrahymena pyriformis, long term (24 h) and short term (30 min) bacterial toxicity (to Vibrio fischeri), and a kinetic glutathione chemoassay are applied for predicting the organic chemicals’ skin sensitization potential. The major results and conclusions obtained are listed as follows: 1. Toxicity enhancement (Te) of 55 chemicals comprising different sensitization potencies were determined and compared with their narcotic toxicity to predict their skin sensitization. Three linear regressions yielded for all allergic sensitizer without nonsensitizers for each bioassay. The linear regressions are improved after classifying sensitizers into five different reaction mechanistic domains. Correspondingly, five different slopes from various reaction mechanisms indicate a decreased sensitivity of toxicity enhancement to skin sensitization potential with order SNAr > SN2 > acylation ≈ Schiff base > aromatic Michael addition. Based on the fact that a key step in the skin sensitization process is forming a covalent adduct between allergic sensitizers and proteins and/or peptides, Te > 10 as a threshold is applied to discriminate these allergic sensitizers, with 100% accuracy for strong (with extreme) and weaker sensitizers, up to 72% accuracy for moderate sensitizers and less than 69% accuracy for nonsensitizers. Compared with these bioassays, a decreasing order of sensitivities is 24 h growth inhibition (Tetrahymena pyriformis) > 24 h growth inhibition (Vibrio fischeri) > 30 min bioluminescence inhibition (Vibrio fischeri). These three bioassays are useful tools for screening sensitization potency of allergic chemicals, and the toxicity enhancement (Te) can be used to discriminate sensitizers from weak or nonsensitizers. However, in this context we should separate aromatic from aliphatic Mas (Michael acceptors). Moreover, metabolic biotransformation should be considered during predicting nonsensitizers’ skin sensitization. 2. Chemical reactivity of selected 55 compounds measuring through kinetic glutathione chemoassay applies to predict their skin sensitization. This chemoassay confirms the fact that the key step of sensitizers eliciting skin sensitization is formatting a covalent adduct between sensitizers and skin proteins or peptides. The chemical reactivity of tested sensitizers strongly relates with their sensitization potential, with strong (extreme) sensitizers presenting the highest reactivity as followed with moderate sensitizers, weak sensitizers as well as nonsensitizers. Moreover, an integrated platform of this chemoassay data and three bioassays data is performed, and this performance shows good sensitivity for monitoring skin sensitization potency, with more rational accuracy for each sensitizing classifications. 3. Thiol reactivity (kGSH) as well as toxicity enhancement (Te) of additional 21 aliphatic α,β-unsaturated compounds are determined for predicting their skin sensitization potential. The linear regressions of skin sensitization versus thiol reactivity and skin sensitization versus toxicity enhancement are significantly improved after classifying these 21 compounds to four chemical subgroups (acrylates, other esters, ketones and aldehydes). Thiol reactivity of these subgroups presented different sensitivity to skin sensitization, with a decreasing order as acrylates (－2.05) > other esters (－1.26) > ketones (－0.43) > aldehydes (－0.21). Moreover, thiol reactivity is confirmed to be a more sensitive tool for predicting skin sensitization, compared with toxicity enhancement. Although the datasets are probably too small to give a definite decision, hydrophobicity reveals contribution to skin sensitization for aliphatic MAs, which is different with literature report. This study suggests that aliphatic MAs should be treated separately into different chemical subgroups for analysis, and their skin sensitization potency can be predicted using kinetic glutathione chemoassay as well as toxicity enhancement bioassay.

1 ABSTRACT Background Breast cancer cell population characteristics are used in common clinical practice for estimation of prognosis of the malignant disease (prognostic factors) and for prediction of reactivity of the tumor to certain therapeutic modality (predictive factors). Also axillary lymph node status is an independent prognostic factor in women with early breast cancer. Therefore, surgical excision and following histopathological examination of the nodes is the obligatory part of primary breast cancer surgery. The extension of axillary surgery varies widely, although sentinel lymph node biopsy is considered to be the standard procedure. However, it must be admitted that this type of procedure need not be optimal for all the breast cancer patients. Aims of the study The aim of this study is the verify the hypothesis whether or not the axillary lymph node metastatic affection can be effectively estimated using non-surgical methods - i.e. by evaluation of the combination of prognostic and predictive factors of the primary breast tumor. Statistical model composed on the basis of data of early breast cancer patients is the basic tool for this prediction. Application of this model In everyday practice can enable to adjust the extent of axillary surgery for each individual patient. Patients and methods A...

Background: A landmark study suggested that wide excision of intermediate-thickness melanoma with sentinel lymph node biopsy (SLNB) and subsequent completion lymph node dissection (CLND) for regional disease may improve prognostication and disease-free survival (DFS) compared with those undergoing wide excision alone. However, these benefits were relatively small and not associated with an improvement in disease-specific survival (DSS). It remains unknown if SLNB and subsequent treatments are beneficial in elderly patients who have a decreased overall (OS) due to other causes. Methods: Adults ≥ 70 years of age, who underwent surgical intervention for intermediate-thickness cutaneous melanoma from 2000-2013 were identified from a prospectively-maintained database. Clinicopathologic variables measured included age, gender, anatomic site, histologic type, tumor thickness, ulceration, receipt and result of SLNB, completion of CLND, OS, and DFS. Results: Ninety-one patients underwent excision of an intermediate-thickness melanoma. Forty-nine patients (54%) received a SLNB. Seven of these biopsies (14%) were positive, and five patients went on to receive CLND. Five-year OS was 41% in patients who did not receive SLNB and 52% in patients who did receive SLNB (p=0.11). DFS was similar between groups independent of receipt of SLNB. Conclusion: Among elderly patients with intermediate-thickness melanoma, patients who received SLNB had similar 5-year OS and DFS compared with those who did not receive SLNB. Routine SLNB for intermediate-thickness melanoma patients may not significantly change outcomes for this age group, and clinical decision-making should consider individual patient comorbidities and goals of care.