L’objectif de ce travail de recherche est d’évaluer la capacité des spectroscopies optiques d’autofluorescence et de réflectance diffuse à caractériser les différents stades de la transformation néoplasique de la peau et ainsi d’aider au diagnostic des deux lésions de peau les plus létales : le mélanome malin et le carcinome épidermoïde. Dans l’étude portant sur le mélanome, un objet-test (« fantôme ») a été développé pour modéliser différentes épaisseurs de mélanome (indice de Breslow). La spectroscopie de réflectance diffuse résolue spatialement (grâce à l’utilisation de cinq fibres optiques réceptrices situées à cinq distances différentes de la fibre optique excitatrice) a montré sa capacité à discriminer (p<0,05) des indices de Breslow simulés grâce à des fantômes d’épaisseur variant par pas d’1 mm. D’autre part, des mesures de spectroscopie bimodale (combinant autofluorescence en multi-excitation et réflectance diffuse) ont été réalisées sur peau murine tout au long des sept mois de photocarcinogenèse. Des prélèvements cutanés ont permis d’établir trois classes histologiques (en plus de la classe saine du groupe contrôle) : hyperplasie compensatoire, hyperplasie atypique et dysplasie. Puis la précision diagnostique a été évaluée par analyse statistique multivariée. Nos principaux résultats montrent que la bimodalité associant autofluorescence (excitation à 410 nm) et réflectance diffuse permet une amélioration de la spécificité de 9% comparées aux performances de chacune des modalités utilisée seule lors de la discrimination des trois types d’hyperplasie. Des études cliniques doivent maintenant confirmer l’intérêt de ces résultats. / Autofluorescence and diffuse reflectance spectroscopies were studied as non-invasive tools to discriminate different stages of skin neoplastic transformation and thus to help diagnose the two most lethal skin lesions: cutaneous melanoma and squamous cell carcinoma. Concerning melanoma, skin phantoms were made to simulate several melanoma thicknesses (Breslow index). Spatially-resolved diffuse reflectance spectroscopy (using five collection optical fibers set at five different distances from the excitation optical fiber) allowed discrimination (p<0.05) of melanoma layers, the thickness of which was 1 mm different. Since diffuse reflectance spectroscopy has already shown good results in assessing malignancy of pigmented skin lesions, such a spectroscopy could be used as a complementary tool of cutaneous melanoma diagnosis. Using ultra-violet induced squamous cell carcinoma of mouse skin, bimodal spectra (multi-excitation fluorescence and diffuse reflectance) were acquired throughout the 7 month-carcinogenesis. Histological sampling followed spectral acquisition and three histological classes were determined by histo-pathological examination: compensatory hyperplasia, atypical hyperplasia and dysplasia. A fourth “healthy” class consisted in the skin sampled on mice that were never irradiated (control group). Multivariate statistical analysis of the spectral data set showed that combining autofluorescence (best results obtained with a 410 nm excitation) and diffuse reflectance resulted in a 9% increase of specificity when discriminating the three types of hyperplasia from one another compared to each modality used alone. Such results need to be confirmed through clinical trials on human patients.

Das maligne Melanom ist ein häufiger Tumor, der bei rechtzeitiger Diagnosestellung eine gute Prognose aufweist. In dieser Arbeit wird die Frage untersucht, ob bestimmte Risikofaktoren die Tumordicke zum Zeitpunkt der Entdeckung des Melanoms, und damit die Prognose, beeinflussen. Werden Patienten mit bekanntem hohen Risiko effektiv erkannt und wird dadurch ein Melanom in einem frühen Stadium mit geringerer Tumordicke entdeckt? Gibt es Faktoren, die dazu führen, dass Melanome besonders spät und damit prognostisch ungünstig entdeckt werden? In dieser Arbeit wurden 347 Patienten mit malignem Melanom zu Risikofaktoren und Diagnosefindung befragt. Die Ergebnisse der Befragung wurden dann statistisch mit der Tumordicke der Melanome korreliert. Es konnte gezeigt werden, das signifikant dünnere Tumore bei Patienten mit bekanntem Hochrisikoprofil, wie heller Hauttyp und viele -besonders atypische- Nävi diagnostiziert wurden. Patienten in der Hochrisikosprechstunde der Dermatologie der Universitätsmedizin Göttingen hatten signifikant dünnere Tumoren und sind offenbar effektiv in Früherkennungsmaßnahmen integriert. Es konnte ebenfalls gezeigt werden, dass Patienten mit niedrigem Schulabschluss, höherem Lebensalter und männlichem Geschlecht signifikant häufiger dickere Tumoren zum Zeitpunkt der Diagnosestellung aufwiesen. Diese Patienten müssen intensiver motiviert werden an Früherkennungsmaßnahmen teilzunehmen.

Introdução: A incidência do melanoma cutâneo (MC) está crescendo mais rapidamente que a de qualquer outro câncer. Devido ao seu potencial para metástases e à falta de terapias efetivas para a maioria dos pacientes em estágio avançado, o diagnóstico precoce do MC é crucial. Alguns dos fatores prognósticos mais importantes no MC são a espessura de Breslow e a presença de metástase linfonodal. O Tecnécio-99m-sestamibi (MIBI) é um radiofármaco usado rotineiramente em cintilografias miocárdicas e tem conhecidas propriedades para detecção de tumores malignos, incluindo câncer de mama, tumores cerebrais e melanomas primários e metastáticos. Objetivo: Avaliar a correlação entre a espessura de Breslow e a intensidade da captação de MIBI (IC-MIBI) em lesões primárias de MC. Métodos: Foram selecionados pacientes com lesões clinica e dermatoscopicamente suspeitas de MC. Os pacientes receberam uma injeção intravenosa de 740 – 1110 MBq (20 mCi) de MIBI. Após 10 minutos, o equipamento gamma-probe foi usado para detectar a IC-MIBI na lesão cutânea e em 2 pontos equidistantes na pele normal. A razão entre as contagens radioativas na lesão e a média da pele normal foi considerada a IC-MIBI. A seguir, pacientes realizaram SPECT (Single Photon Emission Computed Tomography) do local da lesão e da região linfonodal correspondente. Exérese da lesão cutânea e exame anatomopatológico foram então realizados. Pacientes portadores de lesões com Breslow > 1 mm ou < 1mm com ulceração/regressão espontânea realizaram biópsia do linfonodo sentinela. Resultados: Dezesseis pacientes com 20 lesões foram estudados (8 homens, 8 mulheres, de 34 – 81 anos, média 61 anos). Quatorze lesões eram melanomas e 6 eram nevos melanocíticos (NM). Cinco lesões eram melanomas in situ. A média da espessura de Breslow foi de 0,45 mm (variação: 0,30 – 14,90 mm). A média da IC-MIBI foi 1,54 (±0.58) contagens radioativas nos MC e 1,04 (±0.10) nos NM (P = 0.007). Houve forte correlação positiva entre a IC-MIBI e a espessura de Breslow (rs = 0.74, P= 0.003). Analisando as lesões em categorias de Breslow, houve diferença estatisticamente significativa (P < 0.001) entre as lesões com Breslow < 1mm (IC-MIBI = 1.23 ± 0.28 contagens radioativas) e Breslow > 1 mm (IC-MIBI = 2.32 ± 0.32 contagens radioativas). Nenhum dos NM apareceu nas imagens de SPECT. Dos MC, 4 lesões, que apresentavam Breslow > 1mm, apareceram nas imagens de SPECT. Conclusão: Neste estudo, embora tenha demonstrado uma diferença significativa entre melanomas finos (< 1mm) e espessos (> 1mm), a IC-MIBI no local da lesão não foi diferente entre NM e melanomas finos ou in situ. Por isso, MIBI parece ser útil principalmente em melanomas espessos, o que também foi confirmado pela positividade do SPECT apenas nestes casos. Entretanto, a possibilidade de correlacionar a IC-MIBI com categorias de Breslow pode facilitar os procedimentos cirúrgicos, permitindo a remoção de melanomas com margens cirúrgicas adequadas e a realização ou não de biópsia de linfonodo sentinela em um mesmo momento cirúrgico, reduzindo morbidade e custos. / Introduction: Given its propensity to metastasize, and lack of effective therapies for most patients with advanced disease, early detection of melanoma is a clinical imperative. The most important prognostic factors are Breslow thickness and nodal metastases. Technetium-99m-sestamibi (MIBI) is a radiopharmaceutical used routinely for cardiologic scintigraphy and has also well-known tumor-seeking properties. It has been used successfully to detect various tumors, including breast cancer, brain tumors, and primary and metastatic melanoma. Objetive: This study has been designed in order to evaluate the correlation between Breslow thickness and MIBI uptake by primary CM lesions. Methods: Patients were recruited by a dermatologist on the grounds of a clinically and dermoscopically suspicious melanocytic lesion. Patients received intravenous injection of 740 – 1110 MBq (20 mCi) of MIBI. After 10 minutes, gamma-probe was used to detect the intensity of MIBI uptake by the cutaneous lesion and at two equidistant points on normal skin. The ratio number of radioactive counts at cutaneous lesion / mean of radioactive counts at normal skin was considered to determinate the MIBI uptake intensity (MIBI-UI). Then, SPECT imaging of the lesion site and respective lymph node region was obtained. After scintigraphy, exeresis of the cutaneous lesion and histological analysis were performed. Lesions with Breslow thickness > 1 mm or < 1 mm with ulceration/spontaneous regression underwent sentinel lymph node biopsy. Results: Sixteen patients with 20 lesions were investigated (8 males, 8 females, age range 34 – 81 years, mean 61 years). Fourteen lesions were CM and 6 were melanocytic nevi (MN). Five lesions were melanoma in situ. Breslow thickness median was 0.45 mm (range 0.30 - 14,9 mm). The mean MIBI-UI was 1.54 (±0.58) radioactive counts in CM and 1.04 (±0.10) radioactive counts in MN (P = 0.007). There was strong positive correlation between MIBI-UI and Breslow thickness (rs = 0.74, P= 0.003). Grouping the lesions on Breslow categories, there was a statistically significant difference (P < 0.001) between lesions with Breslow thickness < 1 mm (MIBI-UI = 1.23 ± 0.28 radioactive counts) and Breslow thickness > 1 mm (MIBI-UI = 2.32 ± 0.32 radioactive counts). None of the MN appeared at SPECT images. Of melanomas, 4 (28,6%) were SPECT positive at cutaneous site. All those were Breslow thickness > 1 mm. Conclusion: On this study, although there is a significant difference between thin (< 1 mm) and thick (> 1 mm) melanomas, MIBI intensity at the lesion site is not different between benign nevus and in situ or thin melanomas. Then, MIBI seems to be useful mainly in thick melanomas, as also confirmed by the positivity of the SPECT image only in these cases. However, the possibility of correlating MIBI uptake intensity with Breslow categories may facilitate surgical procedures, allowing to remove melanomas with appropriated surgical margins and to perform or not sentinel lymph node biopsy in the same surgical time, reducing morbidity and cost.

Introdução: A incidência do melanoma cutâneo (MC) está crescendo mais rapidamente que a de qualquer outro câncer. Devido ao seu potencial para metástases e à falta de terapias efetivas para a maioria dos pacientes em estágio avançado, o diagnóstico precoce do MC é crucial. Alguns dos fatores prognósticos mais importantes no MC são a espessura de Breslow e a presença de metástase linfonodal. O Tecnécio-99m-sestamibi (MIBI) é um radiofármaco usado rotineiramente em cintilografias miocárdicas e tem conhecidas propriedades para detecção de tumores malignos, incluindo câncer de mama, tumores cerebrais e melanomas primários e metastáticos. Objetivo: Avaliar a correlação entre a espessura de Breslow e a intensidade da captação de MIBI (IC-MIBI) em lesões primárias de MC. Métodos: Foram selecionados pacientes com lesões clinica e dermatoscopicamente suspeitas de MC. Os pacientes receberam uma injeção intravenosa de 740 – 1110 MBq (20 mCi) de MIBI. Após 10 minutos, o equipamento gamma-probe foi usado para detectar a IC-MIBI na lesão cutânea e em 2 pontos equidistantes na pele normal. A razão entre as contagens radioativas na lesão e a média da pele normal foi considerada a IC-MIBI. A seguir, pacientes realizaram SPECT (Single Photon Emission Computed Tomography) do local da lesão e da região linfonodal correspondente. Exérese da lesão cutânea e exame anatomopatológico foram então realizados. Pacientes portadores de lesões com Breslow > 1 mm ou < 1mm com ulceração/regressão espontânea realizaram biópsia do linfonodo sentinela. Resultados: Dezesseis pacientes com 20 lesões foram estudados (8 homens, 8 mulheres, de 34 – 81 anos, média 61 anos). Quatorze lesões eram melanomas e 6 eram nevos melanocíticos (NM). Cinco lesões eram melanomas in situ. A média da espessura de Breslow foi de 0,45 mm (variação: 0,30 – 14,90 mm). A média da IC-MIBI foi 1,54 (±0.58) contagens radioativas nos MC e 1,04 (±0.10) nos NM (P = 0.007). Houve forte correlação positiva entre a IC-MIBI e a espessura de Breslow (rs = 0.74, P= 0.003). Analisando as lesões em categorias de Breslow, houve diferença estatisticamente significativa (P < 0.001) entre as lesões com Breslow < 1mm (IC-MIBI = 1.23 ± 0.28 contagens radioativas) e Breslow > 1 mm (IC-MIBI = 2.32 ± 0.32 contagens radioativas). Nenhum dos NM apareceu nas imagens de SPECT. Dos MC, 4 lesões, que apresentavam Breslow > 1mm, apareceram nas imagens de SPECT. Conclusão: Neste estudo, embora tenha demonstrado uma diferença significativa entre melanomas finos (< 1mm) e espessos (> 1mm), a IC-MIBI no local da lesão não foi diferente entre NM e melanomas finos ou in situ. Por isso, MIBI parece ser útil principalmente em melanomas espessos, o que também foi confirmado pela positividade do SPECT apenas nestes casos. Entretanto, a possibilidade de correlacionar a IC-MIBI com categorias de Breslow pode facilitar os procedimentos cirúrgicos, permitindo a remoção de melanomas com margens cirúrgicas adequadas e a realização ou não de biópsia de linfonodo sentinela em um mesmo momento cirúrgico, reduzindo morbidade e custos. / Introduction: Given its propensity to metastasize, and lack of effective therapies for most patients with advanced disease, early detection of melanoma is a clinical imperative. The most important prognostic factors are Breslow thickness and nodal metastases. Technetium-99m-sestamibi (MIBI) is a radiopharmaceutical used routinely for cardiologic scintigraphy and has also well-known tumor-seeking properties. It has been used successfully to detect various tumors, including breast cancer, brain tumors, and primary and metastatic melanoma. Objetive: This study has been designed in order to evaluate the correlation between Breslow thickness and MIBI uptake by primary CM lesions. Methods: Patients were recruited by a dermatologist on the grounds of a clinically and dermoscopically suspicious melanocytic lesion. Patients received intravenous injection of 740 – 1110 MBq (20 mCi) of MIBI. After 10 minutes, gamma-probe was used to detect the intensity of MIBI uptake by the cutaneous lesion and at two equidistant points on normal skin. The ratio number of radioactive counts at cutaneous lesion / mean of radioactive counts at normal skin was considered to determinate the MIBI uptake intensity (MIBI-UI). Then, SPECT imaging of the lesion site and respective lymph node region was obtained. After scintigraphy, exeresis of the cutaneous lesion and histological analysis were performed. Lesions with Breslow thickness > 1 mm or < 1 mm with ulceration/spontaneous regression underwent sentinel lymph node biopsy. Results: Sixteen patients with 20 lesions were investigated (8 males, 8 females, age range 34 – 81 years, mean 61 years). Fourteen lesions were CM and 6 were melanocytic nevi (MN). Five lesions were melanoma in situ. Breslow thickness median was 0.45 mm (range 0.30 - 14,9 mm). The mean MIBI-UI was 1.54 (±0.58) radioactive counts in CM and 1.04 (±0.10) radioactive counts in MN (P = 0.007). There was strong positive correlation between MIBI-UI and Breslow thickness (rs = 0.74, P= 0.003). Grouping the lesions on Breslow categories, there was a statistically significant difference (P < 0.001) between lesions with Breslow thickness < 1 mm (MIBI-UI = 1.23 ± 0.28 radioactive counts) and Breslow thickness > 1 mm (MIBI-UI = 2.32 ± 0.32 radioactive counts). None of the MN appeared at SPECT images. Of melanomas, 4 (28,6%) were SPECT positive at cutaneous site. All those were Breslow thickness > 1 mm. Conclusion: On this study, although there is a significant difference between thin (< 1 mm) and thick (> 1 mm) melanomas, MIBI intensity at the lesion site is not different between benign nevus and in situ or thin melanomas. Then, MIBI seems to be useful mainly in thick melanomas, as also confirmed by the positivity of the SPECT image only in these cases. However, the possibility of correlating MIBI uptake intensity with Breslow categories may facilitate surgical procedures, allowing to remove melanomas with appropriated surgical margins and to perform or not sentinel lymph node biopsy in the same surgical time, reducing morbidity and cost.

Introdução: A incidência do melanoma cutâneo (MC) está crescendo mais rapidamente que a de qualquer outro câncer. Devido ao seu potencial para metástases e à falta de terapias efetivas para a maioria dos pacientes em estágio avançado, o diagnóstico precoce do MC é crucial. Alguns dos fatores prognósticos mais importantes no MC são a espessura de Breslow e a presença de metástase linfonodal. O Tecnécio-99m-sestamibi (MIBI) é um radiofármaco usado rotineiramente em cintilografias miocárdicas e tem conhecidas propriedades para detecção de tumores malignos, incluindo câncer de mama, tumores cerebrais e melanomas primários e metastáticos. Objetivo: Avaliar a correlação entre a espessura de Breslow e a intensidade da captação de MIBI (IC-MIBI) em lesões primárias de MC. Métodos: Foram selecionados pacientes com lesões clinica e dermatoscopicamente suspeitas de MC. Os pacientes receberam uma injeção intravenosa de 740 – 1110 MBq (20 mCi) de MIBI. Após 10 minutos, o equipamento gamma-probe foi usado para detectar a IC-MIBI na lesão cutânea e em 2 pontos equidistantes na pele normal. A razão entre as contagens radioativas na lesão e a média da pele normal foi considerada a IC-MIBI. A seguir, pacientes realizaram SPECT (Single Photon Emission Computed Tomography) do local da lesão e da região linfonodal correspondente. Exérese da lesão cutânea e exame anatomopatológico foram então realizados. Pacientes portadores de lesões com Breslow > 1 mm ou < 1mm com ulceração/regressão espontânea realizaram biópsia do linfonodo sentinela. Resultados: Dezesseis pacientes com 20 lesões foram estudados (8 homens, 8 mulheres, de 34 – 81 anos, média 61 anos). Quatorze lesões eram melanomas e 6 eram nevos melanocíticos (NM). Cinco lesões eram melanomas in situ. A média da espessura de Breslow foi de 0,45 mm (variação: 0,30 – 14,90 mm). A média da IC-MIBI foi 1,54 (±0.58) contagens radioativas nos MC e 1,04 (±0.10) nos NM (P = 0.007). Houve forte correlação positiva entre a IC-MIBI e a espessura de Breslow (rs = 0.74, P= 0.003). Analisando as lesões em categorias de Breslow, houve diferença estatisticamente significativa (P < 0.001) entre as lesões com Breslow < 1mm (IC-MIBI = 1.23 ± 0.28 contagens radioativas) e Breslow > 1 mm (IC-MIBI = 2.32 ± 0.32 contagens radioativas). Nenhum dos NM apareceu nas imagens de SPECT. Dos MC, 4 lesões, que apresentavam Breslow > 1mm, apareceram nas imagens de SPECT. Conclusão: Neste estudo, embora tenha demonstrado uma diferença significativa entre melanomas finos (< 1mm) e espessos (> 1mm), a IC-MIBI no local da lesão não foi diferente entre NM e melanomas finos ou in situ. Por isso, MIBI parece ser útil principalmente em melanomas espessos, o que também foi confirmado pela positividade do SPECT apenas nestes casos. Entretanto, a possibilidade de correlacionar a IC-MIBI com categorias de Breslow pode facilitar os procedimentos cirúrgicos, permitindo a remoção de melanomas com margens cirúrgicas adequadas e a realização ou não de biópsia de linfonodo sentinela em um mesmo momento cirúrgico, reduzindo morbidade e custos. / Introduction: Given its propensity to metastasize, and lack of effective therapies for most patients with advanced disease, early detection of melanoma is a clinical imperative. The most important prognostic factors are Breslow thickness and nodal metastases. Technetium-99m-sestamibi (MIBI) is a radiopharmaceutical used routinely for cardiologic scintigraphy and has also well-known tumor-seeking properties. It has been used successfully to detect various tumors, including breast cancer, brain tumors, and primary and metastatic melanoma. Objetive: This study has been designed in order to evaluate the correlation between Breslow thickness and MIBI uptake by primary CM lesions. Methods: Patients were recruited by a dermatologist on the grounds of a clinically and dermoscopically suspicious melanocytic lesion. Patients received intravenous injection of 740 – 1110 MBq (20 mCi) of MIBI. After 10 minutes, gamma-probe was used to detect the intensity of MIBI uptake by the cutaneous lesion and at two equidistant points on normal skin. The ratio number of radioactive counts at cutaneous lesion / mean of radioactive counts at normal skin was considered to determinate the MIBI uptake intensity (MIBI-UI). Then, SPECT imaging of the lesion site and respective lymph node region was obtained. After scintigraphy, exeresis of the cutaneous lesion and histological analysis were performed. Lesions with Breslow thickness > 1 mm or < 1 mm with ulceration/spontaneous regression underwent sentinel lymph node biopsy. Results: Sixteen patients with 20 lesions were investigated (8 males, 8 females, age range 34 – 81 years, mean 61 years). Fourteen lesions were CM and 6 were melanocytic nevi (MN). Five lesions were melanoma in situ. Breslow thickness median was 0.45 mm (range 0.30 - 14,9 mm). The mean MIBI-UI was 1.54 (±0.58) radioactive counts in CM and 1.04 (±0.10) radioactive counts in MN (P = 0.007). There was strong positive correlation between MIBI-UI and Breslow thickness (rs = 0.74, P= 0.003). Grouping the lesions on Breslow categories, there was a statistically significant difference (P < 0.001) between lesions with Breslow thickness < 1 mm (MIBI-UI = 1.23 ± 0.28 radioactive counts) and Breslow thickness > 1 mm (MIBI-UI = 2.32 ± 0.32 radioactive counts). None of the MN appeared at SPECT images. Of melanomas, 4 (28,6%) were SPECT positive at cutaneous site. All those were Breslow thickness > 1 mm. Conclusion: On this study, although there is a significant difference between thin (< 1 mm) and thick (> 1 mm) melanomas, MIBI intensity at the lesion site is not different between benign nevus and in situ or thin melanomas. Then, MIBI seems to be useful mainly in thick melanomas, as also confirmed by the positivity of the SPECT image only in these cases. However, the possibility of correlating MIBI uptake intensity with Breslow categories may facilitate surgical procedures, allowing to remove melanomas with appropriated surgical margins and to perform or not sentinel lymph node biopsy in the same surgical time, reducing morbidity and cost.

L'objectif de ce travail de recherche est d'évaluer la capacité des spectroscopies optiques d'autofluorescence et de réflectance diffuse à caractériser les différents stades de la transformation néoplasique de la peau et ainsi d'aider au diagnostic des deux lésions de peau les plus létales : le mélanome malin et le carcinome épidermoïde. Dans l'étude portant sur le mélanome, un objet-test (« fantôme ») a été développé pour modéliser différentes épaisseurs de mélanome (indice de Breslow). La spectroscopie de réflectance diffuse résolue spatialement (grâce à l'utilisation de cinq fibres optiques réceptrices situées à cinq distances différentes de la fibre optique excitatrice) a montré sa capacité à discriminer (p<0,05) des indices de Breslow simulés grâce à des fantômes d'épaisseur variant par pas d'1 mm. D'autre part, des mesures de spectroscopie bimodale (combinant autofluorescence en multi-excitation et réflectance diffuse) ont été réalisées sur peau murine tout au long des sept mois de photocarcinogenèse. Des prélèvements cutanés ont permis d'établir trois classes histologiques (en plus de la classe saine du groupe contrôle) : hyperplasie compensatoire, hyperplasie atypique et dysplasie. Puis la précision diagnostique a été évaluée par analyse statistique multivariée. Nos principaux résultats montrent que la bimodalité associant autofluorescence (excitation à 410 nm) et réflectance diffuse permet une amélioration de la spécificité de 9 points de pourcentage comparées aux performances de chacune des modalités utilisée seule lors de la discrimination des trois types d'hyperplasie. Des études cliniques doivent maintenant confirmer l'intérêt de ces résultats.

This work deals with the enantioselective synthesis of chiral cyclohexenones from substituted 4-nitroisoxazoles and α-bromo-α,β-unsaturated aldehydes using of N-heterocyclic carbenes (NHC) as organocatalysts. The work includes the preparation of commercially unavailable NHC-precursors and the synthesis of starting materials, substituted 4-nitroisoxazoles and α-bromo-α,β-unsaturated aldehydes. The second part of the work deals with the optimization of reaction conditions of the enantioselective synthesis of chiral cyclohexenones, proceeding via an azolium dienolate intermediate, and the detailed substrate scope screening.

No description available.

Le mélanome est un cancer rare de la peau qui se développe à partir des cellules responsables de la pigmentation : les mélanocytes. Depuis quelques années, nous observons une augmentation significative du nombre de personnes atteintes par cette maladie, de mauvais pronostic et très agressive (132 000 nouveaux cas chaque année dans le monde). Le taux de mortalité de ce cancer est très élevé en raison de la rapidité de propagation des cellules cancéreuse dans d’autres régions du corps. En France, on remarque un nombre relativement élevé de cas détectés, plus particulièrement en Bretagne. La tumeur se présente comme une tâche dont l’apparence est très proche du grain de beauté. Si elle est détectée suffisamment tôt, un prélèvement suffit à la guérison et les risques de récidives sont très faibles. En revanche, une fois que les métastases se propagent, les chances de survie à long terme sont très faibles. Malgré les récentes avancées en thérapie ciblée, les traitements du mélanome métastatique restent encore limités. En partenariat avec le groupe Malakoff Médéric, nous développons actuellement un système optique pour la détection précoce du mélanome cutané. Celui-ci est basé sur les propriétés de polarisation de la lumière. La thèse présente la conception du système, de l’étude de faisabilité jusqu’à l’étape finale d’étalonnage. Nous proposons également différents tests sur des échantillons de simulation. Ces derniers nous permettent de démontrer la corrélation qu’il existe entre les effets de polarisation et les modifications biologiques en cours lors du développement du mélanome. Cette étude préliminaire nous prépare aux expérimentations sur de vrais échantillons. / Melanoma is a rare cancer that develops from the pigmentation cells of the skin. Recently, we notice a significant increase in the number of people affected by this aggressive disease with a poor prognosis (132 000 new cases each year worldwide). The mortality rate of this cancer is very high, which is due to the rapid spread of cancerous cells to other parts of the body. In France, there is a relatively high number of cases detected, especially in Britanny. The tumor is a spot which looks like a mole. If detected early, a levy is sufficient to healing and the risk of recurrence is very low. However, once metastasis spread, the long-term prognosis is very low. Despite recent advances in targeted therapy, the treatments of metastatic melanoma are still limited. In partnership with the Malakoff Mederic group, we are currently developing an optical system for early detection of cutaneous melanoma. It is based on the polarization properties of light. The PhD focuses on the design of the system, from the feasibility study to the final calibration. We also present various tests on samples of simulation. These allow us to demonstrate the correlation between the effects of polarization and biological changes during the development of melanoma. This preliminary study prepares us to experiments on real samples.