Tesi sul tema "Carcinome cutané"
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Amouroux, Marine. "Caractérisation de la transformation néoplasique de la peau par spectroscopies optiques sur fantôme de mélanome et carcinome épidermoïde murin photo-induit". Phd thesis, Université Henri Poincaré - Nancy I, 2008. http://tel.archives-ouvertes.fr/tel-00339385.
Colas, Victor. "Modeling and estimation of human skin optical properties using spatially resolved autofluorescence and diffuse reflectance spectroscopy". Electronic Thesis or Diss., Université de Lorraine, 2022. http://www.theses.fr/2022LORR0129.
In the context of cutaneous carcinoma, optical biopsy offers a in-vivo non-destructive alternative to conventional biopsy to inform the dermatologist of the state of health of the deep tissue during cancer resection. The latter is indeed at the origin of morphological and physiological modifications of the skin, which explains why the optical measurements resulting from the light/tissue interactions are sensitive to it. The work presented in this manuscript exploits the data obtained with the optical biopsy device extit{SpectroLive} on about a hundred patients just before cancer resection by the clinician. In contact with the skin, this spectroscopic device acquires diffuse reflectance (white broadband excitation) and autofluorescence (monochromatic emission to excite endogenous fluorophores in the skin) spatially resolved signals, extit{i.e.}, for several separation distances between the light emitting fiber and the collecting fibers at the periphery. This spatial resolution is of particular interest for the skin, since the different distances introduced allow the collection of photons traveling through the different layers in depth (epidermis, dermis and hypodermis) of the organ. The main part of the work presented here concerns the estimation of the optical properties of the skin by solving the inverse problem from these clinical acquisitions. This consists first in establishing a photon transport simulation faithful to the characteristics (geometrical and spectral) of the real device before building a multilayer model of the skin in which the optical parameters (e.g. absorption and scattering coefficients, the anisotropy factor) and geometrical parameters e.g. layer thickness) can be estimated by an optimization process aiming at minimizing the differences between the spectra generated by the simulation and the ``target'' spectra obtained in clinic. The main contributions developed in this manuscript are first the development and the full exploitation of the simulation, with in particular a study whose purpose is to characterize the penetration of the photons detected at the various source/detector separations, and this for various skin models in order to represent the inter- and intra-individual differences. The knowledge acquired with this study of probed depths is then used in the second major contribution, aiming at adapting the process of estimating optical properties from clinical spectra (inverse problem) to the skin. Finally, the last contribution, more metrological, is the development of an optical bench with double integrating spheres allowing to obtain these same optical properties for a sample ex-vivo, and thus to allow the comparison of the estimates resulting from the two modalities
MORAND, TOURAINE PASCALE. "Carcinome neuroendocrine cutane : a propos de sept observations". Limoges, 1989. http://www.theses.fr/1989LIMO0164.
Bourdely, Pierre. "Caractérisation ontogénique, phénotypique et fonctionnelle des cellules dendritiques et des macrophages dans les carcinomes épidermoïdes cutanés". Thesis, Université Côte d'Azur (ComUE), 2017. http://www.theses.fr/2017AZUR4139.
Skin Squamous cell carcinoma (sSCC) are invasive keratinocyte tumor that develop after immune system subversion. The reprogrammation of anti-tumoral immunity using local stimulation of dendritic cells (DC) and macrophages could be useful. In this line, the aim of my thesis was to understand ontogenic, phenotypic and functional heterogeneity of these cell subsets along skin carcinogenesis to develop new immunotherapies. First, we characterized skin macrophage subsets in mouse and those infiltrating sSCC in human. Using spectral flow cytometry, we identified matured autofluorescent tissue-resident macrophages. These macrophages are anti-inflammatory polarized. In human sSCC, autofluorescent macrophages seem to have same properties that their mouse counterparts. In second study, we identified tumor-infiltrating DC with altered functions. We used a local immunotherapy composed by a TLR9 agonist and blocking antibody against α-chain of IL-10 receptor. This combination induced tumor regression through DC reprogrammation and IFNγ+, TNFα+ IL17A+ T CD8+ lymphocyte generation. These results highlight functional myeloid heterogeneity in skin and sSCC. Their reprogrammation could promote the development of immunotherapies against sSCC in human
Brugière, Charlotte. "L'invasion péri-nerveuse des carcinomes épidermoïdes cutanés humains". Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC193.
Cutaneous squamous cell carcinoma (SCC) is an important issue because of its frequency and potential severity.The aggressiveness of this cancer is related to perineural invasion (PNI), a mode of tumor dissemination recognized as a poor prognosis factor.The aim of this work is to study the mechanisms of PNI, comparing 2 matched- groups of human SCC with and without PNI.For this, we studied neurotrophins, epithelial-mesenchymal transition (EMT) markers, and the NCAM1 molecule, by immunohistochemistry analysis on surgical pieces of SCC and by molecular analysis with digital-droplet PCR on laser-microdissected tumor cells.Immunohistochemistry analysis found strong expression of BDNF, TrkB, p75NGFR, Snail 1 and NCMA1 in perineural tumor cells, contrasting with weak expression of these markers in tumor cells distant from the nerves. E-cadherin was decreased in perineural tumor cells.Molecular analysis in ddPCR showed decreased expression for E-cadherin and overexpression of BDNF, TrkB, p75NGFR, Snail1, Slug, Zeb2, Twist1 and NCAM1 in perineural tumor cells compared to tumor cells distant from the nerves.We have demonstrated in this work that PNI in human SCC is linked to neurotrophins and EMT, and involves NCAM1
Zaytsev, Sergey. "Combination of tissular multimodal spectro-imaging and optical clearing methods to improve detection depth in skin in vivo". Electronic Thesis or Diss., Université de Lorraine, 2022. http://www.theses.fr/2022LORR0067.
This thesis presents the results of research in the context of improved analysis of the skin optical properties using various optical techniques, such as multimodal tissular spectroscopy and optical coherence tomography (OCT) imaging. Since many years optical techniques of skin characterization are an effective alternative to traditional invasive diagnostic methods as they allow to get information about the structural and biochemical skin composition in vivo in real time, which led to their extensive implementation in the clinical practice of skin lesions analysis. In the last decades it was demonstrated that combined use of several optical techniques allows to increase the diagnostic accuracy by increasing the variety of data acquired in one measurement. Spatial resolution may also increase the diagnostic potential by providing depth discrimination (resolution) between assessed layers. Even though the main limitation for the use of the optical methods in skin diagnostics is the strong absorption and scattering of the latter, skin optical properties can be changed using the method of skin optical clearing (OC). The combination of optical clearing agents (OCA) with various chemical and physical enhancers of skin permeability may significantly improve the potential of multimodal optical approaches with spatial resolution. The aim of the first experimental study within this thesis framework was (i) to investigate the effect of the OC process applied to ex vivo human skin samples on spatially resolved (SR) diffuse reflectance (DR) and autofluorescence (AF) spectra using two combinations of OCA and chemical permeation enhancers (CPE), and (ii) to quantify the clearing- like effect of drying and of spectroscopic probe pressure on skin. A spatially resolved multimodal spectroscopic device was used on a two- layered “hybrid” model made of ex vivo skin and fluorescent gel. Time kinetics of fluorescence and diffuse reflectance spectra demonstrate d an increase in the gel fluorescence back reflected intensity after optical clearing. In addition, complementary experimental results showed increased light transmittance through the skin and confirmed that the improvement in the depth sensitivity of the multimodal spectroscopic approach was related not only to the dehydration and refractive indices matching due to optical clearing, but also to the mechanical compression of tissues caused by the application of the spectroscopic probe. Since when translating these methods into clinical use there is a need to comply with established regulations, including the use of chemicals on healthy and pathologically changed skin of patients, the concentrations of the OCA used may need to be reduced in order to pass the threshold of clinical utility and biocompatibility. Thus, the main goal of the consecutive experimental study was to experimentally evaluate, by using for the first time a Line-field Confocal OCT (LC-OCT) imaging technique, the e fficacy of OC of human skin in vivo with biocompatible OCA combined with chemical and physical permeability enhancers. To satisfy the biocompatible concentration requirements, the mixtures of OCA and CPE were developed according to the FDA inactive ingredients database. To enhance the clearing effect, physical permeation methods were also used. By analyzing simultaneously the average intensity and contrast of the images obtained by LC-OCT technique, we determined the in-depth effectiveness of skin in vivo biocompatible OC. The results showed that the best increase in image intensity and contrast after 10 minutes of ultrasound-assisted clearing was achieved using a mixture of PEG/OA/PG. The results of the experimental data fitting with the hypothesized biphasic exponential association model are in a good agreement with experimental results. Thus, the effectiveness of OC with biocompatible concentrations of OCA was demonstrated
DUCRON, HAAS ELISABETH. "Tumeur de merkel : revue de la litterature a partir d'une observation". Lille 2, 1994. http://www.theses.fr/1994LIL2M041.
BORDAUX, ISABELLE. "A propos des merkélomes". Toulouse 3, 1990. http://www.theses.fr/1990TOU31118.
Schertenleib, Pierre. "Carcinome neuroendocrine cutané ou à cellules de Merkel /". [S.l.] : [s.n.], 1992. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
Gastaldi, Cécile. "Études des microARNs dans le développement des carcinomes spinocellulaires cutanés". Thesis, Nice, 2013. http://www.theses.fr/2013NICE4120/document.
Cutaneous squamous cell carcinomas (cSCCs) are the second most common cancer and are responsible for up to 25% of all skin cancer deaths. It is therefore essential to characterize the mechanisms responsible for epidermis carcinogenesis to develop new treatments. In this context, miRNAs appear to be prime targets for the development of future anti-tumor therapies. However, their involvement in the pathophysiology of cSCCs is still poorly documented. In this study, I identified using Small RNA sequencing, 112 miRNAs whose expression is altered during tumor development in a mouse model of cutaneous two-stage chemical carcinogenesis. Then, I focused my attention on the miR-193b/365a cluster and on miR-708, that are down-regulated during tumorigenesis, suggesting tumor suppressor functions. Consistent with this hypothesis, the ectopic expression of these miRNAs inhibit the proliferation, survival and migration of tumor cells, while blocking their action with antisense oligonucleotides stimulates these cellular functions in normal keratinocytes. Combining in silico target-prediction approaches and transcriptome analyzes of cSCC cells over-expressing these miRNAs, I identified their potential target genes. I validated KRAS and MAX as direct targets of miR-193b and miR-365a, and I showed that repression of these genes using siRNAs mimics the effects of these miRNAs. These results suggest that targeting these genes might mediate, at least in part, the tumor suppressor action of miR-193b and miR-365a in cSCCs
Simonneau, Marie. "Implication de l'Oncostatine M dans la genèse et le développement des carcinomes épidermoïdes cutanés". Thesis, Poitiers, 2018. http://www.theses.fr/2018POIT1403/document.
Cutaneous squamous cell carcinoma (cSCC) is one of the most frequent keratinocyte malignancies worldwide and is chemotherapy resistant. Surgery is the curative treatment but there isn’t any alternative in advanced cSCC. Reprogramming tumor microenvironment and tumor immunosuppressive mechanisms is a new therapeutic approach. Indeed, depending on cytokine expressed in tumor microenvironment, immune cells can inhibit (Th1/M1 cells) or enhance (Th2/M2 cells) tumor development. It was previously showed that Onconstatin M (OSM) had pleiotropic effects on cancer cells. OSM can promote cancer by inducing tumor cells motility, invasiveness or by reprogramming immune cells toward a more permissive phenotype (M2 polarization). Our previous data showed that OSM has proinflammatory effects on skin and modulate normal keratinocyte phenotype both in vitro and in vivo. In this study, we hypothesized that OSM could be involved in cSCC development. We showed that OSM was overexpressed in human cSCC as well as other cytokines such as IL-6, IL-1β, IFNγ whereas IL-4 was decreased, suggesting a Th1/M1 polarization of cSCC microenvironment. In vitro, OSM induced STAT-3 and ERK signalization, modified gene expression, promoted proliferation and migration of malignant keratinocyte PDVC57 cells. PDVC57 cells grafted in skin mice led to cSCC development associated to OSM overexpression by immune infiltrated cells. Finally, we showed that the absence of OSM led to a 30% reduction of tumor size and reduced M2 polarization in tumor microenvironment. Collectively, these results support a pro-tumoral role of OSM in cSCC development and suggest a new therapeutic approach targeting this cytokine
Mom, Thierry. "Le carcinome neuro-endocrine cutane en orl : a propos d'un cas localise au conduit auditif externe". Clermont-Ferrand 1, 1994. http://www.theses.fr/1994CLF1MS03.
ETIENNE-JULAN, MARYSE. "Le carcinome neuroendocrine cutane : tumeur a cellule de merkel ; a propos d'une observation (travail du service de medecine interne c et de gerontologie clinique)". Montpellier 1, 1993. http://www.theses.fr/1993MON11048.
Luron, Lionel. "Etude des mécanismes moléculaires impliqués dans le développement des carcinomes spinocellulaires cutanés". Paris 11, 2005. http://www.theses.fr/2005PA11T082.
Bayourthe, Pierre. "Les carcinomes neuro-endocrines cutanés ou tumeurs à cellules de Merkel : à propos d'une observation". Bordeaux 2, 1991. http://www.theses.fr/1991BOR2M170.
Mainreck, Nathalie. "Apport potentiel de la spectroscopie Raman dans le traitement chirurgical des carcinomes cutanés (CBC)". Thesis, Reims, 2017. http://www.theses.fr/2017REIMS028/document.
Basal cell carcinoma (BCC) is the most common skin cancer and a major problem for healthcare services worldwide. BCC rarely metastasizes but can become highly damaging for surrounding tissue in case of late diagnosis. Actually, the gold standard for BCC diagnosis relies on histopathological assessment of thin sections, but it is an invasive method which provides a delayed response. Moreover, it will be helpful during surgery of BCC to assess in real-time the optimal size of the security margins, which has to be small enough to minimize aesthetic sequelae but sufficient to avoid recurrence. The aim of this work is to evaluate the potential contribution of Raman spectroscopy in the management of BCC. This technology can be applied in vivo thanks to the development of appropriate probes and allows a relatively rapid tissue exploration at a molecular level. A total of 32 patients were included in this study. From in vivo recorded spectra, a model of discrimination BCC / healthy skin was implemented, from which the width of excision margins was evaluated. Deep margins were also studied after recording spectra on freshly excised pieces. Discriminant Raman markers were identified at different levels in vivo, ex vivo and in vitro; they are potential bio-indicators to help the surgeon to define ideal excision margins. In addition, the contribution of spectral backgrounds, usually removed from Raman analysis, was considered and their interest in this project was discussed
Khou, Sokchea. "Contribution des neutrophiles infiltrant les tumeurs dans la progression des carcinomes épidermoïdes cutanés : neutrophiles et cancer". Thesis, Université Côte d'Azur (ComUE), 2019. http://theses.univ-cotedazur.fr/2019AZUR4014.
Non-melanoma skin carcinomas are the most frequent cancers in Human and their incidence is constantly increasing. Two main types exist: the cutaneous basal cell carcinoma (cBCC) and the cutaneous squamous cell carcinomas (cSCC). Risk factors include sun radiation and immunosuppression. These cancers are mainly treated with surgery and radiotherapy but they can reach an incurable stage. For this reason, novel therapeutic alternatives are needed. At present, immunotherapies constitute a revolution in the treatment of cancers. Its mechanism of action relies on the stimulation of the immune system of cancer patients, so that they develop efficient anti-tumoral immune responses. cSCC may benefit from this type of treatment as they generally develop in the context of an immunosuppression. Immune surveillance involves both immune cells and the tumor microenvironment, in particular the stroma. During the elimination phase, the anti-tumoral responses, mediated mainly by CD8+ T lymphocytes, are efficient. Then, there is an equilibrium phase in which the tumor is stable before the escape phase, when the tumor can evade immune surveillance and grow. Our research interest focused on neutrophils, a subset of myeloid cells that are very rapidly recruited to the sites of inflammation and inside tumors. A recent meta-analysis of 39 human malignancies showed that neutrophils are associated with the worst clinical outcome. Neutrophils harbor both anti- and pro-tumoral functions. This polarization seems to be dependent on type I interferon and TGF-β, respectively. It remains to establish the exact role played by neutrophils in cancer and specifically in skin carcinomas. The aim of our research was to further characterize the functions and the contribution of neutrophils to the development of cutaneous squamous cell carcinomas. We first used a chemically-induced skin carcinoma mouse model that recapitulates the different stages of skin carcinoma development in Human. In this model, we saw a massive infiltration of neutrophils at the precancerous and cancerous stages. We performed transcriptomic analysis of highly purified neutrophil populations from precancerous, cancerous lesions and from the surrounding skin controls. These data revealed a specific gene signature in neutrophils from lesions compared to surrounding skins. Differential gene expression analysis identified a pro-tumoral phenotype for neutrophils infiltrating lesions compared to skins. In a second approach, we studied the growth of a cSCC cell line grafted in the dermis of mice. Specific depletion of neutrophils significantly delayed tumor growth, thus indicating that neutrophils were pro-tumoral. Mechanisms of action included the production of ROS and NO that favor tumor growth and the immune suppression of anti-tumoral responses mediated by tumor-associated CD8+ T cells. In the tumor, neutrophils produced arginase 1 which catalyzes the degradation of arginine, thus inhibiting the proliferation of CD8+ T cells. In addition, we found that the tumor microenvironment induced PD-L1 expression at the cell surface of neutrophils and concomitantly, PD1 on CD8+ and CD4+ T cells. These results suggested that PD-L1/PD1 interaction triggers immune suppression and contributes to SCC progression. Indeed, a positive and significant correlation was observed between tumor size and frequencies of PD-L1-expressing neutrophils inside tumors. Collectively, these results suggest that it is relevant to assess immunotherapies that block PD-L1/PD1 interaction for the treatment for cSCC. These approaches could be combined with treatments that aim to block the recruitment or inhibit neutrophils. Moreover, it remains to evaluate whether the frequency of PD-L1-expressing neutrophils could constitute a good predictive marker of the response to anti-PD-L1 and anti-PD1 immunotherapies
Liboutet, Muriel. "Facteurs de risques et gènes impliqués dans la carcinogenèse cutanée épithéliale". Paris 7, 2006. http://www.theses.fr/2006PA077200.
L/We were able to demonstrate that variants not associated to the phenotype " red hair " (Red Hair Color). As variants V60L and V92M, were strongly associated with the risk of development of CBC in french population(OR3,21 and 2,87). A "dose-gene" effect associated to the development of the CBC, meaning combined expression of several MC1R variants, in the population that we studied, was clearly identified (OR for one : 2. 17 and two variants: 7,72). Besides, we were able to correlate the genotype (C. 3944C > T ( P1315L) of the gene PTCH al the risk of developing CBC (OR 1,94) in patients with CBC multiple (OR 2,16). Il/ To establish the functional role of p16INK4A in the cell cycle arrest and the processes of DNA repair, we decided supress p16INK4A in vitro in HeLa cells by using the strategy of RNAi. HeLa Cell were used as a cellular support of our study since they are also deficient in p53 function. We shovved that the inhibition of the protein expression of p16INK4A in UVB irradiated cells did not modify the cell cycle arrest in G2/M Also. In the given experimental conditions, we did not observe significant difference in terms of DNA repair caused by UVB irradiation in cells expressing or not p16INK4A
ROCA, ROUSSEAUX FREDERIQUE. "Actualites en cryochirurgie : que penser d'un nouveau cryogene, le protoxyde d'azote, dans le traitement des carcinomes cutanes ? apport de l'echographie cutanee, mode b, comme nouvelle methode de controle". Reims, 1992. http://www.theses.fr/1992REIMM033.
Burtica, Elena Cleopatra <1974>. "Incidenza dei carcinomi a cellule squamose in una popolazione sottoposta a terapia fotodinamica". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2011. http://amsdottorato.unibo.it/3767/1/TESI_IMPAGINATA%5B1%5D.pdf.
Burtica, Elena Cleopatra <1974>. "Incidenza dei carcinomi a cellule squamose in una popolazione sottoposta a terapia fotodinamica". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2011. http://amsdottorato.unibo.it/3767/.
Bertoncelli, Marco <1980>. "Studio istologico e follow-up clinico di carcinomi basocellulari trattati con terapia chirurgica". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6332/1/bertoncelli_marco_tesi.pdf.
The study focused attention on the cost-effectiveness among the most popular methods used for removal of basal cell carcinomas: surgical resection and photodynamic therapy. From data it is clear that surgical removal is the most effective method for reducing the frequency of relapses (4.7%) compared to photodynamic therapy (6%). This figure is valid only for superficial carcinomas; for nodular carcinomas frequency of recurrence with photodynamic therapy turns out to be higher (35%). Surgery is a method more expensive than the photodynamic. The variable pain is less with surgery than the photodynamic therapy. The aesthetic result is rather better for photodynamic therapy compared to surgery. The costs however are higher for surgical therapy. One final consideration remains: photodynamic therapy sometimes requires reoperation after months or years and so this choice involves additional costs.
Bertoncelli, Marco <1980>. "Studio istologico e follow-up clinico di carcinomi basocellulari trattati con terapia chirurgica". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6332/.
The study focused attention on the cost-effectiveness among the most popular methods used for removal of basal cell carcinomas: surgical resection and photodynamic therapy. From data it is clear that surgical removal is the most effective method for reducing the frequency of relapses (4.7%) compared to photodynamic therapy (6%). This figure is valid only for superficial carcinomas; for nodular carcinomas frequency of recurrence with photodynamic therapy turns out to be higher (35%). Surgery is a method more expensive than the photodynamic. The variable pain is less with surgery than the photodynamic therapy. The aesthetic result is rather better for photodynamic therapy compared to surgery. The costs however are higher for surgical therapy. One final consideration remains: photodynamic therapy sometimes requires reoperation after months or years and so this choice involves additional costs.
Mathelier-Fusade, Pascale. "Traitement des carcinomes cutanés par cryochirurgie à l'azote liquide et au protoxyde d'azote : expérience rouennaise concernant 621 lésions". Rouen, 1992. http://www.theses.fr/1992ROUEM089.
Gaspari, Valeria <1981>. "Carcinoma a cellule basali: l'esperienza della dermatologia dell'Universita' di Bologna dal 1990 al 2014". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/6976/1/tesi_di_dottorato_def._dottoressa_valeria_gaspari-2.pdf.
Basal cell carcinoma (BCC) accounts for 80 percent of non-melanoma skin cancer, thus representing the most common malignant tumor of the skin. Nonetheless in our country the absolute incidence of BCC is difficult to establish with precision, since non-melanoma skin cancers are excluded from the statistical records of the tumors. The aim of the study we conducted was therefore to analyze retrospectively the cases of BCC of the Dermatology Unit of Bologna, in a period between 1990 and 2014. The inclusion criteria has been the positivity to BCC at histological examination, both in case of a simple biopsy, and in case of radical excision. Patients have been medical and/or surgical treated and followed up, in cases of multiple relapses or occurrance of new skin tumors, at the Oncologic-Dermatological-Surgery Unit of University of Bologna. We concluded that, by far, than any other skin cancers, basal cell carcinoma is the most frequently tumor observed in the Dermatology Unit of the University of Bologna. Not only that, our case study is also the largest so far reported throughout Italy in the last 24 years.
Gaspari, Valeria <1981>. "Carcinoma a cellule basali: l'esperienza della dermatologia dell'Universita' di Bologna dal 1990 al 2014". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/6976/.
Basal cell carcinoma (BCC) accounts for 80 percent of non-melanoma skin cancer, thus representing the most common malignant tumor of the skin. Nonetheless in our country the absolute incidence of BCC is difficult to establish with precision, since non-melanoma skin cancers are excluded from the statistical records of the tumors. The aim of the study we conducted was therefore to analyze retrospectively the cases of BCC of the Dermatology Unit of Bologna, in a period between 1990 and 2014. The inclusion criteria has been the positivity to BCC at histological examination, both in case of a simple biopsy, and in case of radical excision. Patients have been medical and/or surgical treated and followed up, in cases of multiple relapses or occurrance of new skin tumors, at the Oncologic-Dermatological-Surgery Unit of University of Bologna. We concluded that, by far, than any other skin cancers, basal cell carcinoma is the most frequently tumor observed in the Dermatology Unit of the University of Bologna. Not only that, our case study is also the largest so far reported throughout Italy in the last 24 years.
Matas, Nadal Clara. "Carcinomes de queratinòcits: aspectes epidemiològics a Catalunya i caracterització proteica del seu fluid intersticial tumoral". Doctoral thesis, Universitat de Lleida, 2021. http://hdl.handle.net/10803/672236.
Introducción: Los carcinomas de queratinocitos (CQ) son la neoplasia maligna más frecuente a nivel mundial en poblaciones caucásicas. En conjunto, suponen un enorme problema de salud, tanto en términos de morbilidad como de gasto sanitario. En las últimas décadas, su incidencia ha aumentado de manera significativa. Además, en el carcinoma basocelular (CBC), han aumentado dramáticamente los casos entre la gente joven, sobre todo mujeres. Los CQ tienen, en general, un buen pronóstico. A pesar de ello, el CBC puede crecer localmente destruyendo los tejidos circundantes y causar importantes secuelas funcionales y estéticas, y el carcinoma escamoso (CEC) es moderadamente invasivo y se puede asociar a un riesgo sustancial de recurrencias locales, metástasis y muerte (1.5-4 %). La fisiopatología de los CQ es dependiente de la alteración de varias vías de transducción de señales y de control de la proliferación. Uno de los efectos de estas alteraciones es la secreción de nuevas proteínas en el espacio extracelular, que caracterizarán el microambiente tumoral. Las proteínas y metabolitos señalizadores presentes en el fluido intersticial que rodea el tumor (TIF) han sido estudiados en algunos tipos tumorales, pero no hay nada descrito en cuanto a CQ. Objetivos: Esta tesis tiene dos objetivos principales: 1) Estudio epidemiológico y de factores de riesgo del CBC en Cataluña (Capítulo I), y 2) Caracterizar el perfil proteómico del TIF en los CQ y las implicaciones en su fisiopatología (Capítulos II y III). Resultados y conclusiones: En el estudio epidemiológico se ha observado que entre los < 60 años el CBC ya es un tumor que tiene una incidencia mayor en mujeres que en hombres. Los factores de riesgo independientes para el CBC en gente joven son el fototipo cutáneo, la historia familiar de CQ, y la presencia de ≥ 4 quemaduras en la infancia. Además, la presencia de repetidas quemaduras en la infancia es superior entre los casos de CBC en gente joven localizados en zonas cubiertas que entre los localizados en zonas fotoexpuestas. De todos los factores de riesgo, en la población general, el uso de cabinas de bronceado es el único que es más frecuente entre las mujeres que entre los hombres; por lo tanto, la popularización de su uso podría ser la causa de la tendencia a la predominancia femenina del CBC. En la segunda parte de la tesis, primero se ha puesto a punto el método de aislamiento de TIF. La centrifugación a 10 000 g permite obtener una cantidad superior de proteínas extracelulares, mayor sensibilidad y un manejo más rápido y fácil de las muestras, sin implicar un aumento de la lisis celular respecto a los otros métodos. Por estos motivos, la proponemos como método de elección en las muestras de tumores cutáneos. El análisis proteómico muestra que el CBC, el CEC y la piel sana tienen cada uno un perfil específico de proteínas secretadas en su TIF y sugiere la existencia de una diferente respuesta inmunológica del organismo frente al CBC y al CEC. Hemos determinado que la secreción de las proteínas PNP, FABP5, SFN y LAD1 es un perfil propio del CEC, y que están relacionadas con la agresividad tumoral y podrían ser dianas terapéuticas para su tratamiento. Además, el patrón de expresión de FABP5 permite distinguir las zonas diferenciadas de las invasivas en el CEC. También existe una diferente localización celular de la SFN y la LAD1 en la piel sana vs. CEC, que podría estar relacionada con el desarrollo tumoral. Finalmente, la secreción de cornulina es un marcador de CBC y muestra tendencia a asociarse con los subtipos más agresivos.
Introduction: Keratinocyte carcinomas (KC) are the most frequent malignancy in Caucasian populations worldwide. Altogether, they entail a huge health problem, both in terms of morbidity and health costs. In recent decades, their incidence has increased significantly. Moreover, basal cell carcinoma (BCC) cases have increased dramatically among young people, especially women. KC generally have a good prognosis. Despite this, BCC can grow locally, destroying surrounding tissues and causing important functional and aesthetic sequelae; and squamous cell carcinoma (SCC) is moderately invasive and can be associated with a substantial risk of local recurrences, metastasis, and death (1.5- 4 %). The physiopathology of KC depends on the alteration of several signal transduction pathways and proliferation control. One effect of these alterations is the secretion of new proteins in the extracellular space, which will characterize the tumor microenvironment. The signaling proteins and metabolites present in the interstitial fluid surrounding the tumor (TIF) have been studied in some tumor types, but nothing has been described in terms of KC. Objectives: This thesis has two main objectives: 1) Epidemiological and risk factors study of BCC in Catalonia (Chapter I), and 2) Characterization of the proteomic profile of TIF in KC and the implications in their physiopathology (Chapters II and III). Results and conclusions: In the epidemiological study, it has been revealed that, among those <60 years, BCC is already a tumor that has a higher incidence in women than in men. Independent risk factors for BCC in young people are skin phototype, family history of KC, and the presence of ≥ 4 sunburns in childhood. In addition, the presence of repeated sunburns in childhood is higher among BCC cases in young people in covered areas than among those in photo-exposed areas. Of all the risk factors, among the general population, the use of tanning beds is the only one that is more common among women than among men; therefore, the popularization of their use could be the crucial factor for the trend towards the female predominance of BCC. In the second part of the thesis, the TIF isolation method has been first developed. Centrifugation at 10 000 g allows obtaining a higher amount of extracellular proteins, greater sensitivity, and faster and easier handling of the samples, without increasing cell lysis when compared to other methods. For these reasons, we propose it as the method of choice in samples of skin tumors. The proteomic analysis shows that BCC, SCC, and healthy skin each have a specific profile of secreted proteins in their TIF, and suggests the existence of a different immune response of the organism against BCC and SCC. We have determined that the secretion of PNP, FABP5, SFN, and LAD1 proteins is a specific SCC profile, and that they are related to tumor aggressiveness and could be therapeutic targets for its treatment. Furthermore, the expression pattern of FABP5 makes it possible to distinguish differentiated from invasive areas in SCC. There is also a different cellular location of SFN and LAD1 expression in healthy skin vs. SCC, which could be related to tumor development. Finally, cornulin secretion is a BCC marker and tends to associate with the most aggressive subtypes.
Gonçalves, Maia Maria João. "Le syndrome Xeroderma Pigmentosum : Un nouveau modèle pour l’étude du rôle des fibroblastes dans la modulation de la réponse immunitaire innée contre les cellules cutanées cancéreuses". Thesis, Université Côte d'Azur (ComUE), 2019. http://www.theses.fr/2019AZUR4037.
Skin cancer etiology is related to genetic mutations arising after ultraviolet (UV) sun exposure. The propagation of cancer cells is also dependent of a crosstalk with cells present in the surrounding microenvironment, mainly cancer associated fibroblasts (CAF) and immune cells. Xeroderma pigmentosum (XP) is a genetic disease that comprises seven groups of genetic complementation (XP-A to XP-G). XP patients present a default in the mechanism responsible for the repair of UV-induced DNA lesions. They are prone to develop skin cancers with high frequencies early in their life. XP-C is the most represented complementation group in Europe and in XP-C patients squamous cell carcinoma (SCC) are more frequent than basal cell carcinoma (BCC) (ratio 5:1). SCC have high metastatic potential compared to BCC. Previous studies suggested that the immune responses in XP patients could be altered with defects in their NK lytic activity and a decrease in the levels of circulating T lymphocytes. The main objective of this thesis was to identify microenvironment factors that could contribute to the progression of aggressive skin cancers using XP-C disease cells as a model of skin cancer susceptibility. Comparative transcriptomic analysis of WT and XP-C dermal patient’s fibroblasts revealed that CLEC2A, a ligand of the activating NK receptor NKp65 implicated in the activation of the innate immune system, is expressed in WT fibroblasts and absent in XP-C fibroblasts. Additional work showed that CLEC2A level is decreased in WT fibroblasts during replicative senescence, is absent in CAF and SCC, and is down regulated by soluble factors secreted by SCC cells. These results suggest that the loss of CLEC2A may induce a deficit of NK cell activation in the tumor microenvironment of SCC and in the dermis of XP-C patients. Elaboration of 3D skin culture models including NK cells and, in the presence or absence of blocking anti-CLEC2A antibody, allowed us to show that CLEC2A/NKp65 interaction regulates SCC cells invasion through a crosstalk between fibroblasts and NK cells. Our results suggest that the expression of CLEC2A in fibroblasts contributes to skin immune surveillance while, conversely, its absence under yet unidentified factors, favors the development of aggressive cancers in XP-C patients. CLEC2A could be a potential target in the fight against SCC progression
ARFI, CATHERINE. "Exerese en deux temps des carcinomes cutanes etendus de la face : etude retrospective de 87 patients". Nantes, 1994. http://www.theses.fr/1994NANT247M.
Hernández, Ruiz Eugenia. "Mecanismos epigenéticos con valor pronóstico en el carcinoma escamoso cutáneo". Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/669702.
Cutaneous squamous cell carcinoma is the second most common skin cancer. Despite the majority of patients are diagnosed at an early stage and surgical excision is curative, about 5% of patients develop metastasis, usually to regional lymph nodes, and prognosis worsens with a 10- year overall survival of less than 20%. There are different classification systems that allow stratifying patients in function of the metastatic risk. The new American Joint Committee on Cancer classification, AJCC8, is superior in identifying high risk patients but there is much more to investigate in this field. Recently, the expression of the family of transcriptional repressors Polycomb, that silence and inactivate the genes that they regulate, have been detected in different solid tumors and it is increased in metastatic tumors. Two complexes have been identified in mammals, PCR2 or initiation complex, being EZH2 its main catalytic subunit and PRC1 or maintenance complex formed by different proteins such as RING1B and BMI1. We performed a multicentric descriptive study and 107 cutaneous squamous cell carcinomas were included; 56 metastatic carcinomas and 51 non-metastatic carcinomas that hadn´t developed metastases in a 5-year period time. In our first study we have demonstrated, using immunohistochemical stains, that EZH2 and RING1B expression is increased in metastatic cutaneous squamous cell carcinomas. In vitro functional studies using cell lines revealed that EZH2 and RING1B regulate NF-kb, since NF-kb, pathway is upregulated in Polycomb deplected cells. NF-kb, pathway is associated with inflammation. We could observe that chemotaxis of neutrophils is higher towards supernatants from cell cultures in which Polycomb proteins have been deplected. In our group of non-metastatic cutaneous squamous cell carcinomas we detected lower levels of Polycomb proteins expression using immunohistochemical stains, lower percentage of cells expressing Polycomb and lower intensity of Polycomb expression. When evaluating the inflammatory infiltrate, and despite using tissue microarrays we could also observe that non metastatic carcinomas showed higher amount of neutrophils and eosinophils in their stroma. Polycomb proteins may act silencing genes implicated in the immune response of keratinocytes and may favour the escape of tumoral cells from the immune system and the development of distant metastasis. Tumor microenvironment is not just an observer and plays an important role interacting with tumoral cells. Besides inflammatory cells, stromal fibroblasts can facilitate or inhibit tumoral cell dissemination, since they can produce different types of fibrosis with a prognostic value. Desmoplasia has always been linked to worse prognosis and some solid tumors such as pancreatic adenocarcinoma are characterized by a desmoplastic stroma which is a barrier to immune cell infiltratrion and also to chemotherapy. Ueno et al described three different types of fibrotic reaction in colorrectal carcinoma with prognostic value. In our second study we investigated the different fibrotic reaction patterns in whole hematoxilin-eosin stained sections in our series. The immature pattern characterized by myxoid changes with no inflammation was associated with tumoral budding, desmoplasia, perineural invasion, tumoral depth and metastatic risk.
García, Díez Irene. "Estudio del perfil genómico y de expresión en carcinomas escamosos cutáneos intraepiteliales e invasivos". Doctoral thesis, Universitat Autònoma de Barcelona, 2021. http://hdl.handle.net/10803/671613.
El carcinoma escamoso cutáneo (CEC) es el segundo tumor maligno cutáneo más frecuente. La mayoría de los CECs se desarrollan a partir de lesiones precursoras (queratosis actínicas ([QA]). Sin embargo, sólo una minoría de QAs evolucionan a CECs, sin que se conozcan de forma precisa los mecanismos que participan en dicha transformación. A pesar de que en la mayoría de los casos el pronóstico del CEC es excelente, existe un pequeño grupo de tumores considerados de alto riesgo (metastásicos o localmente avanzados) que presentan una evolución agresiva y mal pronóstico. En la actualidad no existen biomarcadores fiables en la práctica clínica que permitan detectar los CECs con mayor riesgo metastásico. Se ha propuesto que la expresión de PD-L1 por las células tumorales podría ser un marcador pronóstico en distintos tumores, si bien su utilidad en el CEC no ha sido previamente estudiada, distintos ensayos clínicos con nuevos fármacos dirigidos frente al eje PD1/PD-L1 en CECs han mostrado resultados esperanzadores. El objetivo de esta tesis es valorar los mecanismos moleculares implicados en las distintas etapas de la carcinogénesis del CEC (desde la piel sana fotoexpuesta [PF] hasta el CEC metastásico) con la finalidad de identificar los genes y las vías moleculares implicadas en su progresión y determinar posibles factores pronósticos. En la primera parte de este trabajo estudiamos las diferencias transcripcionales y genómicas en PFs, QAs y CECs a partir de 30 muestras apareadas por paciente, analizadas utilizando plataformas de arrays. Los resultados obtenidos se confirmaron por técnicas de RT-qPCR, inmunohistoquímica y Western blot. Identificamos dos factores de transcripción, BNC1 y FOSL1, cuya expresión se hallaba aumentada en el CEC y que podrían actuar como genes esenciales en la transformación tumoral. La integración de los datos obtenidos en los estudios de transcriptómica y de genómica reveló que las alteraciones en el número de copias del gen NEK10 se correlacionaban con los niveles de expresión de NEK10. Este gen codifica una quinasa relacionada con el gen NIMA (“Never in Mitosis gene A”), localizada dentro una región de pequeño tamaño en la banda 3p24.1, delecionada en 7 de los 10 CECs estudiados. Mediante técnicas inmunohistoquímicas y Western blot confirmamos la pérdida progresiva de la expresión de NEK10 desde la PF hasta el CEC y la práctica de estudios funcionales permitió demonstrar su participación en la regulación del ciclo celular en células epiteliales HaCaT. Todo ello apoyaría el papel de NEK10 como gen supresor tumoral en el CEC. En la segunda parte de este trabajo evaluamos el valor pronóstico de los niveles de PD-L1 en el CEC, analizando su expresión mediante inmunohistoquímica en 99 CECs primarios con metástasis linfáticas (n=48) y sin metástasis (n=51) y en 24 metástasis linfáticas. Detectamos una asociación entre la expresión de PD-L1 por ≥ 1% de las células tumorales y la presencia de metástasis linfáticas, así como con la recurrencia, una mala diferenciación histopatológica y la presencia de invasión perineural. En la mayoría de los casos (90%) existía una buena concordancia en la expresión de PD-L1 entre los CEC primarios y sus metástasis, con una tendencia hacia una mayor expresión en las últimas. No encontramos diferencias entre los tres tipos de muestras analizadas con respecto a la expresión de PD-L1 o de CD8 por las células del infiltrado peritumoral. Nuestros resultados sugieren que PD-L1 podría ser un biomarcador útil con posible valor pronóstico en el CEC.”
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Most cSCCs develop from precursor lesions (actinic keratosis [AK]). However, only a minority of AKs will eventually progress into cSCCs and the key mechanisms for this transformation remain unclear. Although in most cases the prognosis of cSCC is excellent, there is a small percentage of tumors with high metastatic risk. Metastatic or locally advanced cSCCs have high mortality, with no effective treatments available. Unfortunately, there is a lack of reliable biomarkers in clinical practice for detecting those cSCCs with the highest metastatic risk. Expression of PD-L1 by tumor cells has been proposed as a prognostic marker in different tumors. While the usefulness of PD-L1 expression in cSCC has not been addressed yet, new drugs aimed to block the PD1/PD-L1 axis are showing encouraging results in clinical trials in cSCC. The objective of this thesis is to evaluate the molecular mechanisms involved in the different stages of cSCC carcinogenesis (from healthy sun-exposed skin to metastatic cSCC) in order to identify the genes and molecular pathways involved, and their putative role as prognostic biomarkers. In the first part of this work we studied the differences in the transcriptome and the genome of sun-exposed skin, AKs and cSCCs of 30 samples matched by patient, using different array platforms. The results obtained were confirmed by quantitative RT-PCR, immunohistochemistry, and Western blot. We detected two transcription factors, BNC1 and FOSL1, whose expression was increased in cSCC and that could contribute to cSCC development. Additionally, a strong correlation between copy numbers and gene expression of NEK10 was identified by integrating the transcriptomic and genomic array data. NEK10 gene encodes a NIMA (“Never in Mitosis gene A”) related kinase, located within a small region in the 3p24.1 band, which was found to be deleted in 7 out of 10 cSCCs studied. By immunohistochemistry and Western blot, we confirmed the progressive loss of NEK10 from sun-exposed skin to cSCC and functional studies demonstrated the role of NEK10 in the regulation of the cell cycle in the epithelial HaCaT cells. These data support the role of NEK10 as a tumor suppressor gene in cSCC. In the second part of this work we evaluated the usefulness of PD-L1 expression, determined by immunohistochemistry, as a prognostic marker in cSCC. PD-L1 expression was analyzed in ninety-nine primary cSCCs with lymphatic metastases (n = 48) and without metastases (n = 51), and 24 metastases. An association between PD-L1 expression by ≥1% of tumor cells and the presence of lymphatic metastases, as well as with recurrence, poor histopathological differentiation and perineural invasion was detected. In most cases (90%), PD-L1 expression remained constant between primary cSCCs and their metastases, with a trend towards a higher expression in the latter. No differences among the three types of samples analyzed with respect to the expression of PD-L1 or CD8 by the cells of the peritumoral infiltrate were found. Our results suggest that PD-L1 could be useful as a prognostic biomarker in cSCC.
Aguayo, Ortiz Rafael. "Caracterització de les alteracions moleculars dels carcinomes basocel·lulars esporàdics". Doctoral thesis, Universitat de Lleida, 2013. http://hdl.handle.net/10803/123548.
El carcinoma basocelular (CBC) es la neoplasia más frecuente en el ser humano. La importancia de este tumor radica tanto en la gran morbilidad que produce como en el enorme gasto sanitario que ocasiona a los sistemas de salud de casi todo el mundo. A pesar de que su tratamiento es esencialmente quirúrgico, existen casos donde no está indicado este abordaje terapéutico y sería interesante el hecho de conocer las alteraciones moleculares que comportan la formación la neoplasia para establecer posibles dianas farmacológicas. Por estas razones hemos creído conveniente profundizar en el estudio de este tumor, centrándonos en la fisiopatología e intentando su cultivo “in vitro”. A través del estudio del síndrome de Gorlin-Goltz se ha establecido la importancia de la via Sonic hedgehog (Shh) en la fisiopatología del CBC. Nosotros, mediante técnicas como el inmunoblot y la inmunohistoquímica (midiendo los niveles de proteína Gli1) hemos determinado que esta vía está activada en aproximadamente la mitad de los casos de CBC esporádico, confirmando los datos que se conocían sobre este tema. Analizando vías alternativas, hemos encontrado muestras con alta actividad de b-catenina sin afectación de la vía Shh y esto nos hace pensar que la vía Wnt puede tener un papel fundamental en estos casos. Hemos detectado por inmunoblot la acumulación de b-catenina en la mitad de los casos estudiados, relacionándose de forma directa con la actividad proliferativa de la neoplasia.
Basal cell carcinoma (BCC) is the most common malignancy in humans. The importance of this tumor lies both in the high morbidity produced as in the high costs caused to the health systems of whole world. Although its treatment is essentially surgical, there are cases where it is not indicated this therapeutic approach, then it would be interesting to know the molecular alterations that involve the formation of this neoplasm to establish potential drug targets.For these reasons we have decided to study this tumor, focusing on the physiopathology and their culture "in vitro". Through the study of Gorlin-Goltz syndrome, the importance of the Sonic hedgehog pathway (Shh) in the pathophysiology of BCC was well established. Using techniques such as immunoblotting and immunohistochemistry (measuring protein levels Gli1), we have determined that this pathway is activated in about half of cases of sporadic BCC, confirming the previously known data. Analyzing alternative pathways, we found samples with high activity of b-catenin pathway without affecting Shh. This fact makes us think that the Wnt pathway may have a important role in these cases. We detected by immunoblot the accumulation b-catenin in half of the cases studied, interacting directly with the proliferative activity of the neoplasm.
GIOVANNACCI, ILARIA. "Quantificazione spettrofotometrica dell'autofluorescenza come potenziale strumento diagnostico per lesioni maligne della cute e della mucosa orale". Doctoral thesis, Università degli studi di Modena e Reggio Emilia, 2020. http://hdl.handle.net/11380/1211519.
Autofluorescence (AF) is defined as the fluorescence emission observed when certain cell molecules are excited by UV or visible light of suitable wavelenghts. When a biologic molecule is illuminated at an excitation wavelength within the absorption spectrum of that molecule, it will absorb this energy and be activated from its ground state to an excited state. The molecule (fluorophore) can then relax back from the excited to the ground state by generating energy in the form of fluorescence, at emission wavelengths, which are longer than that of the excitation wavelength. The most important endogenous fluorophores are molecules widely distributed in cells and tissues, like proteins containing aromatic aminoacids, flavins and lipopigments. The main fluorophores of healthy skin are located in the epithelium (eg. keratin, nicotinamide adenine dinucleotide or NADH and flavin adenine dinucleotide or FAD) and the submucosa (e.g. collagen and elastin). These molecules when irradiated between the wavelengths from 375 and 440 nm, show fluorescence in the green spectral range. Nonmelanoma skin cancer (NMSC) is the most common malignancy worldwide. The developement of NMSC is accompanied by histopathological changes in epidermis such as loss of cellular maturation, alteration in keratin production, overall thickening of the epithelial layer and biochemical alterations (NADH decrease). NMSC is also accompanied by histopathological changes in the underlying stroma and submucosa, including neovascularization and destruction of the collagen cross-link by proteases. These alterations lead to a general decrease in AF due the alteration in distribution of the fluorochromes and in particular to NADH and collagen. In the last two decades, studies concerning cell and tissue AF has had a dramatic increase. AF studies have been performed both in vitro and in vivo, for the study of normal tissue and for the discrimination between normal tissues and neoplastic lesions of oral mucosa, skin, esophagus, colon, lung, bronchi, brain and bladder. The methods used are both direct visual fluorescence examination (DVFE) and spectrophotometry. In particular, DVFE has been widely used for clinical studies on oral mucosa. Regarding AF of the skin, this has been studied more frequently by using spectrophotometry. The principle is scanning and analyzing reflected light from the skin after exposure to an activating light source. AF spectroscopy is a very sensitive technique for quantitative measurements of tissue constituents. However, to date no methods have emerged that can be translated into clinical practice. The primary objective of this study is to investigate the correlation between spectral mesurement of cutaneous AF and the histopathological characteristics of malignant and pre-malignant skin in NMSC. Following surgical removal of the cancer, an ex vivo evaluation of the AF will be performed. The specimen will be irradiated with a probe that emits a light in the blue spectrum (wavelength 400-440 nm) and the fluorescence emitted by the tissue will be measured using a spectrophotometer in a standardized spot modality. Any changes detected will be reported on the surgical specimen with the application of a surgical mark. Histopathological examination of the lesion will be performed and any changes in the fluorescence pattern will be correlated with possible alterations in the histopathological pattern, referring to surgical marks. Alterations in AF spectral measurement correlate with histopathological alterations in NMSC. the spectral measurement can be a new support for the early diagnosis of NMSCs, a guide for the targeted incisional biopsies, a tool for the definition of the intraoperative surgical margins, and for the follow-up of treated patients.
Bal, Élodie. "Les voies Hedgehog et NF-κB au coeur de l'homéostasie cutanée : apport de la caractérisation génétique et physiopathologique de deux dysplasies ectodermiques liées à l'X, le syndrome de Bazex-Dupré-Christol et l'Incontinentia Pigmenti". Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB116/document.
Genodermatoses are rare genetic diseases with cutaneous expression. Among them, ectodermal dysplasia (ED) characterized by abnormal development of at least two ectodermal structures (teeth, nails, sweat glands and hair) constitute a heterogeneous group of genodermatoses of more than 200 rare syndromes. While most of these syndromes associate only abnormalities of the ectodermal derivatives, others more complex, such as Bazex-Dupré-Christol syndrome and Incontinentia Pigmenti, bring together disparate manifestations. Bazex-Dupré-Christol syndrome (BDCS) associates ED with predisposition to early basal cell carcinoma (BCCs). The study of 6 families allowed us to identify, in 2 of them, a truncated mutation in the ACTRT1 gene, encoding the Arp-T1 protein. In the epidermis, Arp-T1 protein is decreased in all patients with BDCS, carrying or not of mutations in ACTRT1 gene. High-throughput sequencing of the candidate region allowed to identify mutations in transcribed enhancer regions, regulating the ACTRT1 gene in patients of the remaining 4 families. Noting that the Hedgehog pathway is deregulated in more than 70% of BCCs, we have demonstrated that ACTRT1 is a novel inhibitor of this pathway, via its binding to GLI1 promoter and inhibiting its expression. Finally, ACTRT1 is a new tumor suppressor gene capable of reducing in vivo the tumor progression of certain cancer lines by the regulation of genes involved in proliferation, death and cell survival, or migration. Incontinentia Pigmenti (IP) is a multisystemic disorder characterized by involvement of skin, teeth, eyes and sometimes the central nervous system. It results from mutation in the NEMO gene and the abolition of activation of NF-KB pathway. The study of a family concerned with IP allowed to identify a new splicing mutation of NEMO gene leading to a truncated protein expression. This protein retains all the functional domains of NEMO known. Its characterization revealed a loss of interaction with SHARPIN, components of LUBAC complex allowing linear ubiquitination. This is the first human mutation of NEMO showing the importance of its linear ubiquitination in the activation of the NF-KB pathway. Thus, my thesis work revealed novel physiopathological mechanisms responsible for two forms of ectodermal dysplasia. These mechanisms reflect the complexity of the molecular pathways involved in the development of the skin and the maintenance of its homeostasis during adult life
PIREDDU, ROSA. "Nanosized systems for efficient delivery of antitumoral and anti-inflammatory drugs". Doctoral thesis, Università degli Studi di Cagliari, 2015. http://hdl.handle.net/11584/266618.
Muller, Margot. "Le syndrome Xeroderma Pigmentosum-C - étude des mécanismes moléculaires impliqués dans la prédisposition des patients XP-C aux cancers cutanés non mélanocytaire agressifs". Thesis, Université Côte d'Azur (ComUE), 2019. http://www.theses.fr/2019AZUR6031.
Skin as the outer layer of the body is constantly exposed to UV, the main cause of skin cancer. Non-Melanoma Skin Cancer are divided in two cancer types: Squamous cell carcinoma (SCC) and Basal cell carcinoma (BCC). BCC arise after early acute UV exposure during childhood and present a low metastatic potential; while SCC arise after low chronic UV exposure during life time, present higher metastatic potential. Ratio between BCC and SCC is 4 to 1 in general population.In the lab, we are interested in Xeroderma Pigmentosum (XP) pathology. XP is a rare autosomal recessive genetic disease. In Europe, a large majority of XP patients carry a mutation in XPC gene. resulting in the absence of XPC protein. Canonical role of XPC is to recognize UV DNA damage and allowed DNA reparation by Nucleotide Excision Repair mechanism (NER). XP-C patients present a hypersensitivity to UV radiations and develop very early skin cancer with a higher incidence. They develop 10 000 times more non-melanoma skin cancer (NMSC) compare to general population. Interestingly, we observe that XP-C patients develop 1 BCC for 4 SCC. The objective of my PhD is to decipher the molecular mechanisms underlying XP-C keratinocytes susceptibility to SCC.In our laboratory, we used human primary keratinocytes isolated from biopsies of XP-C patients or healthy individuals. We developed a protocol to mimic chronic solar exposure by exposing primary keratinocytes to chronic low UV irradiation. We have chosen to perform an unbiased approach using whole genomic sequencing (WGS) from XP-C and WT keratinocytes exposed or non-UV exposed. As expected, chronically irradiated XP-C keratinocytes presented an increase of mutation burden particularly in coding sequence. A gene network analysis of UV mutation shows a defect in chromatin organization. Very interestingly, without UV exposure, we saw already an increase of mutation in coding sequence even though no differences in mutation burden was observed. Then performing again, a network analysis focusing only on stop mutations, we highlighted a defect in chromatin organization. These results suggested a chromatin organization defect and a more open state of chromatin in XP-C keratinocytes. Our putative model is that open chromatin could be linked to a more stem cell state of XP-C keratinocytes, suggesting a new role of XPC in chromatin organization. To validate this putative model, we mimic chromatin organisation defects by using epigenetic modifier drugs on WT primary keratinocytes. After this treatment, WT cells presented terminal differentiation defect. We then checked our XP-C keratinocytes differentiation potential. And we observed a similar phenotype to treated WT cells. XP-C keratinocytes seems to have defect in cell differentiation and cell fate commitment. We showed that XP-C keratinocytes presented a higher percentage of stem cell, a higher expression of interfollicular epidermis markers and presented a defect in terminal differentiation program. These results strongly supported our hypothesis that the absence of XP-C leads to a switch in cell identity.In conclusion, the absence of XP-C reveals a stem cell like phenotype of XP-C deficient keratinocytes with a more open chromatin that could be linked to the more aggressive type of cancer observed in patients. Indeed, the cell of origin of NMSC are different. Thus, the aggressive one has a progenitor like cell as a cell of origin. Altogether, these data correlate nicely with our putative model, giving a first clue in the explanation of the inverted ratio of NMSC cancer in XP-C pathology
Valin, Alexandre. "Rôles de la voie SONIC HEDGEHOG/PATCHED et des interactions dermo-épidermiques dans la prédisposition aux carcinomes basocellulaires chez les patients atteints du syndrome de Gorlin". Paris 7, 2009. http://www.theses.fr/2009PA077009.
The germinal mutations of the tumor suppressor gene PATCHED are responsible for rare, autosomal and dominant syndrome called Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS). PATCHED is the transmembrane receptor of the diffusible morphogen SONIC HEDGEHOG (SHH). NBCCS patients are predisposed to basal cell carcinoma (BCC), the commonest human cancer, originating from keratinocytes. Ultraviolet (UV) irradiation represents the major etiologic factor of sporadic BCC, but its role in NBCCS is not known. Our results show that NBCCS and control primary fibroblasts and keratinocytes exhibit similar survival and DNA repair capacities following UV irradiation, suggesting that UVs are not responsible for BCC predisposition in NBCCS patients Control fibroblasts and NBCCS keratinocytes in skin organotypic cultures mimic the loss of one PATCHED allele that is thought to occur in keratinocytes early upon sporadic BCC development. In this model, the keratinocytes proliferate and invade the dermis, their differentiation is altered and the SHH/PATCHED pathway seems to be active, as in BCC. Stromal activated fibroblasts stimulate the tumorigenesis. We aimed at determining if healthy NBCCS fibroblasts could play such a role in the BCC predisposition of NBCCS patients. A microarray screen between NBCCS and control fibroblasts, cultivated in dermal equivalents, revealed the over-expression by NBCCS fibroblasts of proliferation and invasion facilitating factors. In NBCCS patients, these pro-tumoral characteristics, associated with "pre-tumoral" keratinocytes could favour BCC development, including in photo-protected skin areas
Perrier-Trudova, Victoria. "Molecular characterization of hereditary and sporadic papillary renal cell carcinoma type 2 (PRCC2)". Thesis, Paris, EPHE, 2015. http://www.theses.fr/2015EPHE3085.
Papillary Renal Cell Carcinoma type 2 (PRCC2) is known to be a very aggressive type of kidney cancer with a high metastatic potential, poor outcome and absence of effective therapy. Hereditary form of PRCC2 is associated with rare hereditary leiomyomatosis and renal cell carcinoma (HLRCC). HLRCC is characterized by germline heterozygous mutations in the Fumarate Hydratase (FH) gene that encodes an enzyme of the Krebs cycle, Fumarase. It has been shown that the accumulation of fumarate induces activation of Hypoxia Inducible Factor (HIF) and ROS (Reactive Oxygen Species) pathways. Nevertheless, no FH gene mutation has been reported in sporadic PRCC2 tumors. The goal of this study is to better characterize hereditary and sporadic PRCC2. Our transcriptome analysis identified the set of genes that are differentially expressed between the two types of PRCC2. Subsequent immunohistochemistry screening did not reveal any potential diagnostics biomarkers. Further, the comprehensive computational analysis of gene profiling data revealed that hereditary and sporadic PRCC2 share the similar molecular signature with NRF2-KEAP1 axis deregulation as one of the major pathway in both forms. We demonstrated that over expression of Aldo-keto reductase family 1 member B10 (AKR1B10) is the direct consequence of the antioxidant response element (ARE) activation shared in hereditary and sporadic tumors. Finally, we have established FH-deficient cell line (NCCFH1) a new preclinical model of hereditary PRCC2. It presents the perfect platform for studying the metabolic features and testing new therapies for hereditary PRCC2, while bortezomib appears to be a potential efficient therapeutic option
ECHCHAKIR, HAMID. "Etude de la reponse ctl dans deux modeles de tumeurs solides : les cancers bronchiques non a petites cellules et le lymphome t cutane. clonage des antigenes associes a un carcinome bronchique a larges cellules". Paris 12, 2000. http://www.theses.fr/2000PA120051.
Maubec, Eve. "Prédisposition génétique au mélanome : de la génétique à la recherche clinique". Thesis, Paris 11, 2012. http://www.theses.fr/2012PA11T034.
This thesis had two main objectives: 1) To define groups of patients which may benefit from genetic counseling by identifying predictors of mutations of the CDKN2A gene, a major gene predisposing to cutaneous melanoma (CM) in families with only two cases. 2) Epidemiological and clinical characterization of specific entities of melanoma with the secondary objective of contributing to the identification of susceptibility genes for these entities. Coexistence of CM with renal cell carcinoma and mucosal anogenital melanomas were studied.The study populations are a collection of 293 melanoma patients that were ascertained systematically and the French collection MELARISK which is a collection including over 3000 subjects drawn from families with multiple cases of melanoma or melanoma occurring in a particular context (association with another cancer, rare locations, occurrence before the age of 20, multiple sporadic melanomas).We investigated association of three clinical features with the presence of a CDKN2A mutation in a family by extent of CM family clustering (2 versus ≥3 CM patients among first-degree relatives in a family).The study was conducted in 483 French families including 387 families with two melanoma patients, and 96 families with three or more patients with melanoma. The factors examined individually and in a joint analysis in a family were: median age at diagnosis <50 years, ≥1 patient in a family with multiple primary melanomas (MPM) or with pancreatic cancer. The frequency of CDKN2A mutations was higher in F3+ families (32%) than in F2 families (13%). While early age at melanoma diagnosis and occurrence of MPM in ≥1 patient were significantly associated with the risk of a CDKN2A mutation in F2 families, early age at melanoma diagnosis and occurrence of pancreatic cancer in a family were significantly associated with CDKN2A mutations in F3+ families. Thus this study showed that clinical features associated with CDKN2A mutations vary, in France, a country of low incidence of melanoma, according to the degree of familial clustering. Identifying predictors of CDKN2A mutations in families with two melanoma cases has helped to define subgroups of families (early age at CM diagnosis, and/or ≥1 MPM patient) in which the frequency of CDKN2A mutations is above 20% such that these subgroups of F2 families should be offered genetic testing.The analysis of two series of patients, either patients with melanoma coexisting with renal cell carcinoma or patients with anogenital mucosal melanoma identified their clinical and histological features by comparing them to a series of melanomas that were ascertained systematically. In both series, our results suggested a genetic predisposition at least partly independent of CDKN2A. The study of the c renal cell carcinoma; coexistence of CM and renal cancer in the same patient had two practical consequences for clinicians: it suggests the interest of a dermatologic screening visit in patients with renal cell carcinoma and that abdominal ultrasonography or computed tomography scanning performed at the initial workup and during the follow-up of patients with CM may be of value for the early detection of renal cancer. Regarding genetic research, this series has contributed to the identification of a germline mutation in the MITF gene that increases the risk of developing melanoma, renal cancer or both cancers and has interesting biological properties. The study of anogenital melanoma has shown that these melanomas could be associated with cutaneous melanoma in the same patient and it has also shown a high frequency of family history of melanoma associating mucosal and CM suggesting a shared genetic predisposition. Consequently dermatological screening or monitoring must include examination of both skin and mucosa in families with multiple cases of CM; and in case of a mucosal melanoma, a dermatological examination should be offered to relatives. The genetic mechanism has to be identified
PETROLATI, ALESSANDRA. "La sede non influenza la probabilità di ablazione completa precoce, di recidiva locale e di sopravvivenza in 164 pazienti con 182 piccoli epatocarcinomi (< 4 cm) trattati con terapia laser per cutanea: analisi retrospettiva". Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2009. http://hdl.handle.net/2108/1132.
Background. Percutaneous laser ablation (PLA) has been proposed as an active treatment in patients with hepatocellular carcinoma with a significant activity in inducing complete ablation in HCC <4cm,. However, to date no data reported using PLA in treating lesions at high-risk located. Aim. To evaluate if the so-called high-risk location (e.g. close to vital structures) affects initial complete ablation rate, local recurrence rate and overall survival in cirrhotic patients with small hepatocellular carcinoma (HCC) treated with US-guided percutaneous laser ablation (LA) Materials and Methods. 182 small HCC nodules in 164 cirrhotic patients were treated by US-guided PLA (USg-PLA) between 1996 and 2008. One hundred six patients (52M/54F; mean age 69 yrs) had 116 HCC nodules (mean diameter 2.7 cm ; range 0.8- 4.0 cm ), either with exophytic growth or located <1cm from the liver edge or vital structures (high-risk group). Fifty eight patients (38M/20F, age 68yrs) had 66 HCC tumors (mean diameter 2.4 cm ; range 0.8- 4.8 cm ) located in not high-risk sites (low-risk group). Survival curves obtained via the Kaplan-Meier method were compared using the Log-Rank test. Multivariate analysis was based on Cox model. Results. The initial complete ablation did not significantly differ between the two groups ( 96.5 % vs 92.4%) (p= .497). The overall median follow-up was 81 months. For patients who achieved a complete response, the estimated local recurrence median time was 84 months in the low-risk group and 132 months in the high-risk group. Location did not significantly affect local recurrence free survival (p= .53) at both univariate and multivariate analysys after adjusting for diameter and tumour histology. Results by Cox model suggest the maximum diameter as the only significant predictor of local recurrence (p= .01). The overall survival did not differ significantly between the two groups (p= .374) and the 1-, 3- and 5-yr survival probability was 0.90 (s.e.=0.029), 0.54 (s.e.=0.053) and 0.33 (s.e.=0.054) in the high-risk group and 0.95 (s.e.=0.030), 0.66 (s.e.=0.070) and 0.33 (s.e.=0.074) in the low-risk one. At multivariate analysis location turned out not to be a significant predictor of overall survival. Conclusion. High-risk location of small HCC nodules treated with USg-PLA seems not to affect complete tumor ablation rate, local tumour recurrence rate and patients’ survival.
Mestre, Claire. "Pachydermie plicaturée frontale, syndrome paranéoplasique accompagnant une tumeur carcinoi͏̈de bronchique métastasée". Bordeaux 2, 1991. http://www.theses.fr/1991BOR23095.
GIUFFRIDA, ROBERTA. "Role of noninvasive imaging in the management of skin cancer". Doctoral thesis, 2020. http://hdl.handle.net/11570/3169685.
GIOFRE', MANUEL. "Valutazione del ruolo e dell’efficacia dell’anoscopia ad alta risoluzione (HRA) come strumento di screening delle precancerosi anali e di diagnosi precoce del cancro anale nelle popolazioni ad alto rischio". Doctoral thesis, 2019. http://hdl.handle.net/11573/1480800.