OBJETIVO: Avaliar a eficácia e segurança da imunoterapia tópica com imiquimode creme 5% no tratamento do carcinoma basocelular nodular periocular. MÉTODOS: Pacientes com carcinoma basocelular confirmado por biopsia e com contraindicação clínica para a cirurgia reconstrutiva devido ao alto risco ou que recusaram a cirurgia por razões estéticas ou fobia foram incluídos no estudo. O tratamento foi iniciado após treinamento do paciente e de acompanhante. A posologia foi de 5 vezes por semana por 8 a 16 semanas. Acompanhamento quinzenal foi realizado durante a vigência do tratamento com questionário, exame biomicroscópico, medida da acuidade visual e documentação fotográfica. As características clínicas das lesões foram mensuradas através do software ImageJ. Após 12 semanas do fim da terapia, uma nova biópsia na região da lesão foi guiada por fotografia. O seguimento dos pacientes foi semestral, após fim do tratamento, com biópsias anuais da região até o presente momento. RESULTADOS: 19 foram tratadas. A taxa de cura histológica foi de 89,5% após três meses do final do tratamento, e de 84,2% nos três anos de seguimento (39,5 meses). A taxa de cura histológica em três anos foi de 100% para lesões menores que 10 mm, e de 81,8% para lesões maiores que 10 mm. De uma forma geral, os efeitos colaterais da medicação foram mais frequentes durante as oito primeiras semanas de tratamento. Quanto menor foi a distância da lesão à margem palpebral, maior foi chance de o paciente desenvolver ectrópio no tratamento (p = 0,045). Assim, como quanto maior foi a inflamação, maior foi a chance de desenvolver ectrópio, dor e edema durante o tratamento (p = 0,017, p = 0,016 e p = 0,044, respectivamente). CONCLUSÕES: Imiquimode creme 5% mostrou-se eficaz para o tratamento alternativo do carcinoma basocelular periocular, principalmente em lesões menores que 10 mm. Em adição, demonstrou um interessante efeito neoadjuvante sobre as lesões maiores que 10 mm que não foram curadas. Mostrou-se um tratamento seguro; entretanto, um cuidado maior deve ser dado às lesões próximas à margem palpebral devido ao maior risco de complicações e desenvolvimento de ectrópio / Objective: to evaluate the efficacy and safety of topical administration of 5% imiquimod cream in the treatment of periocular nodular basal cell carcinoma (BCC). Methods: Patients with periocular nodular basal cell carcinoma confirmed by biopsy and clinical contraindication to reconstructive surgery due to high risk or who decline surgery for aesthetic reasons or phobia were included in the study. The medication was applied once a day, five days a week for 8-16 weeks. Treatment was initiated after provision of patient and caretaker training. During treatment, patients were followed up twice a month with questionnaires, biomicroscopic examinations, measurement of visual acuity and photographic documentation. The clinical characteristics of the tumors were registered with the software ImageJ. Twelve weeks after the end of treatment, an image-guided biopsy of the tumor site was performed. Patients have since been attending follow-up visits every six months, and biopsies of the region are performed annually. Results: 19 tumors were treated with imiquimod. The average histological cure rate was 89.5% after 3 months at the end of the treatment and 84.2% after 3 years of follow-up (39.5 months). The 3-year histological cure rate was 100% for smaller tumors and 81.8% for larger tumors (>10 mm). In general, drug-related side effects were more frequent during the first 8 weeks of treatment. The smaller the distance between tumor and lid margin, the greater the probability of developing ectropion during treatment (p=0.045). Likewise, the more severe the inflammation, the greater the probability of developing ectropion, pain and edema during treatment (p=0.017, p=0.016 and p=0.044 respectively). Conclusion: Topical administration of 5% imiquimod cream was found to be an efficacious and relatively safe alternative treatment for periocular BCC, especially for tumors smaller than 10 mm, with interesting neoadjuvant effects on uncured tumors larger than 10 mm. However, special care is required when treating tumors near the eyelid margin due to the risk of complications and development of ectropion

Le développement de nouveaux médicaments, la validation et la standardisation des marqueurs de neuroimagerie et biochimie de la Maladie d'Alzheimer (MA) seront les principaux objectifs de la recherche de cette maladie dans les années à venir. La présente thèse vise à aborder ces questions cruciales. La première partie de la thèse fait le point sur l’application correcte des Procédures Opérationelles Standards (SOPs) pour l'acquisition de protocoles de neuroimagerie structurelle et l’application des marqueurs de neuroimagerie cérébrale dans 10 cliniques italiennes spécialisées dans les troubles de la mémoire. La deuxième partie traite de l'application de plusieurs marqueurs de neuroimagerie structurelle et fonctionnelle dans le cadre des études cliniques sur des patients ayant des troubles précoces de la maladie d'Alzheimer. Les résultats ont révélé que la mise en oeuvre des SOPs pour l’acquisition des séquences d’imagerie par résonance magnétique (IRM), au niveau multicentrique, réduit la variance des mesures des marqueurs de neuroimagerie détectée par différents scanners. En outre, les résultats de la deuxième partie de la thèse ont montré un impact significatif des thérapies anticholinestérasiques pour réduire l'atrophie de l'hippocampe, l'amincissement cortical ainsi que une augmentation de l'activation de zones du cerveau liées à l'IRM fonctionnelle chez des patients ayant des troubles précoces de la MA. Ces résultats prometteurs confirment l'hypothèse que les marqueurs de neuroimagerie structurelle et fonctionnelle appliqués avec SOPs pourraient être utilisés comme critère d'évaluation substitutif dans les études cliniques pour les patients ayant des troubles précoces de la maladie d'Alzheimer. / The development of new drugs and the validation and standardization of neuroimaging and biological markers for Alzheimer’s Disease (AD) clinical treatment trials is expected to be one of the major goals of AD research in the upcoming years. The present thesis aims to adress these critical issues. The first part of the thesis is focused on the proper application of Standard Operating Procedures (SOPs) for the structural neuroimaging protocols of acquisition and the implementation of neuroimaging markers in 10 Italian Memory Clinics. The second part of the thesis deals with the application of several structural and functional neuroimaging markers in the context of clinical trials investigation in mild cognitive impairment individuals. Results revealed that the implementation of SOPs at multicentre level reduces the variance of neuroimaging markers measurement detected by different scanners. Moreover, results from the employment of neuroimaging markers in pre-dementia trials in mild cognitive impairment individuals showed a significant impact of anticholinesterase therapies in reducing the hippocampal rate of atrophy, the cortical thinning as well as in increasing the activation of brain areas related to functional Magnetic Resonance Imaging (fMRI) face and location macthing tasks. These promising results support the hypothesis that structural and functional neuroimaging markers applied in a standardized manner migh be utilized as candidate surrogate outcomes in future pre-dementia trials for AD.

Les structures du système nerveux responsables des modalités de la prise de décision forment un circuit constitué par les ganglions de la base, le cortex, le thalamus et leurs nombreuses interconnexions. Ce circuit peut être décrit comme un ensemble de boucles fonctionnant en parallèle et interagissant en différents points. Des interactions entre ces boucles et de la plasticité de leurs connexions émergent les choix et donc les actions d’un individu. Ces comportements émergents et les phénomènes d’apprentissage qui en découlent sont abordés à travers une approche en boucle fermée dans laquelle le modèle théorique est en interaction constante avec l’environnement où se déroule la tâche comportementale étudiée. A cette fin, des outils de modélisation neuronale et d’analyse dédiés ont été développés dans le laboratoire d’accueil. Nous explorons donc ici la dynamique des flux d’information au sein de ce circuit à travers un modèle computationnel décrit à l’échelle du neurone et de la synapse. A partir d’observations expérimentales préalables réalisées sur le primate et de modèles computationnels antérieurs, nous avons développé de manière incrémentale un réseau capable d’apprendre à réaliser les tâches comportementales dans plusieurs protocoles et conditions. Le résultat obtenu ici est un modèle computationnel d’apprentissage et de prise de décision dans les ganglions de la base qui permet de tester des hypothèses expérimentales et d’effectuer des investigations physiopathologiques ou pharmacologiques in silico à l’échelle cellulaire. Le développement de ce modèle computationnel a été mené en parallèle avec l’étude expérimentale d’un protocole de prise de décision et la mise au point d’un modèle de maladie de Parkinson chez la salamandre (Pleurodeles waltlii). / The nervous system structures involved in decision making constitute a circuit formed by the basal ganglia, the cortex, the thalamus and their numerous interconnections. This circuit can be described as a set of loops operating in parallel and interacting at different points. The decisions and therefore the actions of an individual emerge from the interactions between these loops and the plasticity of their connections. These emerging behaviors and arising learning processes are addressed through a closed-loop approach in which the theoretical model is in constant interaction with the environment of the task. To this end, neural modeling and dedicated analysis software tools were developed in the laboratory. We explore here the dynamics of information flows within this circuit through a computational model described at the neuron and synapse level. Taking into account previous experimental observations from primates and earlier computational models, we incrementally developed a network capable of learning to perform behavioral tasks under several protocols and conditions. The result here is a computational model of learning and decision making in the basal ganglia that allows for the testing of experimental hypotheses and also to conduct in silico pathophysiological or pharmacological investigations at the cellular level. The development of this computational model was conducted in parallel with the development of an experimental protocol of decision making and with the adjustment of a model of Parkinson disease in the salamander (Pleurodeles waltlii).

Melanoma is one of the most aggressive types of cancer. It originates from the transformation of melanocytes present in the epidermal/dermal junction of the human skin. It is commonly accepted that melanomagenesis is influenced by the interaction of environmental factors, genetic factors, as well as tumor-host interactions. DNA photoproducts induced by UV radiation are, in normal cells, repaired by the nucleotide excision repair (NER) pathway. The prominent role of NER in cancer resistance is well exemplified by patients with Xeroderma Pigmentosum (XP). This disease results from mutations in the components of the NER pathway, such as XPA and XPC proteins. In humans, NER pathway disruption leads to the development of skin cancers, including melanoma. Similar to humans afflicted with XP, Xpa and Xpc deficient mice show high sensibility to UV light, leading to skin cancer development, except melanoma. The Endothelin 3 (Edn3) signaling pathway is essential for proliferation, survival and migration of melanocyte precursor cells. Excessive production of Edn3 leads to the accumulation of large numbers of melanocytes in the mouse skin, where they are not normally found. In humans, Edn3 signaling pathway has also been implicated in melanoma progression and its metastatic potential. The goal of this study was the development of the first UV-induced melanoma mouse model dependent on the over-expression of Edn3 in the skin. The UV-induced melanoma mouse model reported here is distinguishable from all previous published models by two features: melanocytes are not transformed a priori and melanomagenesis arises only upon neonatal UV exposure. In this model, melanomagenesis depends on the presence of Edn3 in the skin. Disruption of the NER pathway due to the lack of Xpa or Xpc proteins was not essential for melanomagenesis; however, it enhanced melanoma penetrance and decreased melanoma latency after one single neonatal erythemal UV dose. Exposure to a second dose of UV at six weeks of age did not change time of appearance or penetrance of melanomas in this mouse model. Thus, a combination of neonatal UV exposure with excessive Edn3 in the tumor microenvironment is sufficient for melanomagenesis in mice; furthermore, NER deficiency exacerbates this process.

Les cils et flagelles sont des organites cellulaires retrouvés des protozoaires aux mammifères. Une dérégulation de l’assemblage (ciliogenèse) ou de la fonction des cils, entraîne diverses maladies chez l’homme. Parmi les acteurs de la ciliogenèse, se trouvent les facteurs de transcription RFX. La recherche de gènes cibles de RFX chez la drosophile a permis d’identifier le gène Chibby (Cby), précédemment décrit comme un antagoniste de la voie de signalisation Wnt/wingless. Contrairement aux vertébrés, chez les invertébrés aucun lien n’est encore établi entre cil et voie wg. L’identification de cby comme cible de dRFX chez la drosophile suggère une fonction ciliaire de cby et permettrait l’établissement du lien cil/voie wg. CBY se localise à la zone de transition des cils des neurones sensoriels du système nerveux périphérique et aux centrioles des spermatides. Les drosophiles invalidées pour cby présentent un phénotype de non coordination, mais aucun phénotype de type wg. Ces mutants ont des défauts des cils sensoriels, ainsi que des défauts d’organisation des spermatides. De plus, chez les embryons, les protéines actrices du transport intra-flagellaire, NompB et CG11356, sont mal distribuées lorsque CBY est absente. Enfin, chez les mutants, la localisation de la protéine UNC est affectée dans les cellules germinales en fin de spermatogenèse. En conclusion, chez la drosophile, CBY est impliquée dans le tri protéique organisé à la base du cil de neurones sensoriels, de concert avec les autres protéines localisées à la zone de transition. Dans le testicule, CBY est nécessaire à la maturation des spermatides. En revanche, CBY n‟intervient pas dans la régulation de la voie wg / Cilia and flagella are organelles found from protozoa to mammals. Deregulation of the assembly (ciliogenesis) or function of cilia, causes various diseases in humans. Among those involved in ciliogenesis are the RFX transcription factors. The search for RFX target genes in Drosophila identified the Chibby (CBY) gene, previously described as an antagonist of the Wnt / wingless pathway. Unlike in vertebrates, in invertebrates is still no link established between cilia and the wg pathway. The identification of CBY as a target of dRFX in Drosophila suggests a ciliary function of CBY and would allow the establishment of the link cilia / wg pathway. CBY is localized at the transition zone of cilia of sensory neurons of the peripheral nervous system and at centrioles in spermatids. Drosophila invalidated for CBY present a phenotype of uncoordination, but no wg phenotype. These mutants have defects in sensory cilia and defects in organization of spermatids. In addition, in embryos, the distribution of proteins involved in intra-flagellar transport, NompB and CG11356, is affected when CBY is absent. Finally, in the mutants, the localization of the UNC protein is affected in germ cells at the end of spermatogenesis. In conclusion, in Drosophila, CBY is involved in the protein sorting organized at the base of cilia of sensory neurons, with the other proteins located at the transition zone. In the testes, CBY is necessary for the maturation of spermatids. However, CBY is not involved in the regulation of the wg pathway

The cancers of the skin, melanoma and the keratinocyte cancers, basal cell andsquamous cell carcinomas (BCC and SCC), are among the most common cancersin white populations. While ultraviolet radiation (UVR) is their principal cause,links with non-UVR-related factors have also been noted. Ultimately, theinteraction of these elements results in malignancy however, understanding oftheir specific contributions remains incomplete. This thesis reports findings fromsix studies aiming to investigate gaps in current knowledge of the role of UVR andnon-UVR-related risk factors on skin cancer. The papers are groupedaccording to the aspects of skin cancer epidemiology and aetiology they address. The first two papers address the descriptive epidemiology of melanoma inEngland, a country with low ambient solar UVR. They arise from ecologicalstudies using national melanoma registration data and document rising trends inmelanoma incidence by anatomic site (Paper 1), and by region of residence andsocio-economic deprivation (Paper 2). Their findings were consistent with thesuggestion that increases in recreational UVR exposure are driving rises inmelanoma rates. These results emphasise both the need to closely monitor UVRexposure and melanoma trends and the importance of public health campaigns. The second group of three papers considers the assessment of associations ofnutritional factors with keratinocyte cancer. Two studies use data from aprospective cohort to evaluate the relationship between dietary intake (Paper 3)and blood concentrations (Paper 4) of omega-3 and omega-6 polyunsaturatedfatty acids (PUFA) in relation to BCC and SCC risk. Associations with both PUFAtypes were observed. In addition, Paper 5, a three-way correlational assessment,demonstrated that questionnaire and blood circulating levels of omega-3 PUFAwere highly correlated with measures of skin bioavailability. Collectively, thesestudies give evidence for associations of these nutrients with skin cancer and forthe utility of both intake and biomarker measures for assessing the relationships. The final paper explores the relationship between a widely cited non-UVR riskfactor, namely scars and cancers of the skin. It reports a systematic review of allpublished observational studies quantifying this association. While innumerablecase reports were found, quantitative analyses were rare. The review identifieda major gap in the literature where knowledge of scar malignancies is notevidence-based, but rather founded mainly on cumulative anecdotal reporting. Taken together, this body of published work highlights the largely unrecognisedcomplexity of the aetiology of cancers of the skin. Future research must bebroad in scope in order to advance understanding of the interaction betweenUVR and other risk factors and to provide a base for health messages aimed atreducing the burden of these malignancies.

Les noyaux gris centraux (ganglions de la base en anglais) sont un réseau de structures sous-corticales dont la persistance dans l'ensemble des vertébrés plaide en faveur d'une fonction clef au cours de l'évolution. Comme ce fut remarqué dès le 18ème siècle, ils ont l'unique particularité de concentrer des afférences de l'entièreté de la surface corticale. Cette position centrale et l'analyse de l'anatomie du réseau leur ont valu le rôle d'arbitre central du cerveau, réglant les conflits entre processus neuronaux concomitants bien qu'incompatibles. Au sein du réseau, le noyau subthalamique jouit d'une notoriété particulière. Ce noyau, sur la base de ses afférences corticales, et en vertu de ses projections sur le soma des neurones pallidaux, aurait pour fonction de filtrer les programmes comportementaux codés par le striatum et concourant pour leur expression. Rapporté aux théories de la prise de décision, le noyau subthalamique fixerait le seuil décisionnel, ou la quantité d'information à accumuler en faveur d'une option comportementale afin qu'elle soit exprimée. Mais si ce petit noyau est devenu si célèbre, c'est surtout qu'il est la cible d'une procédure chirurgicale spectaculaire: la stimulation cérébrale profonde. Cette opération du cerveau est le dernier recours pour les patients souffrant d'une maladie de Parkinson ou d'un trouble obsessionnel compulsif sévère. Elle parvient même parfois à faire disparaître leurs symptômes. Malgré cette efficacité remarquable, les mécanismes de la stimulation cérébrale profonde restent inconnus. Il faut, entre autres, blâmer l'obscurité qui règne encore sur le noyau subthalamique, car les fonctions mentionnées ci-dessus restent des conjectures théoriques en manque de validation expérimentale. La première étape de ce travail a été d'en valider les bases anatomiques. En effet, l'existence d'une voie fronto-subthalamique - nécessaire au modèle - n'était connue que sur la base d'études menées chez le rat. Nous avons démontré, par des méthodes de traçage axonal, l'existence de cette connexion chez le primate. En sus, cette connexion aura permis de redéfinir les frontières médiales du noyau subthalamique avec les conséquences cliniques qui peuvent en être tirées. Le deuxième objectif global de cette thèse était de tester la validité fonctionnelle du modèle, la stimulation cérébrale profonde offrant un accès rare aux activités du noyau subthalamique. Cependant, il était d'abord nécessaire de caractériser la population étudiée, à savoir des patients souffrants d'un trouble obsessionnel compulsif. Grâce à l'imagerie de diffusion nous démontrons une diminution ainsi qu'une désorganisation des connexions cortico-sous corticales, se traduisant probablement par un défaut de contrôle conscient sur le processus de sélection. Une étude de magnétoencéphalographie est en cours pour approfondir les changements d'activité corticale. Pour tester le rôle du noyau subthalamique dans l'établissement du seuil décisionnel nous avons enregistré son activité électrophysiologique pendant que les patients effectuaient une tâche de prise de décision perceptuelle. Nous démontrons que les neurones du noyau subthalamique ont une réponse multimodale, concordant en cela avec nos données anatomiques qui montrent une convergence d'informations au niveau du noyau subthalamique. De plus, une augmentation de l'activité est retrouvée dans les conditions attendues... / The basal ganglia are a network of subcortical structures of which the invariant architecture throughout vertebrate evolution suggests a key function in evolution. As was noted as early as the 18th century, they have the unique characteristic of concentrating afferences from the entire cortical surgace. Given this central position and the internal architecture of the network, they could provide a centralised selection mechanism in the brain, arbitrating between any two conflicting processes. Among the basal ganglia, the subthalamic nucleus has become of particular interest as it is the target of deep brain stimulation, a neurosurgical procedure used to treat severe Parkinson’s disease and obsessive-compulsive disorder. It would have for function to integrate contextual information from its cortical inputs to filter behavioural programs encoded by the striatum. Within the framework of decision-making models, this filtering function is akin to setting the decision threshold, or the amount of evidence required before selecting a program. However, this considerations remain hypothetical as they are lacking experimental support. The first objective of this work was to validate the anatomical basis of these assumptions. Indeed, the existence of a prefrontal-subthalamic pathway, necessary to expand the decision models to every type of decision, had only been demonstrated in rodents. We demonstrated its existence in the primate using anterograde axonal tracing. In addition, this projection will have allowed us to redefine the medial border of the subthalamic nucleus with the clinical consequences that that may have. The second objective of this thesis was to test the functional validity of the models, and specifically the role of the subthalamic nucleus in setting decision thresholds. Deep brain stimulation offers a rare access to the electrophysiology of this structure; however, it is a patient population, here obsessive-compulsive disorder patients. A first step was, therefore, to characterise this population, anatomically and behaviourally, to understand how it might be of use as a model of decision-making in the basal ganglia. We demonstrated a reduction in the strength of cortico-subcortical anatomical connections. We suggest that this prevents accurate conscious control over decision mechanisms. Behaviourally, patients displayed a pathologically low confidence levels in their decisions and we hypothesised that this would lead to an increase of the decision threshold and matching subthalamic activity. To test this, we recorded the activity of the subthalamic nucleus during a decision-making task. We demonstrate that subthalamic neurons have a multimodal activity, consistent with our demonstration of convergent cortical inputs. However, we were unable to demonstrate a link between subthalamic activity and decision threshold, although this may be due to technical considerations…

No abstract available. / Dissertation (MSc)--University of Pretoria, 2013. / gm2014 / Clinical Epidemiology / unrestricted

Das Basalzellkarzinom ist nicht nur die häufigste Neoplasie der Haut generell, es stellt auch die häufigste maligne Entität im Bereich der Augenlider dar. Es handelt sich um eine Erkrankung vornehmlich des höheren Lebensalters, jedoch sind auch zunehmend jüngere Patienten betroffen. Trotz geringer Metastasierungstendenz kann es bei Tiefeninfiltration zu schweren Krankheitsverläufen kommen. Aufgrund wachsender Inzidenz und damit stetig steigender Kosten im Gesundheitswesen sollte die Behandlungsstrategie kontinuierlich überprüft und optimiert werden. Ziel der vorliegenden Arbeit ist es, ein ausgewähltes Patientenkollektiv im Zeitraum von 2003 bis 2006 hinsichtlich epidemiologischer, klinischer und therapeutischer Aspekte zu analysieren und mit der Literatur zu vergleichen. Therapie der Wahl ist die chirurgische Exzision. Es wurden 216 Fälle von 204 Patienten auf Grundlage der Krankenakte detailliert untersucht und ausgewertet. Zwar konnten keine signifikanten Prädiktoren zur Vorhersage des Behandlungsverlaufes und der Rezidiventwicklung gefunden werden, anhand der 216 klinischen Fälle können die aktuelle Datenlage aber unterstützt und Empfehlungen zur Therapie und Nachbehandlung erweitert werden.

Context: The facial subunit principle organizes the facial skin into subunits. Facial reconstruction for skin cancer based on aesthetic units consists of replacing the entire subunit when a large part of a subunit has been removed. Aims: To determine the prevalence of facial skin cancer, their location by facial aesthetic units, and the type of facial reconstruction used in each of them. Settings and Design: An observational cross-sectional study was conducted at the Head and Neck Surgery Service of a general hospital between 2017 and 2018. Materials and Methods: A population census was conducted during this period. Statistical Analysis Used: The categorical variables were expressed as frequencies (percentages). Continuous variables were described as the means and standard deviations or medians and interquartile ranges. Results: The most common skin cancer was basal cell skin cancer, followed by epithelial skin cancer and, at last, melanoma. In general, the most frequent localization of these cancers was the nose. Conclusions: In spite of primary closure being the most common form of reconstruction, a considerable number of patients required facial reconstruction based on aesthetic facial units, with satisfying results. / Revisión por pares