INTRODUÇÃO: Os macrófagos associados aos tumores (MAT) sólidos estão relacionados à progressão ou à involução das neoplasias, dependendo da diferenciação em M1 ou M2. No carcinoma basocelular (CBC), as formas mais agressivas apresentam aumento de macrófagos às custas do fenótipo M2, se comparadas às formas não invasivas. O tratamento do CBC sólido pela Cirurgia Micrográfica de Mohs (CMM) proporciona elevados índices de cura, porém recidivas podem ocorrer. OBJETIVOS: Comparar a população total de macrófagos e as subpopulações M1 e M2 nos casos de CBC sólidos recidivados e não recidivados após exérese pela CMM. METODOLOGIA: Cortes histológicos obtidos a partir dos blocos de parafina de nove casos de CBC sólidos recidivados após CMM e de 18 casos de CBC sólido operados pela CMM não recidivados foram marcados imunoistoquimicamente para iNOS, CD204, CD163 e CD68. A expressão desses marcadores foi analisada pelo método de análise de imagens. RESULTADOS: Não foram encontradas diferenças significativas entre os grupos em relação à porcentagem média de células M1 (INOS), células M2 (CD163 e CD204) e total de células (CD68). CONCLUSÃO: A recidiva dos tumores estudados não ocorreu por influência do MAT, mas pode ser decorrente da falha técnica na realização da CMM ou de algum outro mecanismo imunológico desconhecido / INTRODUCTION: The macrophages associated with solid tumors (MAT) are related to the progression or regression of tumors, depending on the differentiation in M1 or M2. In basal cell carcinoma (BCC), the most aggressive forms show an increase in macrophages at the expense of M2 phenotype compared to non-invasive forms. The treatment of BCC solid by Mohs micrographic surgery (MMS) provides high cure rates, but relapses can occur. OBJECTIVES: To compare the total population of macrophages and subpopulations M1 and M2 in cases of recurrent BCC solid and not recurrent after excision by MMS. METHODS: Histological sections obtained from paraffin blocks of 9 cases of recurrent solid CBC after MMS and 18 cases of solid CBC operated by MMS not relapsed were labeled immunohistochemically for iNOS, CD204, CD163 and CD68. The expression of these markers was analyzed by image analysis. RESULTS: No significant differences were found between the groups in relation to the average percentage of M1 cells (INOS), M2 cells (CD163 and CD204) and total cells (CD68). CONCLUSION: The recurrence of the tumors studied did not occur under the influence of MAT, but may be due to technical failure in achieving MMS or some other unknown immune mechanism

O carcinoma basocelular (CBC) é malignidade de incidência elevada e crescente na população caucasiana, e sua expressiva prevalência nos serviços de saúde remete à necessidade de avaliação dos índices de cura. O presente estudo analisou marcadores clínicos preditivos do comprometimento das margens cirúrgicas do CBC, em conjunto com um painel de marcadores imuno-histoquímicos (IHQ). Analisou-se 1294 laudos histopatológicos de CBC, emitidos durante 2011, e incluídos 674 casos de excisão cirúrgica completa realizada por diferentes especialidades em hospital terciário. Foram selecionados 40 casos dos diferentes subtipos histológicos para realização de IHQ para os marcadores Ber-EP4, MNF116, E-Caderina e VEGF, analisados por sistema digital de captação de imagens e programa de computador. Na amostra, houve predomínio de homens (60,4%) com idade média de 68 anos, da localização cefálica (71%) e do subtipo nodular (61%); da ulceração (p= 0,003) e do diâmetro médio superior dos CBC nos homens (307,41 mm2 x 190,74 mm2; p< 0,001); do subtipo superficial de localização no tronco (p< 0,001) e em mais jovens (<73 anos; p= 0,001); do subtipo nodular (p< 0,001) e ulcerado (p= 0,05) no segmento cefálico. A especialidade Dermatologia foi responsável pela maioria das cirurgias (78%), cuja dimensão média e índice de margens cirúrgicas livres dos CBC excisados foram respectivamente 274 mm2 e 95%, seguida por 279 mm2 e 89% na Cirurgia Plástica, 218 mm2 e 60% na Cirurgia de Cabeça e Pescoço (CCP), 87 mm2 e 49% na Oftalmologia. O risco para desfecho em margens cirúrgicas comprometidas foi determinado para: subtipo micronodular (OR 3,41; IC 95% 1,71 6,80; p= 0,001); localização cefálica (OR 8,33 IC 95% 1,05 50; p= 0,045); excisões realizadas pelas especialidades Oftalmologia (OR 10,12; IC 95% 4,40 23,27; p= 0,001) e CCP (OR 9,67; IC 95% 5,14 18,21; p= 0,001). A imunomarcação pelo Ber-EP4, MNF116 e ECaderina foi homogênea e de intensidade moderada a acentuada nas células neoplásicas em todos os subtipos; os valores de intensidade da marcação, percentual de área e escore para o MNF116 discriminaram os CBC agressivos (esclerodermiforme e micronodular) daqueles não agressivos (nodular e superficial); e foram superiores para ECaderina no subtipo superficial; o percentual de células marcadas pelo VEGF foi superior nos tumores agressivos (p< 0,001). O segmento cefálico e o subtipo micronodular, seguido do esclerodermiforme, implicam em riscos elevados para o comprometimento das margens e merecem atenção quanto ao manuseio cirúrgico. A imunomarcação por Ber-EP4, MNF116 e E-Caderina pode auxiliar na identificação de ninhos tumorais multifocais no subtipo superficial, ou em meio ao processo inflamatório nos subtipos agressivos. A marcação da E-Caderina pode representar o padrão menos agressivo e de crescimento radial do subtipo superficial; e a do VEGF, nos tumores mais agressivos, ser indicativa do papel desta proteína no comportamento mais invasivo. A especialidade Dermatologia tem expressiva participação institucional e níveis de resolubilidade superiores, representada pelas maiores frequências de excisão de CBC e de margens cirúrgicas livres. O reconhecimento de fatores preditivos para desfecho em margens cirúrgicas comprometidas é de fundamental relevância para o planejamento cirúrgico e obtenção das mais elevadas taxas de cura. / Basal cell carcinoma (BCC) is the most common human malignancy and it is increasing its incidence in the Caucasian population. The significant prevalence of cases in specialized health services indicates the need of assessment of cure rates. The present study analyzed clinical predictive markers of compromised surgical margins in BCC in association with a panel of Immunohistochemistry (IHC) markers. We analyzed 1294 BCC histopathological reports during 2011, and 674 cases of complete surgical excision performed by different specialties in a tertiary hospital were included. From the sample, 40 cases of different histological subtypes were selected to perform IHC markers Ber-EP4, MNF116, E-cadherin and VEGF, which were analyzed by digital image capture system and computer program. There was male predominance (60.4%) with mean age of 68 years, location at cephalic segment (71%) and nodular subtype (61%); ulceration (p= 0.003) and higher average size of CBC in men (307.41 mm2 x 190.74 mm2; p< 0.001); superficial subtype was more frequent on trunk (p< 0.001) and in younger than 73 years (p< 0.001); nodular subtype (p< 0.001) and ulceration (p= 0.05) at cephalic segment. The specialty Dermatology performed the majority of surgeries (78%), and the average size and the index of free surgical margins were 274 mm2 and 95% in Dermatology, 279 mm2 and 89% in Plastic Surgery, 218 mm2 and 60% in Head and Neck Surgery (HNS), 87 mm2 and 49% in Ophthalmology. The risk for compromised surgical margins was determined for: micronodular subtype (OR 3.41; 95% CI 1.71 6.80; p= 0.001); location at cephalic segment (OR 8.33; 95% CI 1.05 50; p= 0.045); excisions performed by Ophthalmology (OR 10.12; 95% CI 4.40 23.27; p= 0.001) and HNS (OR 9.67; 95% CI 5.14-18.21; p= 0.001). Immunostaining by Ber-EP4, MNF116 and E-cadherin was homogeneous and moderate to high intensity within the neoplastic cells in all BCC subtypes; values obtained from staining intensity, percentage of area and score for the MNF116 showed difference between aggressive BCC (morpheaform and micronodular) and non-aggressive (superficial nodular); and were higher for E-cadherin in superficial BCC; the percentage of marked cells by VEGF was higher in aggressive tumors (p< 0.001). The cephalic segment and micronodular subtype, followed by the morpheaform, imply high risks for compromised margins and deserve attention during the surgical treatment by trained experts. The immunohistochemistry markers Ber-EP4, MNF116 and E-cadherin may help the identification of multifocal tumor nests in superficial subtype or amid the inflammatory process in the aggressive subtypes. E-cadherin staining may represent the least aggressive and radial pattern of growth of superficial subtype. VEGF staining in peritumoral inflammatory cells of aggressive tumors may be indicative of the role of this protein in more invasive behavior of these subtypes of the BCC. Dermatology has significant institutional participation with highest resolution, represented by higher frequency of BCC excision and less compromised surgical margins. Knowing the predictive factors for compromised surgical margins is important for planning surgical treatment and obtaining the highest cure rates.

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Der Hedgehog (Hh)-Signalweg ist an der Entstehung verschiedener Tumorentitäten beteiligt. Es wird vermutet, dass die Signalwegskomponente Patched (Ptch) physiologischerweise als Oxysterolpumpe dient und ein Molekül - vermutlich ein Vitamin D3 Derivat - sezerniert, welches den Hh Signalweg durch Bindung an das Transmembranprotein Smoothened (Smo) hemmt. Durch inaktivierende Ptch Mutationen wird die Sekretion dieses Moleküls vermutlich gestört, was zu einer Aktivierung des Signalwegs führt. Vorarbeiten lassen vermuten, dass es sich bei dem sezernierten Vitamin D3-Derivat um 1α,25(OH)2D3 (Calcitriol) handeln könnte. Da Calcitriol seine antitumorale Wirkung neben der Hemmung der Hh-Signalkaskade auch über die Aktivierung des Vitamin-D-Rezepor (Vdr) -Signalwegs vermitteln kann, sollten in dieser Arbeit mögliche Schnittpunkte der Hh-Signalkaskade, des Vdr-Signalwegs und des Calcitriol Metabolismus untersucht werden. Zunächst ergaben die Untersuchungen, dass Ptch-defiziente Rhabdomyosarkom Zellen, verglichen mit Wildtyp-Ptch Zellen, eine verminderte Calcitriol-Synthese aufweisen, die vermutlich durch eine herabgesetzte Aktivität der 1α Hydroxylase bedingt ist. Die dadurch verminderte Calcitriol Konzentration ist wahrscheinlich die Ursache der gleichzeitig erhöhten Hh Signalwegsaktivität in den Zellen. Dies bestätigten weitere Untersuchungen mit dem 1α Hydroxylaseinhibitor Itraconazol an Ptch-/- Zellen. Weiterhin konnte gezeigt werden, dass Itraconazol mit Calcitriol hinsichtlich der Hemmung des Hh-Signalwegs kooperiert. Die verstärkte Hemmung ist aber unabhängig von einer Itraconazol-abhängigen Herabsetzung der 24 Hydroxylaseaktivität. Zudem zeigten die Untersuchungen, dass Calcitriol (neben der Aktivierung des Vdr Signalwegs) den Hh-Signalweg in Ptch / Zellen effizienter hemmt als Cyclopamin. Weiterhin konnte gezeigt werden, dass Calcitriol auch mit Cyclopamin bezüglich der Hemmung der Hh-Signalkaskade kooperiert. Weitere Untersuchungen bekräftigen die Hypothese, dass Calcitriol, ähnlich wie der bekannte Smo-Inhibitor Cyclopamin, an Smoothened (Smo) bindet. Daneben weisen die Untersuchungen darauf hin, dass 1α,25(OH)2D3 den Hh-Signalweg zusätzlich über einen nicht-kanonischen, Suppressor of fused-unabhängigen Weg hemmen könnte. Transfektionsuntersuchungen an Gli-Knock-Out-Zellen zeigten, dass Gli3 möglicherweise die Vdr-Expression und dadurch auch die Calcitriol/Vdr-vermittelte Proliferationshemmung von Calcitriol reguliert. Schließlich konnte im Tiermodell für BCC die antitumorale Wirkung von 100 ng/kg/d Calcitriol gezeigt werden. Die Studie zeigte die effektive Wirkung von Calcitriol, wenn die Substanz ab einem frühen Tumorstadium verabreicht wird. Daneben scheint die Dauer der Behandlung eine entscheidende Rolle für die antiproliferative in vivo Wirkung von Calcitriol zu spielen.

Basal cell carcinoma is a form of a non-melanoma skin tumour, that commonly forms over the sun exposed regions of the head and neck. Investigation of the rate of occurrence at different sites on face and neck shows considerable variation from site to site. The inner canthus has a disproportionate number when compared to more exposed sites. The eye brow ridge, cheek bone and nose limit the field of view of the inner canthus, thus it is expected to receive less radiation than other more exposed regions. To explain the disproportionate rate, it is hypothesised that a portion of radiation incident onto the eye is reflected to the inner canthus. The aim of this thesis is to investigate the contribution that the radiation reflected off the surface of the eye makes to the overall dose on the inner canthus. The inter reflections between the eye and inner canthus were studied through the use of the ray tracing program Zemax. Zemax was used to trace rays in a non sequential mode incident onto a model eye and periorbital region. To obtain the models of the eye and periorbital region, both magnetic resonance imaging and a casting process was investigated, with the later being superior for our uses. With the model obtained, it was used in a series of three dimensional ray tracing programs. On a macroscopic scale there is a small increase in the irradiance on the inner canthus (2 % over a 1 cm2 area). Peaks of high irradiance (19 % increase in irradiance above direct irradiance) were discovered over the surface when the detector was divided into 200 mm elements. It was concluded that these increases above the direct irradiance in these small regions, increases the possibility of the occurrence of a Basal cell carcinoma. Individual facial geometry, will greatly effect the location and size of these peaks and as a result an experimental method to measure the dose distribution across the inner canthus was proposed. Initially it was planned to use polysulphone film to measure the erythemal dose on the inner canthus. Results from the modelling indicated that any measurements made had to be at a high spatial resolution. Polysulphone film was found to be inadequate for this, due to its large uncertainties. An alternative method was investigated so that a population study could be performed in future studies using visible radiation and high dynamic range images gave a simple and effective clinical assessment tool. The high dynamic range images showed hot spots in the irradiance across the inner canthus agreeing with the model. The small spots of high relative irradiance may not be the only reason for the increased rate in this region. Greater skin sensitivity and absence of sun screen use at this site are other possibilities. It is believed however that the irradiance distribution across the inner canthus on a microscopic scale goes a long way to increasing the risk for certain people.

Submitted by Johnny Rodrigues (johnnyrodrigues@ufcg.edu.br) on 2018-04-13T18:27:12Z No. of bitstreams: 1 ADRIANA DA COSTA BRAZ - DISSERTAÇÃO PPG-CEMat 2014..pdf: 2523605 bytes, checksum: 90e198ea98d95b535e91044abaf7e15f (MD5) / Made available in DSpace on 2018-04-13T18:27:12Z (GMT). No. of bitstreams: 1 ADRIANA DA COSTA BRAZ - DISSERTAÇÃO PPG-CEMat 2014..pdf: 2523605 bytes, checksum: 90e198ea98d95b535e91044abaf7e15f (MD5) Previous issue date: 2014-12-12 / O Carcinoma basocelular é o câncer mais comum do mundo, e apesar da sua evolução muitas vezes benigna, com altas taxas de cura, algumas vezes nos deparamos com casos mais agressivos, invasivos, destrutivos e de difícil controle. É sabido que já houve avanços terapêuticos para estes casos específicos, a exemplo do Vismodegib, entretanto o uso desta droga ainda é uma realidade distante para nossos pacientes brasileiros que se expõe a índices elevados de radiações solares, na maioria trabalhadores rurais de baixa renda e com grande dificuldade a acessibilidade ao sistema público de saúde. Por isso, o presente trabalho sugere uma alternativa para o controle das formas graves do carcinoma basocelular, através da produção de um filme de quitosana dopado de colchicina substância sabidamente antimitótica e com evidência clínica já citada na literatura no carcinoma basocelular, por via transdérmica por liberação controlada da droga que permita mantê-la em um nível sérico contínuo, suficiente para sua ação antimitótica, causando morte seletiva das células tumorais, diminuindo ou extirpando esses tumores, com custos mais acessíveis, pois é uma droga de baixo custo, melhorando consequentemente a morbidade da doença e a qualidade de vida destes pacientes. E os resultados obtidos através das caracterizações apresentaram membranas com variações de cristalinidade (por DRX) de acordo com o processo de reticulação. Por FTIR pode-se observar certa interação entre o fármaco e os grupos amina da quitosana. Pelas microscopias ótica e eletrônica, pode-se observar que o acréscimo de fármaco proporcionou alguma rugosidade a membrana. Também pelas microscopias verificou-se a reticulação não homogênea da superfície da membrana. Por EDS não se verificou nenhum elemento estranho a estrutura da quitosana e do fármaco. Por medida do ângulo de molhabilidade pode-se verificar aumento do perfil hidrofílico da membrana por adição do fármaco, perfil este que foi modificado pelo processo de reticulação. A partir do ensaio de citotoxicidade pode-se constatar que a membrana apresenta certa citotoxicidade. Este resultado demonstra também o potencial da membrana de quitosana em liberar o fármaco, considerando que a membrana apenas de quitosana não apresenta toxicidade em meio biológico, sendo a toxicidade observada no ensaio decorrente do fármaco liberado. / Basal cell carcinoma is the most common cancer in the world, and despite its evolution often benign, with high cure rates, sometimes we are faced with more aggressive, invasive cases, destructive and difficult to control. It is known that there have been advances in treatment for these specific cases, such as the Vismodegib, however this drug is still a distant reality for our Brazilian patients who are exposed to high levels of solar radiation in most rural workers from low-income, great difficulty accessibility to the public health system. Therefore, this study suggests an alternative for the control of severe forms of basal cell carcinoma, through the production of a chitosan film doped colchicine known antimitotic substance and with clinical evidence already mentioned in the literature in basal cell carcinoma, transdermally for release controlled drug that allows keep at a steady serum level, enough for their antimitotic, causing selective killing of tumor cells, reducing or extirpating these tumors, with more affordable because it is an inexpensive drug, consequently improving morbidity the disease and the quality of life of these patients. And the results obtained from the characterization showed membranes crystallinity variations (XRD) according to the crosslinking process. By FTIR one can observe some interaction between the drug and amino groups of chitosan. Through optical and electronic microscopy, it can be seen that addition of drug has provided some roughness to the membrane. Also by microscopy verified the inhomogeneous crosslinking of the membrane surface. EDS there was no foreign object the structure of chitosan and the drug. By measuring the wetting angle can be checked increase the hydrophilic profile of the drug by adding the membrane, this profile has been modified by the crosslinking process. From the cytotoxicity assay can be seen that the membrane has some cytotoxicity. This result also demonstrates the potential of chitosan membrane to release the drug, whereas only chitosan membrane shows no toxicity in biological medium, with the toxicity observed in this trial due to the released drug.

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.

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.

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.