Orientador: Glauco Issamu Miyahara / Coorientador: Sandra Helena Penha de Oliveira / Coorientador: Daniel Galera Bernabé / Banca: Fábio de Abreu Alves / Banca: Éder Ricardo Biasoli / Resumo: O papilomavírus humano (HPV) vem sendo associado ao carcinoma espinocelular (CEC) de orofaringe, como um possível fator etiológico. As oncoproteínas virais E6 e E7 são capazes de inibir a produção de citocinas do padrão Th1 e iniciar a produção de citocinas do padrão Th2, prejudicando a resposta celular frente à infecção. O propósito deste trabalho é avaliar o efeito das oncoproteínas virais E6 e E7 do HPV-16 sobre a resposta de células T (CD4 e CD8) de pacientes com e sem CEC de cabeça e pescoço. Foram recrutados para o estudo 20 indivíduos, sendo 10 pacientes com diagnóstico de CEC de cabeça e pescoço e 10 indivíduos sem câncer. Para avaliar a proliferação celular e liberação de citocinas (TNF-α, IFN-γ, IL-2, IL-4 e IL-10) das células T CD4 e CD8 frente ao estímulo com os peptídeos sintéticos dos genes E6 e E7 do HPV-16, a técnica ELISA foi utilizada. O mapeamento do DNA do HPV-16 foi realizado em amostras de plasma e saliva pela técnica de PCR em tempo real. Os resultados mostraram que o peptídeo E7 do HPV-16 inibiu a produção das citocinas pelas células T CD4 e CD8 derivadas dos indivíduos sem câncer (6/10) e pacientes com CEC de cabeça e pescoço (5/10) (p<0,05). A proteína Concanavaliana A induziu a proliferação das células T CD4 e CD8 dos indivíduos sem câncer e pacientes com CEC de cabeça e pescoço (p<0,05). As respostas celulares quanto à atividade proliferativa e a produção de citocinas dos pacientes com CEC de cabeça e pescoço foram semelhantes às respostas dos indivíduos sem câncer / Abstract: The human papillomavirus (HPV) has been associated with squamous cell carcinoma (SCC) of the oropharynx, as a possible etiologic factor. The viral oncoproteins, E6 and E7 are able to inhibit the production of Th1 cytokines and initiate the production of Th2 cytokines, damaging the cellular response to infection. The purpose of this study is to evaluate the effect of viral oncoproteins E6 and E7 of HPV-16 on the response of T cells (CD4+ and CD8+) in patients with or without SCC of the head and neck. It was recruited for the study, 20 individuals, 10 patients with SCC of the head and neck and 10 individuals without cancer. To assess cell proliferation and cytokine release (TNF-α, IFN-γ, IL-2, IL-4 and IL-10) of CD4 and CD8 stimulation against synthetic peptides of the HPV-16 E6 and E7 genes, ELISA technique was used. The mapping of the HPV-16 DNA was performed in plasma and saliva samples by real time PCR. The results showed that the HPV-16 E7 peptide inhibited the production of cytokines by CD4 and CD8 T cells derived from subjects without cancer (6/10) and patients with SCC of the head and neck (5/10) (p <0, 05). The concavaline A protein induced proliferation of CD4 and CD8 T cells from individuals without cancer and patients with SCC of the head and neck (p <0.05). Cellular responses as to proliferative activity and cytokine production in patients with SCC of the head and neck were similar to the responses of individuals without cancer / Mestre

Aproximadamente 3% das neoplasias malignas são originadas da cavidade bucal e representadas na maioria pelo carcinoma espinocelular (CEC). Estudos tem demostrado variações nas características clínico-epidemiológicas do CEC de boca de acordo com área geográfica da população estudada. A compreensão das características de uma população específica é importante por muitas razões, incluindo a compreensão da extensão do problema, fatores relacionados com seu desenvolvimento, seu diagnóstico e prognóstico. No entanto, poucos estudos têm sido relatados sobre essa lesão na população Uruguaia. O objetivo deste estudo foi avaliar o perfil demográfico, os aspectos clínicos e terapêuticos, assim como, os fatores prognósticos dos carcinomas espinocelulares de boca (CECB) diagnosticados em serviços públicos no Uruguai. Foram selecionados todos os prontuários médicos de pacientes com diagnóstico histopatológico de carcinoma espinocelular de boca primário atendidos no período de Janeiro 2000 a Dezembro de 2010 em Hospitais Públicos de Uruguai. Os prontuários foram avaliados manualmente e foram coletadas informações quanto aos dados demográficos, fatores de risco, características clínicas do tumor, tratamento e evolução. Foi confeccionado um banco de dados com as informações coletadas nos prontuários. A análise descritiva de todas as variáveis foi realizada e a existência de associação entre as variáveis independentes e os desfechos (estadiamento clínico e evolução) foi avaliada através do teste Qui-quadrado de Pearson e o teste de Fisher, o nível de significância estabelecido foi de 5%. Dentre os 200 prontuários de pacientes analisados, 79.4% eram homens com distribuição homem:mulher de 3.8:1. A média de idade foi de 60,75 anos. A análise univariada mostrou que o estadiamento clínico tem associação significativa com o tabagismo (p = 0,04), quantidade de tabaco (p = 0,018), aspecto clínico (p = 0,009), tamanho do tumor (p = 0,001) e metástases regionais (p = 0,001). Os homens portadores de CEC foram associados com o consumo de tabaco e álcool. O prognóstico desfavorável dos CECB (óbito) foi significativamente relacionado com aspecto clínico (p = 0,02), tamanho (p = 0,001), metástases regionais (p = 0,016), estadiamento clínico (p = 0,002) e tratamento (p = 0,001). A maioria dos pacientes com CECB que evoluiram a óbito (pior prognóstico), exibiram úlcera (93,9%), tamanhos avançados - T3/T4 (90,2%), metástases regionais (66%), foram classificadas no estágio III/IV (94,1%) e receberam tratamento não cirúrgico ou paliativos. Conclui-se que no Uruguai o diagnóstico do CECB é tardio e associado a baixas taxas de sobrevida. Medidas educativas e preventivas para a população assim como, investimentos em estratégias para melhorar o diagnóstico precoce devem ser uma meta neste país. / Nearly 3% of malignant neoplasms originate from the oral cavity and are mostly represented by squamous cell carcinoma (SCC). Studies have demonstrated variations in clinical and epidemiological features of oral SCC according to geographical area of the study population. Understanding the characteristics of a specific population is important for many reasons, including the comprehension of the extent of the problem, factors associated with their development, diagnosis and prognosis. However, few studies have been developed in Uruguayan population about this lesion. The aims of the present study were to evaluate the demographic, clinical and therapeutic features, as well as, the predictive factors of poor prognosis in patients with primary OSCC evaluated during a period of 10-years in public health services in Uruguay. Medical records of patients with histological diagnosis of primary OSCC treated between January 2000 and December 2010 in Uruguayan Public Hospitals were selected. Information regarding demographics, risk factors, clinical features, treatment and outcome was collected. A descriptive analysis was performed, and the existence of association between independent variables and outcomes (clinical stage and evolution) was assessed using the Pearson Chi-Square test and Fisher's test. Out of a total of 200 patients with OSCC, 79.4% were men with 3.8:1 male:female ratio. The mean age was 60.75 years. Univariate analysis showed that clinical stage have significant association with smoking (p=0,04), amount of tobacco (p=0.018), clinical aspect (p=0.009), tumor size (p=0.001) and regional metastasis (p=0.001). OSCC male patients were associated with tobacco and alcohol comsumption. Worse overall survival (poor prognosis) was significant associated with clinical aspect (p=0.02), size (p=0.001), regional metastasis (p=0.016), clinical stage (p=0.002) and treatment (p=0.001). The majority of OSCC patients with worse overall survival presented oral ulcer (93.9%), T3/T4 tumor size (90.2%), regional metastasis (66%), were classified at stage III/IV (94.1%) and received nonsurgical or palliatives treatment. We conclude that in Uruguay the diagnosis of OSCC is late associated to low survival rate. Educational and preventive measures for the population and investment in strategies to improve early diagnosis should be a goal in this country.

Orientador: Fabio Ramoa Pires / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-10T12:35:07Z (GMT). No. of bitstreams: 1 Romanach_MarioJose_M.pdf: 13585930 bytes, checksum: 1f4259a1bbb4368dbbba0d6f8a98f50f (MD5) Previous issue date: 2008 / Resumo: O carcinoma espinocelular (CEC) é a neoplasia maligna mais comum da boca, possuindo diversas variantes clinicopatológicas incomuns, incluindo o carcinoma de células fusiformes (CCF), que diferem quanto ao comportamento clínico, critérios diagnósticos e prognóstico. Os objetivos deste estudo foram analisar a expressão imunohistoquímica de marcadores epiteliais no CCF de cabeça e pescoço, avaliando sua importância diagnóstica, comparar os achados histopatológicos e imunohistoquímicos do CCF de cabeça e pescoço com os CECs convencionais da cavidade oral e definir um perfil sócio-demográfico e clinicopatológico do CCF oral. Para isso, foram analisados ao todo 20 casos de CECs: 10 casos de CCF, e 10 casos de CECs orais convencionais como controle, sendo 5 casos de CECs bem diferenciados e 5 casos de CECs pouco diferenciados. A metodologia incluiu avaliação de todos os casos em microscopia óptica em cortes corados em hematoxilina e eosina e reações imunohistoquímicas para anticorpos contra citoqueratinas, vimentina, desmina, actina músculoespecífica, actina de músculo liso, proteína S100, EMA, p53 e ki-67, usando a técnica da peroxidase. Os achados morfológicos dos CCFs estudados mostraram maior proximidade entre estes tumores e os CECs pouco diferenciados e a expressão imunohistoquímica das citoqueratinas AE1/AE3, 6, 8 e 14 e de EMA nos componentes carcinomatoso e fusocelular do CCF mostrou-se útil como auxiliar em seu diagnóstico final. Ainda, os CCFs apresentaram índices de expressão de p53 e de Ki-67 superiores àqueles encontrados nos CECs bem diferenciados. O CCF oral apresentou predileção por homens na 6ª década de vida, manifestando-se através de úlceras infiltrativas ou lesões polipóides ulceradas, usualmente dolorosas, localizadas preferencialmente no rebordo alveolar e lábios / Abstract: Squamous cell carcinoma (SCC) is the most common malignant oral tumor and several uncommon clinicopathological variants, including spindle cell carcinoma (SpCC), which differ on clinical behaviour, diagnostic criteria and prognosis, have been described. The aims of this study were to analyze the immunohistochemical expression of epithelial markers on head and neck SpCC, evaluating their diagnostic relevance, to compare the histopathological and immunohistochemical features of head and neck SpCC and conventional oral SCC, and to define a socio-demographic and clinicopathological profile of oral SpCC. Material included a total of 20 cases, including 10 cases of head and neck SpCC, and 10 cases of oral SCC used as controls (5 well-differentiated SCC and 5 poorly-differentiated SCC). Methods included evaluation of hematoxilin and eosinstained histological slides from all cases through optic microscopy and immunohistochemical reactions for antibodies against cytokeratins, vimentin, desmin, smooth-muscle actin, muscle-specific actin, S-100 protein, EMA, p53 and ki-67, using the peroxidase technique. Morphological features of SpCC showed similarities to the features from poorly differentiated SSC and immunohistochemical expression of the cytokeratins AE1/AE3, 6, 8 and 14, and EMA on both carcinomatous and spindle cell components of the tumor, proved to be useful as an auxiliary tool on final diagnosis. In addition, SpCC presented higher p53 and ki-67 expression indexes when compared to well-differentiated SCC. Oral SpCC showed predilection for males on their 6th decade of life, presenting clinically either as painful infiltrative ulcers or ulcerated exophytic polypoid masses, preferally located on the alveolar mucosa and lips / Mestrado / Estomatologia / Mestre em Estomatopatologia

Aproximadamente 3% das neoplasias malignas são originadas da cavidade bucal e representadas na maioria pelo carcinoma espinocelular (CEC). Estudos tem demostrado variações nas características clínico-epidemiológicas do CEC de boca de acordo com área geográfica da população estudada. A compreensão das características de uma população específica é importante por muitas razões, incluindo a compreensão da extensão do problema, fatores relacionados com seu desenvolvimento, seu diagnóstico e prognóstico. No entanto, poucos estudos têm sido relatados sobre essa lesão na população Uruguaia. O objetivo deste estudo foi avaliar o perfil demográfico, os aspectos clínicos e terapêuticos, assim como, os fatores prognósticos dos carcinomas espinocelulares de boca (CECB) diagnosticados em serviços públicos no Uruguai. Foram selecionados todos os prontuários médicos de pacientes com diagnóstico histopatológico de carcinoma espinocelular de boca primário atendidos no período de Janeiro 2000 a Dezembro de 2010 em Hospitais Públicos de Uruguai. Os prontuários foram avaliados manualmente e foram coletadas informações quanto aos dados demográficos, fatores de risco, características clínicas do tumor, tratamento e evolução. Foi confeccionado um banco de dados com as informações coletadas nos prontuários. A análise descritiva de todas as variáveis foi realizada e a existência de associação entre as variáveis independentes e os desfechos (estadiamento clínico e evolução) foi avaliada através do teste Qui-quadrado de Pearson e o teste de Fisher, o nível de significância estabelecido foi de 5%. Dentre os 200 prontuários de pacientes analisados, 79.4% eram homens com distribuição homem:mulher de 3.8:1. A média de idade foi de 60,75 anos. A análise univariada mostrou que o estadiamento clínico tem associação significativa com o tabagismo (p = 0,04), quantidade de tabaco (p = 0,018), aspecto clínico (p = 0,009), tamanho do tumor (p = 0,001) e metástases regionais (p = 0,001). Os homens portadores de CEC foram associados com o consumo de tabaco e álcool. O prognóstico desfavorável dos CECB (óbito) foi significativamente relacionado com aspecto clínico (p = 0,02), tamanho (p = 0,001), metástases regionais (p = 0,016), estadiamento clínico (p = 0,002) e tratamento (p = 0,001). A maioria dos pacientes com CECB que evoluiram a óbito (pior prognóstico), exibiram úlcera (93,9%), tamanhos avançados - T3/T4 (90,2%), metástases regionais (66%), foram classificadas no estágio III/IV (94,1%) e receberam tratamento não cirúrgico ou paliativos. Conclui-se que no Uruguai o diagnóstico do CECB é tardio e associado a baixas taxas de sobrevida. Medidas educativas e preventivas para a população assim como, investimentos em estratégias para melhorar o diagnóstico precoce devem ser uma meta neste país. / Nearly 3% of malignant neoplasms originate from the oral cavity and are mostly represented by squamous cell carcinoma (SCC). Studies have demonstrated variations in clinical and epidemiological features of oral SCC according to geographical area of the study population. Understanding the characteristics of a specific population is important for many reasons, including the comprehension of the extent of the problem, factors associated with their development, diagnosis and prognosis. However, few studies have been developed in Uruguayan population about this lesion. The aims of the present study were to evaluate the demographic, clinical and therapeutic features, as well as, the predictive factors of poor prognosis in patients with primary OSCC evaluated during a period of 10-years in public health services in Uruguay. Medical records of patients with histological diagnosis of primary OSCC treated between January 2000 and December 2010 in Uruguayan Public Hospitals were selected. Information regarding demographics, risk factors, clinical features, treatment and outcome was collected. A descriptive analysis was performed, and the existence of association between independent variables and outcomes (clinical stage and evolution) was assessed using the Pearson Chi-Square test and Fisher's test. Out of a total of 200 patients with OSCC, 79.4% were men with 3.8:1 male:female ratio. The mean age was 60.75 years. Univariate analysis showed that clinical stage have significant association with smoking (p=0,04), amount of tobacco (p=0.018), clinical aspect (p=0.009), tumor size (p=0.001) and regional metastasis (p=0.001). OSCC male patients were associated with tobacco and alcohol comsumption. Worse overall survival (poor prognosis) was significant associated with clinical aspect (p=0.02), size (p=0.001), regional metastasis (p=0.016), clinical stage (p=0.002) and treatment (p=0.001). The majority of OSCC patients with worse overall survival presented oral ulcer (93.9%), T3/T4 tumor size (90.2%), regional metastasis (66%), were classified at stage III/IV (94.1%) and received nonsurgical or palliatives treatment. We conclude that in Uruguay the diagnosis of OSCC is late associated to low survival rate. Educational and preventive measures for the population and investment in strategies to improve early diagnosis should be a goal in this country.

Orientador: Antonio Santos Martins / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-07T06:49:57Z (GMT). No. of bitstreams: 1 ScanaviniJunior_RuiCarlos_M.pdf: 989083 bytes, checksum: 9b013db47c9ffb39e508299508218360 (MD5) Previous issue date: 2005 / Resumo: O carcinoma espinocelular ou de células escamosas constitui a segunda neoplasia de pele mais freqüente e apresenta índice de cura superior a 90%, quando tratado na fase mais inicial. Tumores maiores e uma pequena fração dos tumores iniciais costumam apresentar evolução desfavorável, representada pelas recidivas loco-regional e a distância, apesar do tratamento inicial. Objetivo: Identificar, por análise retrospectiva, os fatores histológicos e clínicos associados à evolução adversa, identificando os tumores de alto risco. Material e método: Foram analisados trinta e cinco prontuários de pacientes submetidos ao tratamento cirúrgico do carcinoma espinocelular (CEC) cutâneo de cabeça e pescoço, sendo coletadas informações sobre espessura (milímetros), invasão perineural, grau de diferenciação e invasão angiolinfática. Realizou-se a análise estatística da associação desses fatores com as variáveis da evolução do CEC (recidiva local, metástase linfática, metástase a distância e óbito). Procedeu-se de forma similar na comparação das variáveis da evolução do CEC entre si. Admitiu-se diferença estatística de 5%. Resultados: Ocorreu associação estatística entre a recidiva local e invasão perineural; metástase linfática e invasão angiolinfática, espessura e invasão perineural; metástase a distância e invasão angiolinfática; óbito e invasão perineural, invasão angiolinfática, espessura tumoral. Entre as variáveis do CEC, verificou-se que a metástase linfática e a metástase a distância estiveram associadas ao óbito. Conclusão: Os fatores histológicos e clínicos observados na evolução permitem definir pacientes de alto risco para os quais o seguimento e novos protocolos terapêuticos prospectivos devem ser melhor estabelecidos. Unitermos: Carcinoma de células escamosas, pele, prognóstico / Abstract: Squamous cell carcinoma represents the second most common cancer of the skin. Most of the patients, especially with the small tumors, can be cured at rates that exceed 90%. Larger tumors and a subset of the small ones will present substantial risk of recurrence. Objective: To identify, by retrospective analysis, histological and clinical features associated with recurrence and metastasis. Material and method: There were analyzed thirty five records of patients treated by surgery for squamous cell carcinoma of the skin of the head and neck. From them we collected information about: tumor depth (millimeters), perineural invasion, grade (Broders) and angiolymphatic invasion. After that we verified the association of these features with the variants of prognosis: local recurrence, lymph node metastasis, distant metastasis and death caused by the disease. In a similar fashion we compared these variants of prognosis between them. Statistical significance was admitted at the level of 5%. Results: We found statistical significance between: local recurrence and perineural invasion; lymph node metastasis and perineural invasion, angiolymphatic invasion and depth; distant metastasis and angiolymphatic invasion; death and perineural invasion, depth and angiolymphatic invasion. Between the variants of prognosis we found association of death with distant and lymph node metastasis. Conclusion: Histological and clinical features of squamous cell carcinoma of the skin of the head and neck may help to define high risk patients. Prospective protocols should be established for better treatment results in these patients / Mestrado / Cirurgia / Mestre em Cirurgia

Squamous cell carcinomas of the head and neck (SCCHN) is a diverse group of tumours includingtumours of the mouth, of which most are manifested in the tongue. Previous studies have shown that assessment of histological risk factors including worstpattern of invasion (WPOI) and lymphocytic response (LR) is of clinical relevance in treating SCCHN. It hasalsobeen suggested that evaluation of the inflammatory infiltrate could be of prognostic importance.The purpose of this study was to further investigate, analyze and map histological factors associated with TSCC.A total of 58biopsies fromtwo different ethnic groups,Swedish and Italian,were evaluated regarding factors like WPOI andLR. Results were thencorrelated to clinical data.Approximately halfof the patients, 53%, displayed patches ofdense lymphocytic infiltrate at the tumour interface. There was,however,no statistically relevant correlation seen between LR, recurrence of disease, survival rate or ethnicity. Considering WPOI, 83% of patients showed a tumour growth pattern withsmall invasive islands &lt;15 cells (WPOI 4). No correlationbetween WPOI, recurrence of disease, survival rate, ethnicity or lymphocyticresponse was found.Our findings confirm that SSC of the tongue hasa very split patternof invasion. No conclusive result was found concerning inflammatory response and prognostic factors. Data collected showed that ethnic differences could potentiallybe of interest for further study of the prevalence of tongue SCC.

Abstract Traditional clinicopathological factors are not accurate enough to predict the behavior of head and neck squamous cell carcinoma (HNSCC). The most powerful indicator of prognosis is the stage of the disease. New prognostic markers have, however, been searched for in order to better identify patient groups in need of different treatments or follow-up. Gelatinases (MMP-2, -9) are endopeptidases associated with tumor invasion and angiogenesis, and their tissue inhibitors (TIMP-1, -2) are also linked to cancer cell invasion and metastasis formation. In some cancer types they are even prognostic and relate with a more aggressive clinical course of the disease. In the present work the expression and the clinical significance of tumor tissue and circulating immunoreactive proteins for MMP-2, -9, TIMP-1 and -2 were assessed in HNSCC. The study group included 74 patients with HNSCC and 44 healthy controls. The expression of immunoreactive proteins was examined in paraffin-embedded tumor sections by immunohistochemical staining using specific antibodies, and the pretreatment serum levels of those proteins were quantitatively measured by ELISA assay. Immunohistochemical overexpression of MMP-9 in tumor was for the first time found to predict the prognosis for shortened survival in HNSCC, the cause-specific survival rates being 45% and 92% and relapse-free survival being 42% and 79% in MMP-9 positive or negative cases, respectively. Additionally, tissue TIMP-1, MMP-2 and TIMP-2 positivity were all also linked with poorer survival of patients with HNSCC. However, these differences remained less distinct than with MMP-9. The expression of gelatinases and their inhibitors in tumor tissue was also an indicator for later lymph node or hematogenic relapses in HNSCC patients. Circulating MMP-9 and TIMP-1 levels were significantly higher in HNSCC patients than in healthy controls. Further, the cause-specific and relapse-free survival rates were lower among HNSCC patients with high MMP-9 and TIMP-1 serum levels compared to patients with low levels of circulating MMP-9 and TIMP-1. A significant correlation was shown between circulating MMP-9 and MMP-9 immunohistochemical staining in the corresponding tumors. No correlation was found between tissue or circulating levels of gelatinases or their inhibitors and the traditional clinical or histopathological factors, except for the association between tissue and circulating TIMP-1 and the size of the primary tumor. Taken together, these results suggest that tissue expression of gelatinases and their inhibitors as well as pretreatment circulating MMP-9 and TIMP-1 levels could be prognostic in estimation of the clinical course of HNSCC. The results indicate further studies are needed with larger patient materials.

Abstract Degradation of extracellular matrix (ECM) and basement membrane (BM) are required both in normal physiological conditions such as wound healing and in pathological tissue remodelling such as chronic ulcers and cancers. Matrix metalloproteinases (MMPs) are an enzyme family, which can cleave most ECM and BM components. They are associated with physiological and pathological processes but their exact roles are still largely unknown. The expression of MMP-8 and MMP-26 in acute and chronic human cutaneous wounds using histological and cell culture methods were investigated. MMP-8 was expressed in epithelial cells, neutrophils, and other inflammatory cells especially in chronic ulcers while in acute wounds MMP-8 expression was weak or absent. MMP-26 was temporarily present in acute wounds while it was strongly expressed in close vicinity to the BM in multiple cell types of most chronic ulcers. In vitro keratinocyte wound assay showed that MMP-8 and -26 were expressed in migrating cells. Bone formation, collagen metabolism, and inflammation in MMP8-/- mice tooth extraction wounds and also periapical lesion formation were analysed. No differences between wild type or MMP-8-deficient mice in the new bone area or periapical lesion size were found. However, type III procollagen production was increased and inflammatory cell influx was decreased in MMP8-/- mice. In addition, Fas ligand (FasL) production was increased in mandibular alveolar mucosa but decreased in alveolar bone of MMP-8 deficient mice. MMP-8 was also found to cleave FasL in vitro. A total of 90 human mobile tongue squamous cell carcinoma (SCC) samples were collected. Bryne’s malignancy scores, thickness of the SCCs, expression of microvessel density (CD31 and factor VIII), cyclooxygenase-2 (COX-2), the laminin-5 (currently termed laminin-332) γ2-chain, integrin αvβ6, estrogen receptor-α (ER-α), estrogen receptor-β (ER-β), and MMPs (-2, -7, -8, -9, -20, and -28) were analysed. The high expression of MMP-8 was associated with a better prognosis for the patients, particularly in females. In addition, tongue carcinoma formation in MMP8-/- mice was investigated. Tongue SCC developed more often in MMP8-/- female mice than wild type littermates. In addition, MMP-8 can cleave ER- α and -β and estrogen can induce MMP-8 production in vitro. A total of 22 biopsies, 10 resection sections, and three lung metastases of 25 osteosarcoma patients samples were stained with MMP-2, -8, -13, -26, and tissue inhibitor of metalloproteinase-1 (TIMP-1) using immunohistological methods. Expression of these markers was mostly present in sarcoma cells but MMP-8 was not present in lung metastases. In resection sections, chemotherapy altered MMP-2, -8, and -13 expressions compared to biopsies. However, an association between the expression and prognosis of osteosarcoma patients could not been found. In conclusion, MMP-8 seems to be an estrogen-related protective factor in tongue SCC and can regulate ECM and BM components and inflammation during wound healing. Further studies are needed to evaluate the exact function especially of MMP-8 in human osteosarcoma.

Receptor Tyrosine Kinase (RTK) inhibitors, such as erlotinib/tarceva, have been introduced in the past decade as a promising therapeutic option in Head and Neck Squamous Cell Carcinoma (HNSCC), however, they lack significant efficacy as single agents. As a result, RTK inhibitors require a combination based therapeutic approach with other treatment modalities. To uncover such a combination of agents, we performed a high throughput Prestwick library screen that included 1200 compounds approved by the FDA on HNSCC cell lines and found that monensin, a coccidial antibiotic, synergistically enhanced the cytotoxicity of erlotinib. RT-PCR revealed that monensin induced the expression of Activation of Transcription Factor (ATF) 3 and its downstream target C/EBP homologous protein (CHOP) which are key regulators of apoptosis. Furthermore, RNA-Seq analysis suggests that monensin augments erlotinib cytotoxicity by disturbing lipid and sterol biosynthesis. Therefore, identifying the mechanism of action exerted by monensin may open alternative avenues of cancer treatment.

Orientadores: Marcio Ajudarte Lopes, Ana Lúcia Carrinho Ayroza Rangel / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-26T15:42:38Z (GMT). No. of bitstreams: 1 Frare_JulianaCristina_D.pdf: 1500588 bytes, checksum: a3865c52c3a98f44b6f09c260fd6cdca (MD5) Previous issue date: 2015 / Resumo: O carcinoma espinocelular (CEC) é considerado uma doença relativamente incomum em pacientes com idade inferior a 40 anos e existem especulações que este tumor apresenta um comportamento biológico mais agressivo neste grupo. Sendo assim, o objetivo deste estudo foi analisar o perfil clinicopatológico de pacientes jovens (? 40 anos) com CEC oral e correlacioná-lo com o de um grupo controle (? 50 anos) através de quatro sistemas de gradação histopatológica ¿ (1) Sistema da Organização Mundial de Saúde ¿ Sistema OMS, (2) Sistema de Gradação de Malignidade de Margens Invasivas Profundas ¿ Sistema MG, (3) Modelo de Risco Histológico ¿ Sistema HR e (4) Escore de risco BD. Foram selecionados 14 pacientes jovens e 14 pacientes controle com similar estadiamento clínico e localização do tumor. Dados demográficos e clínicos foram obtidos de prontuários de pacientes e os cortes histológicos das peças cirúrgicas emblocadas em parafina foram avaliados de acordo com os quatro sistemas de gradação. As associações entre as categorias foram realizadas através do teste de Qui-quadrado ou teste Exato de Fischer. As análises de sobrevida foram realizadas de acordo com o método de Kaplan-Meier. A comparação entre os grupos mostrou maior associação de modalidades de tratamento em pacientes jovens (p=0.022) e que estes apresentaram maior taxa de recidiva local e metástase regional (p=0.018 / OR= 3.998). Pacientes jovens tiveram menor sobrevida livre de doença em 5 anos (p=0.069). Não houve diferença na sobrevida global em 5 anos entre grupos estudados (p=0.376). Não houve diferença na gradação histológica entre os grupos estudados de acordo com os quatro sistemas utilizados (OMS, MG, HR e BD). Nos sistemas HR e BD mais tumores foram classificados como de alto risco prognóstico que nos sistemas OMS e MG. Este estudo mostrou que, apesar de o grau de diferenciação histológica dos tumores ter sido semelhante entre os grupos e terem sido utilizadas mais modalidades terapêuticas (cirurgia, radioterapia e quimioterapia adjuvantes) no grupo jovem, maior incidência de recidivas e metástases foi observado em pacientes jovens, mostrando uma tendência de um comportamento mais agressivo / Abstract: Squamous cell carcinoma (SCC) is considered a relatively uncommon disease in patients younger than 40 years old and there are speculations that this tumor has a more aggressive biological behavior in this group. Thus, the aim of this study was to analyze the clinicopathologic profile of young patients (? 40 years) with oral squamous cell carcinoma and correlate with a control group (? 50 years) by means of four histopathological grading systems - (1) World Health Organization System - WHO System (2) Deep Invasive Margins Deep Malignancy Grading System - MG System, (3) Histologic Risk Model - HR System, and (4) BD Risk Score. Fourteen young patients and 14 control patients with similar clinical stage and tumor location were selected. Demographic and clinical data were obtained from patient's records and histological sections of the paraffin-embedded blocks of surgical specimens were evaluated according to four histopathological grading systems. Associations between categories were performed through Chi-square test and Exact Fisher test. The survival analyzes were performed according to Kaplan-Meier method. The comparison between groups showed that a greater association of treatment modalities in younger patients (p = 0.022) and these had a higher incidence of local recurrence and regional metastasis (p = 0.018 / OR=3.998). Younger patients had lower disease-free survival in 5 years (p = 0.069). There was no difference in overall 5-year survival between the studied groups (p=0.376). There was no difference in histological grading between groups according to the four used systems (WHO, MG, HR and BD). In HR and BD systems more tumors were classified as high risk prognosis than in WHO and MG systems. This study showed that, despite tumors histologic grade was similar between groups and more therapeutic modalities (surgery, adjuvant radiotherapy and chemotherapy) were used in the young group, higher incidence of recurrence and metastasis were observed in young patients, showing a tendency to a more aggressive behavior / Doutorado / Patologia / Doutora em Estomatopatologia