O carcinoma diferenciado de tireóide (CDT) constitui a neoplasia maligna mais comum do sistema endocrinológico, respondendo por aproximadamente 95% dos casos. O CDT é considerado uma neoplasia de comportamento indolente com baixas taxas de morbidade e mortalidade. No entanto, alguns pacientes apresentam doença mais agressiva e a identificação desses pacientes (com maior risco de recorrência, morbidade e mortalidade) permanece como um dos grandes desafios no manejo dessa neoplasia. Na tentativa de individualizar o risco e identificar esse grupo de pacientes mais propensos a desfechos desfavoráveis, diversos fatores prognósticos já foram descritos. Os primeiros fatores identificados foram derivados de estudos que avaliaram características clínicas e patológicas dos pacientes e, mais recentemente, novas estratégias, como uso de marcadores laboratoriais e moleculares, e resposta ao tratamento inicial têm sido propostas. Neste artigo revisamos criticamente os principais fatores prognósticos descritos na literatura, discutindo as suas aplicações e limitações na prática clínica. Observamos que praticamente todos os fatores prognósticos descritos até o momento apresentam limitações: 1) os fatores clínico-patológicos são derivados de estudos antigos, nos quais o curso da doença parece diferir do padrão atual, e utilizam a mortalidade como desfecho principal; 2) a determinação da tireoglobulina sérica, o mais estudado fator prognóstico laboratorial, advém de estudos com limitações metodológicas que dificultam a sua interpretação e aplicação; 3) os fatores moleculares ainda carecem de dados que demonstrem superioridade na individualização dos pacientes, quando comparados aos fatores disponíveis. Na análise comparativa, a avaliação da resposta ao tratamento inicial parece apresentar o melhor desempenho como fator prognóstico para a evolução do paciente em médio e longo prazo.

Carcinoma medular da tiroide (CMT), tumor maligno originário de células C ou parafoliculares tireoidianas, representa cerca de 4% de todos os tumores malignos dessa glândula. O CMT ocorre principalmente na forma esporádica (75%), mas também pode ocorrer como parte de uma doença hereditária transmitida de forma autossômica dominante, com 100% de penetrância, chamada neoplasia endócrina múltipla tipo 2 (NEM 2). A síndrome NEM 2 é classificada em três subtipos clínicos distintos: NEM tipo 2A (NEM 2A); NEM tipo 2B (NEM 2B) e câncer medular de tireoide familiar (CMTF). O protooncogene RET (REarranged during Transfection) é o gene de susceptibilidade para CMT hereditário e mutações somáticas nesse gene são descritas em aproximadamente 50% dos casos CMT esporádicos. Polimorfismos de nucleotídeo único (SNPs) do proto-oncogene RET têm sido implicados na patogênese e progressão do carcinoma medular da tireoide. A presença da variante genética silenciosa S836S tem sido associada com o risco de desenvolver ou modificar o curso clínico do CMT. No entanto, o mecanismo exato com que esse polimorfismo exerce seu efeito ainda é pouco compreendido. Uma das hipóteses propostas sugere que outras variantes funcionais do RET possam estar em desequilíbrio de ligação (DL) com o polimorfismo S836S, sendo essas capazes de modular a expressão gênica. Na doença de Hirschsprung, a variante S836S está em DL com polimorfismos da região 3’UTR do RET e associada ao desenvolvimento da doença. Nesse estudo, nós investigamos a frequência dos polimorfismos rs76759170 e rs3026785 da região 3’UTR do proto-oncogene RET em pacientes com CMT e verificamos a presença de desequilíbrio de ligação entre essas variantes e o polimorfismo S836S. De forma interessante, observamos que as variantes 3’UTR podem afetar a estrutura e a flexibilidade do mRNA do RET, o que sugere um envolvimento funcional dessas variantes sobre a estrutura secundária do mRNA desse gene. Além disso, o haplótipo contendo os alelos polimórficos S836S e 3’UTR foi associado ao desenvolvimento de doença metastática em pacientes com CMT. / Medullary thyroid carcinoma (MTC), a malignant tumor originating in parafollicular C cells of the thyroid, represents about 4% of all thyroid cancers. MTC is mainly sporadic (75%), but may also be part of an inherited disorder transmitted as an autosomal dominant trait with 100% penetrance, referred as multiple endocrine neoplasia type 2 (MEN 2). The MEN 2 syndrome is classified into three distinct clinical subtypes: MEN type 2A (MEN 2A); MEN type 2B (MEN 2B) and familial MTC (FMTC). The RET (REarranged during Transfection) proto-oncogene is the susceptibility gene for hereditary MTC and somatic RET point mutations are described in approximately 50% of MTC cases. The RET single nucleotide polymorphisms (SNPs) have been implicated in the pathogenesis and progression of MTC. The presence of S836S neutral variant might modify disease susceptibility and clinical phenotype in MTC. However, the exact mechanism by which this polymorphism modulates the MTC pathogenesis is still poorly understood. One of the proposed mechanisms suggests that the S383S neutral variant might be in linkage disequilibrium (LD) with unknown functional variants; these might be modulating gene expression. In patients with Hirschsprung's disease, strong LD between S836S and RET 3'UTR variants has been reported. Here, we evaluated the frequency of rs76759170 and rs3026785 3'UTR polymorphisms in patients with MTC and observed strong LD between these variants and S836S polymorphism. Interestingly, we demonstrated that the 3’UTR variants may affect the RET mRNA structure and flexibility, supporting the hypothesis of a functional involvement of the 3’UTR variant allele on secondary structure of RET mRNA. Furthermore, the haplotype harboring these variants was associated with development of metastatic disease in individuals with MTC.

Submitted by ROBERTO PAULO CORREIA DE ARAÚJO (ppgorgsistem@ufba.br) on 2015-07-17T19:51:36Z No. of bitstreams: 1 PEREIRA, Danielle Pessôa.pdf: 2273847 bytes, checksum: 9fd911d989bc9942943233a4ba36bf38 (MD5) / Made available in DSpace on 2015-07-17T19:51:36Z (GMT). No. of bitstreams: 1 PEREIRA, Danielle Pessôa.pdf: 2273847 bytes, checksum: 9fd911d989bc9942943233a4ba36bf38 (MD5) / Este trabalho foi financiado pela Fundação de Amparo à Pesquisa no Estado da Bahia (FAPESB) / Introdução: A oncogênese tireoidiana frequentemente envolve a ativação constitutiva da via RAS-RAF-MEK-ERK. A mutação BRAFV600E contribui para a sua ativação e tem sido considerada o evento oncogênico mais frequente do carcinoma papilífero de tireoide (CPT). Estudos clínicos e experimentais têm predominantemente demonstrado associação positiva entre a presença da mutação BRAFV600E e mau prognóstico do CPT. No entanto, alguns estudos não constataram esta associação, indicando que ainda há discrepâncias e variabilidade nos resultados obtidos. Objetivos: Determinar a prevalência da mutação BRAFV600E em casos consecutivos de CPT em pacientes diagnosticados e tratados no Hospital São Rafael, SalvadorBahia-Brasil e associar a presença da mutação com aspectos clinicopatológicos conhecidos do CPT e risco de recorrência segundo protocolos do Consenso Brasileiro e a American Thyroid Association. Metodologia: Estudo retrospectivo de 135 casos consecutivos de CPT. Extração de DNA de tecido tumoral parafinado. Reação em cadeia da polimerase e sequenciamento direto do exon 15 do gene BRAF. Dados clínicos e patológicos foram obtidos através da revisão de prontuários físicos e eletrônicos. A positividade da mutação BRAFV600E foi confrontada com os aspectos clinicopatológicos dos pacientes utilizando Teste de Qui-Quadrado e análise multivariada de regressão logística. Resultados: A prevalência da mutação BRAFV600E foi de 65,1% (28/43). A mutação BRAFV600E esteve positivamente associada com idade avançada (40,96 ± 13,69 vs 29,73 ± 10,18; P = 0,008) e negativamente com presença de tireoidite de Hashimoto (TH) (25% vs 66,7%; P = 0,008). Contudo, o efeito independente foi somente observado para TH (OR: 0,14; P = 0,024). Neste estudo, não foram observadas associações com o sexo do paciente, história familiar, subtipo histológico, tamanho tumoral, multifocalidade, invasão vascular, metástases linfonodais e à distância, estádio clínico avançado (TNM/AJCC) e risco de recorrência tumoral. Conclusão: A prevalência da mutação BRAFV600E foi semelhante à apresentada em estudos prévios. A mutação BRAFV600E não esteve associada com a maioria dos aspectos clinicopatológicos investigados. Tireoidite de Hashimoto esteve negativamente associado com a mutação BRAFV600E . / Background: Thyroid oncogenesis often involves constitutive activation of the RAS-RAFMEK-ERK pathway. BRAFV600E mutation contributes to this activation and has been considered the most frequent oncogenic event in papillary thyroid carcinoma (PTC). Clinical and experimental studies have predominantly demonstrated positive association between presence of BRAFV600E mutation and poor PTC prognosis. However, some studies have not found this association, so there still are discrepancies and variability in the results obtained. Objectives: To determine the BRAFV600E mutation prevalence in consecutive cases of PTC in patients diagnosed and treated at São Rafael’s Hospital, Salvador-Bahia-Brazil, and associate its presence with known clinicopathological aspects of PTC and recurrence risk according to Brazilian's Consensus and American Thyroid Association guidelines. Methods: Retrospective study of 135 consecutive cases of PTC. DNA extraction from paraffin-embedded tumor tissue. Polymerase chain reaction and direct sequencing of exon 15 of BRAF gene. Clinical and pathological data were obtained through review of physical and electronic records. BRAFV600E mutation positivity was confronted with the clinicopathological features of patients using chisquare test and multivariate logistic regression analysis. Results: BRAFV600E mutation prevalence was 65.1% (28/43). BRAFV600E mutation was positively associated with older age (40.96 ± 13.69 vs 29.73 ± 10.18, P = 0.008) and negatively with the presence of Hashimoto's thyroiditis (HT) (25% vs 66.7%; P = 0.008). However, the independent effect was only observed for HT (OR: 0.14, P = 0.024). In this study, associations with patient gender, familial history, histologic subtype, tumor size, multifocality, vascular invasion, lymph node and distant metastases, advanced clinical stage (TNM/AJCC) and risk of tumor recurrence were not observed. Conclusion: BRAFV600E mutation prevalence was similar to the presented in previous studies. BRAFV600E mutation was not associated with most clinicopathological aspects investigated. Hashimoto's thyroiditis was negatively associated with BRAFV600E mutation.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Odontologia, Florianópolis, 2016. / Made available in DSpace on 2016-09-20T04:36:04Z (GMT). No. of bitstreams: 1 339917.pdf: 1826007 bytes, checksum: 243c62e86307b651b7169fb44f9ec134 (MD5) Previous issue date: 2016 / Para inibir a diferenciação e manter as características das células-tronco, proteínas inibidoras da ligação de DNA (ID) antagonizam os fatores de transcrição basic helix-loop-helix (bHLH). A ubiquitinização da proteína ID ocorre em diferentes tecidos, mas em muitos neoplasmas esta consegue escapar da degradação. O complexo proteico USP1/WDR48 pode estar envolvido nesse processo. Paralelamente, a proteína p53, guardiã do genoma humano, controla a auto renovação neoplásica. Este estudo objetivou associar a expressão imuno-histoquímica das proteínas p53, USP1 e WDR48 aos dados clínico-histopatológicos de Carcinomas Epidermóides Intrabucais (CEI). Trinta casos de CEI, grupo teste, e 40 casos de Hiperplasia Fibrosa (HF), grupo controle, foram utilizados para as análises imuno-histoquímicas (anticorpos anti-p53, anti-USP1 e anti-WDR48). A expressão destes marcadores foi dividida em 4 categorias (núcleo+, citoplasma+, núcleo e citoplasma+ e células-). As fichas de biópsia, laudos e prontuários foram avaliados. A classificação histopatológica (Bryne et al., 1992) foi realizada por meio de lâminas com coloração HE. Após, os dados foram submetidos a análise estatística (Kruskal Wallis). Os resultados imuno-histoquímicos apresentaram diferença estatisticamente significante entre os três marcadores (p53, USP1 e WDR48) (p=0,0001 para todos os grupos), e também entre as lesões (CEI ou HF) em 5 grupos (p=0,0000; 0,0028; 0,0010; 0,0000; 0,0413), sendo que, na maiora das vezes, a expressão em HF foi inferior à expressão em CEI. Nenhuma associação com os achados clínicos foi identificada (TNM), mas observou-se com os histopatológicos. Os CEIs bem diferenciados foram os que obtiveram as menores médias de expressão dos marcadores. Conclui-se que parece haver uma associação entre a expressão das proteínas investigadas e CEI, bem como com o grau de malignidade deste tipo de lesão, porém não com as suas características clínicas. Deste modo, os marcadores p53, USP1 e WDR48 têm potencial determinante de prognóstico e tratamento de CEI.<br> / Abstract: To inhibit differentiation and maintain stem cell fate, Inhibitors of DNA binding (IDs) antagonize basic helix-loop-helix (bHLH) transcription factors. ID ubiquitination occurs in differentiated tissues, but IDs in many neoplasms appear to escape degradation. The protein complex USP1/WDR48 can be involved in this process. At the same time, p53 protein, human genome guardian, controls the neoplastic self renewal. When occurs loss of function of the tumor suppressor gene TP53 there is the possibility of cancer development. This study aimed to associate the immunohistochemical expression of p53, USP1, WDR48 and clinical-histopathological characteristic of OSCC (oral squamous cell carcinoma). Thirty OSCC cases, test group, and 40 FH cases (fibrous hyperplasia), control group, were used for immunohistochemical analysis (anti-p53, anti-USP1 and anti-WDR48). The expression of these markers was divided into 4 categories (nucleus+; cytoplasm+, nucleus and cytoplasm+ and cells-). Biopsy form, histopathological results and patients? records were evaluated. The histopathological classification (Bryne et al., 1992) was performed using HE staining. After that, data were subjected to statistical analysis (Kruskal Wallis). The immunohistochemical results revealed a statistically significant difference among the three markers (p53, USP1 and WDR48) (p=0,0001 to all groups), and also between the lesions (OSCC or FH) in 5 groups (p=0,0000; 0,0028; 0,0010; 0,0000; 0,0413). The expression in FH was less commonly found than expression in OSCC. No association with clinical findings was identified (TNM), but it was noted regarding histopathological issues. Well differentiated OSCC achieved the lowest average of expression of the markers. We may conclude that, possibly, exist an association between these proteins and OSCC, its immunolocalization can be connected with malignant grading. However, the association with clinical findings cannot be determined. The p53, USP1 and WDR48 have the potential to define OSCC prognosis and treatment.

<b>Introduction:</b> Almost 7,000 people are diagnosed with ductal carcinoma in situ (DCIS) in the United Kingdom each year, but there remains uncertainty regarding its natural history and optimal management. The aim of this thesis was to evaluate factors contributing to the epidemiology of DCIS and its outcomes. <b>Methods:</b> 1) A cohort study comparing risk factors for DCIS and invasive breast cancer (IBC) using UK Biobank; 2) A cohort study examining the accuracy of preoperative biopsy in DCIS using clinical records from the Netherlands Cancer Institute; 3) A cohort study examining the rate of invasive breast cancer following treatment for screen-detected DCIS in England using the National Health Service Breast Screening Programme (NHSBSP) audit; 4) A methodological study to develop an algorithm to identify invasive breast cancer recurrences, which in the future may used to identify DCIS recurrences, using all relevant routinely collected data stored within Public Health England (PHE). <b>Results:</b> (1) For both DCIS and IBC, postmenopausal BMI was associated with an increased risk of developing disease, and the number of live births was associated with a decreased risk of developing disease. However, the magnitude of the effect differed between DCIS and IBC. The increased risk from postmenopausal BMI &GE;35 kg/m² was larger for DCIS than for IBC (RR 2.35, 95% CI 1.14-4.82), and the trend of reduction in risk with each additional live birth was greater for DCIS than for IBC (p for trend = 0.03). (2) Consideration of mammographic lesion size and the absence of necrosis on biopsy may be helpful in selecting low-risk women for non-operative management of DCIS in the future, as may use of the 9G vacuum-assisted method of biopsy. (3) The cumulative risks of IBC at 5, 10 and 15 years after screen-detected DCIS in England were 3.5%, 7.1%, and 9.4% respectively. Women with clear surgical margins of 1-2 mm had a higher IBC rate than women with clear margins of 5+ mm (RR 1.85, 95% CI 1.20-2.84). Women given breast-conserving surgery (BCS) without radiotherapy had a higher ipsilateral IBC rate than women given BCS with radiotherapy (RR 1.63, 95% CI 1.27-2.10). Women given hormone therapy had a lower rate of any IBC compared with oestrogen receptor (ER) positive women not given hormone therapy (RR 0.76, 95% CI 0.63-0.93). (4) There was good agreement between the number of recurrences indicated by the developed algorithm using routinely collected data sources and the number of recurrences recorded in the test dataset. This finding supports the potential value of compiling recurrence information on a nationwide basis from routinely collected data, for use in future descriptive and epidemiological studies and in follow-up for randomised trials. <b>Conclusions:</b> Using a variety of methods these studies have all succeeded in adding to knowledge about the epidemiology of DCIS. This knowledge can be used to help the future management of women with DCIS. In addition, each of the studies has planned extensions and will continue to contribute further knowledge periodically into the future.

Macroautophagy (hereafter referred to as autophagy) is a highly conserved cellular process that promotes cytoplasmic homeostasis via lysosomal degradation of proteins and organelles. Dysfunctional autophagy occurs in numerous human pathologies, including neurodegeneration and cancer. Vinexin (encoded by SORBS3) is a physiologically important adaptor protein for two main reasons: 1. SORSB3 mRNA expression increases in normal human brain ageing, 2. SORBS3 is a candidate tumour suppressor in hepatocellular carcinoma (HCC). This dissertation builds on published data from an siRNA screen for autophagy regulations under basal conditions, which indicates vinexin knockdown upregulates autophagy. I replicate this finding in multiple cell lines, before characterising the impact of siSORBS3 treatment on autophagy; autophagosome biogenesis is increased, while flux through the autophagy pathway remains intact. Having excluded several possible mechanisms suggested by the literature, I focus on the transcriptional coactivators YAP and TAZ. The rationale here is: 1. YAP/TAZ activity is implicated in autophagy, 2. YAP/TAZ and vinexin are both linked to HCC. My data show that YAP/TAZ transcriptional activity is upregulated upon vinexin depletion. Moreover, increased autophagy following siSORBS3 treatment requires YAP and TAZ. A key focus of this dissertation is the mechanism by which vinexin knockdown upregulates YAP/TAZ and hence, autophagy. This centres on altered actin cytoskeleton dynamics; an increase in F-actin structures appears to compete with YAP/TAZ for binding to angiomotins, established sequesterers of YAP/TAZ in the cytosol. In this way, siSORBS3 treatment facilitates YAP/TAZ nuclear localisation and consequent transcriptional activity. Angiomotin overexpression therefore ameliorates the increase in autophagy caused by vinexin depletion. Published RNA sequencing data is used to confirm that SORBS3 mRNA expression increases in normal brain ageing, not only in the frontal cortex (as previously published), but also in the hippocampus. This sits alongside decreased expression of core autophagy genes in both tissues. Accordingly, vinexin could contribute to the decline in autophagic potential thought to occur in normal brain ageing. With regards to SORBS3 as a candidate tumour suppressor in HCC, I show that stably re-expressing vinexin in a HCC cell line downregulates YAP/TAZ and hence, autophagy. These cells also show reduced clonogenicity. My data therefore support the hypothesis that SORBS3 is a tumour suppressor in HCC; YAP and TAZ are well-known to increase proliferation and resistance to apoptosis, while autophagy can enable tumour cells to survive stressors such as nutrient starvation. The conclusions of this dissertation are that vinexin depletion upregulates autophagy in a YAP/TAZ-dependent manner and that this has physiologically important implications, especially with regards to HCC.

Introdução/Objetivo: Existem evidências indicando que a resposta virológica sustentada (RVS) ao tratamento com interferon pode estar associada com menor incidência de carcinoma hepatocelular (CHC) em pacientes com cirrose causada pelo vírus da hepatite C (VHC). O objetivo do presente estudo foi comparar a incidência de CHC em cirróticos com RVS versus sem RVS. Métodos: Foram selecionados 85 pacientes com cirrose compensada (Child A) secundária ao VHC, confirmada por biópsia, sem quaisquer outras causas de doença hepática. Todos foram submetidos a tratamento com interferon ± ribavirina por pelo menos 24 semanas. Antes do tratamento nenhum paciente apresentava evidência de CHC à ultrassonografia abdominal (US). RVS foi definida como RNA do VHC negativo (PCR qualitativo com limite de detecção de 50 UI/ml) 24 semanas após o final do tratamento. Foram incluídos apenas pacientes com seguimento semestral com US e alfa-fetoproteína e anual com PCR por mais de 12 meses após o final do tratamento. O CHC foi diagnosticado por biópsia ou achados coincidentes de lesão focal com diâmetro superior a 2cm na US e tomografia computadorizada helicoidal trifásica com sinais de hipervascularização arterial. Resultados: Dos 85 pacientes, 38 (45%) alcançaram RVS e 47 (55%) não. A média do seguimento em pacientes com RVS versus sem RVS foi de 32,1 ± 20 meses (variação: 12-84 meses) e 28,2 ± 18 meses (variação: 12-96 meses), respectivamente (P=0,51). O CHC foi diagnosticado em 1 (3%) dos 38 pacientes com RVS e 8 (17%) dos 47 pacientes sem RVS (P=0,02; Razão de chance: 0,13; Intervalo de confiança de 95%: 0,006-0,9). As características pré-tratamento foram semelhantes entre os pacientes com e sem RVS, tanto demográficas (idade e sexo) quanto clínicas (Child A, média da dose total de interferon e tempo de seguimento). Além da ocorrência de CHC, a única outra variável com diferença significativa encontrada entre os grupos com e sem RVS foi o percentual de pacientes com genótipo 1 (13% versus 35%, respectivamente; P = 0,04). Comparando-se os pacientes com e sem CHC, a única variável com diferença estatisticamente significativa encontrada foi o percentual de RVS (11% versus 49%, respectivamente; P = 0,03). Conclusões: Pacientes com cirrose pelo VHC que atingem RVS têm menor incidência de CHC quando comparados àqueles sem RVS. A única diferença entre os grupos com e sem CHC foi a ocorrência de RVS. Este achado indica que a ausência do VHC pode tanto representar fator protetor direto contra o CHC, quanto servir como marcador indireto para identificar cirróticos com menor probabilidade de desenvolver CHC. / Background/Aim: There is strong evidence that sustained virologic response (SVR) to interferon treatment has an impact on the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HVC) related cirrhosis. The aim of this study was to compare the rate of HCC among HCV cirrhotics with vs without SVR. Methods: Eighty five biopsy proven cirrhotic patients with HCV infection (PCR positive), without any other form of liver disease were included. All were treated with interferon (IFN) ± ribavirin (RBV) for at least 24 weeks. Before treatment, all patients were compensated (Child A) and had no evidence of HCC on abdominal ultrasound (US). None had previous hepatic decompensation. SVR was defined as negative HCV-RNA (qualitative PCR with a limit of detection of 50 IU/ml) 24 weeks after end of treatment. Patients followed every 6 months with US and alpha-fetoprotein (AFP) for > 12 months after end of therapy were included. HCC was diagnosed by liver biopsy and/or coincident findings of focal lesion > 2 cm on US and spiral CT with arterial hypervascularization. Results: Thirty eight (45%) were SVRs and 47 (55%) were not. Mean follow-up was 32,1 ± 20 months (range:12-84 months) in SVRs vs 28,2 ± 18 months (range:12-96 months) in no-SVRs (P=0.51). HCC was diagnosed in 1 (3%) of 38 SVRs vs 8 (17%) of 47 patients without SVR (P=0.02; OR:0.13, 95% CI:0.006-0.9). All had similar pre-treatment characteristics (age, sex, liver function, Child A, total interferon dose and follow-up time). Besides HCC incidence, the only significant difference between SVRs and no-SVRs was the rate of genotype 1 (13% vs 35%, respectively, P = 0.04). Comparing patients with and without HCC, the only significant difference was found in the rate of SVR (11% vs 49%, respectively; P = 0,03). Conclusion: HCV cirrhotics with SVR have a lower incidence of HCC compared to those without SVR. The only difference between the groups with and without HCC was the rate of SVR. This finding may indicate that either absence of HCV-RNA truly protects against HCC, or acts as surrogate marker to identify cirrhotics that have a low probability of HCC development on long-term follow-up.

Made available in DSpace on 2014-06-11T19:32:50Z (GMT). No. of bitstreams: 0 Previous issue date: 2004Bitstream added on 2014-06-13T19:22:31Z : No. of bitstreams: 1 andrade_jc_dr_botfm.pdf: 2650759 bytes, checksum: 3247fedde23c0a35497a64d9285fa833 (MD5) / Universidade Estadual Paulista (UNESP) / O objetivo deste trabalho foi estudar através do exame Imunoistoquimico, a correlação entre alguns fatores Anatomopatológicos (tipo histológico e grau nuclear) e alguns fatores biológicos (receptores hormonais de estrógeno e de progesterona, proteína c-erbB-2 e proteína p53, no carcinoma de Paget da mama, doença rara e especial. No período entre Janeiro de 1980 a Dezembro de 1998 foram tratados no Instituto Brasileiro de Controle do Câncer, 6.303 casos de câncer de mama, deste total 98 casos foram diagnosticados como carcinoma de Paget, cuja incidência foi de 1,55%. Estudamos retrospectivamente 60 casos, sendo que 38 deles foram excluídos da análise, devido a limitação e escassez da amostra no material disponível, a idade das pacientes variou entre 26 e 84 anos, com média de 55,4 anos, as informações clínicas e terapêuticas foram obtidas dos prontuários das pacientes considerando, idade na época do diagnóstico, tamanho do tumor quando palpável, estadiamento clínico, e o tipo de cirurgia realizada. As amostras de tecido mamário foram recuperadas dos arquivos do Departamento de Anatomia Patológica do I.B.C.C. / MATTOSINHO. Após a revisão histológica, realizada por dois patologistas os casos foram classificados em quatro grupos: Grupo A- Doença de Paget (forma pura) n = 09 Grupo B- Doença de Paget + neoplasia ductal “in situ”, n = 12 Grupo C- Doença de Paget, neoplasia ductal invasora, n = 30 Grupo D- Doença de Paget + neoplasia ductal “in situ”+ neoplasia ductal invasora, n = 09. Entre as variáveis anatomopatológicas, o grupo C prevaleceu com 30 casos (50%). O grau nuclear (GN-II) predominou com 45 casos (75%). Em relação as variáveis biológicas o receptor de estrógeno negativo predominou com 41 casos (68,3%), seguido pelo receptor de progesterona negativo com 40 casos (66,7%), podemos dizer que... / The objective of this paper was to study the immunohistochemical efects of Paget’s disease, a rare and special carcinoma of the breast, by correlating anatomopathological (histological and nuclear grade) and biological (estrogen and progesterone hormonal receptors, c-erbB-2 protein and p53 protein) factors. Between January 1980 and December 1998, 6303 cases of breast cancer were treated at the Brazilian Institute of Cancer Control; 98 of these were diagnosed with Paget’s carcinoma, an incidence of 1.55%. We retrospectively studied 60 of these cases; 38 were excluded due to lack of available sample material. Patient age varied between 26 and 84 years (mean 55.4), clinical and therapeutic information were obtained from patient’s medical records considering age at time of diagnosis, tumor size when palpable, clinical stage, and type of surgery performed. Samples of breast tissue were retrieved the Anatomical Pathology Department, I.B.C.C. / MATTOSINHO. After histological review, by two different pathologists, they were classified into four groups: Group A- Paget’s disease (pure form) n = 09 Group B- Paget’s disease + “in situ” duct neoplasia n = 12 Group C- Paget’s disease, invasive duct neoplasia n = 30 Group D- Paget’s disease + “in situ” duct neoplasia + invasive duct neoplasia n = 09.Invasive duct neoplasia was the most prevalent anatomopathological variable (Group C, n = 30, 50%). Nuclear grade (GNII) was found in 45 cases (75%). In relation to the biological variables, the negative estrogen receptor was predominant with 41 cases (68.3%), followed by the negative progesterone receptor with 40 cases (66.7%); this correlation had good concordance by the Kappa test. The c-erbB-2 protein was positive in 53 cases (88.3%) and p53 was negative in 47 cases (78.3%). From these results, we concluded that there was no statistical... (Complete abstract click electronic address below)

Made available in DSpace on 2014-06-11T19:33:24Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-07-31Bitstream added on 2014-06-13T19:44:10Z : No. of bitstreams: 1 000757746.pdf: 1927597 bytes, checksum: 54d5961ec9abfb730ff68a427c6b569c (MD5) / Desordens orais potencialmente malignas como a Queilite Actínica (QA) e neoplasias malignas como os Carcinomas Epidermoides (CE) apresentam comportamentos biológicos variáveis em função de diversos fatores teciduais que levam a desregulação do metabolismo celular. As Metaloproteinases de Matriz (MMP), endopeptidases responsáveis pela degradação dos componentes da matriz extracelular, podem estar relacionadas com o comportamento biológico dos carcinomas. O objetivo deste estudo foi avaliar a expressão imuno-histoquímica da MMP-2 e da MMP-9 e dos Inibidores Teciduais de Metaloproteinases (TIMP) 1 e 2 na QA e nos CE de lábio e de língua e relacionar os resultados com as características histopatológicas das lesões com uma possível relação entre a QA e o CE de lábio. Para tanto, neste estudo foram analisados 35 casos de QA em lábio inferior, 32 casos de CE primário em lábio inferior e 34 casos de CE primário em língua, todos com diagnóstico clínico e histopatológico, do Ambulatório da Disciplina de Propedêutica Estomatológica e da Disciplina de Patologia Bucal, da Faculdade de Odontologia do Instituto de Ciência e Tecnologia, São José dos Campos – UNESP, respectivamente. O grupo controle contou com 16 casos, sem alteração clínica ou histopatológica no tecido epitelial e sem inflamação, provenientes de biópsias realizadas na mesma instituição para confirmação do diagnóstico de hiperplasia fibrosa ou mucocele.Os resultados foram submetidos à análise estatística. Pode-se observar que, em nossas amostras de QA e de CE de lábio e de língua, a MMP-2 e seu regulador, a TIMP-2, encontra-se subexpressa, assim como a MMP-9 e seu inibidor, a TIMP-1. A expressão de MMP-9 não mostrou diferença estatisticamente significativa entre os casos de QA e de CE, no entanto não se pode negar o claro aumento de expressão de MMP-9 nas lesões de QA quando estas são comparadas as lesões ao grupo controle. Portanto.... / Potentially malignant oral disorders as actinic cheilitis (QA) and neoplastic as squamous cell carcinomas (EC) of the lip and tongue, exhibit biological behavior that varies with several factors, such as genetic changes that lead to dysregulation of cellular metabolism. The aim of this study was to evaluate the expression of matrix metalloproteinases (MMPs) 2 and 9 and tissue inhibitors of metalloproteinases (TIMP) 1 and 2, using the technique of immunohistochemistry. MMPs are responsible for endopeptidase degradation of the extracellular matrix. Was investigated in QA and CE lip and tongue, the presence and activity of these proteolytic enzymes and a possible relationship between that and the transition from QA to EC lip; besides trying to relate the results with pathologic features and compare the found between the groups. For both the study included 35 cases of QA in the lower lip, 32 CE primary lip and 34 CE of tongue with clinical and histopathological diagnosis of Ambulatory Discipline Propedeutics Stomatological and Oral Pathology, Faculty of Dentistry Institute Science and Technology, São José dos Campos - UNESP, respectively. The control group was consisted of 16 patients without clinical or histopathological changes in the epithelial tissue and without inflammation; this material came from biopsies performed to confirm the diagnosis of other pathologies, such as fibrous hyperplasia and mucocele. The data collected in the morphometric were analyzed and subjected to statistical analysis. The study concluded that both MMP-2 as their regulator TIMP-2 are low expression in our samples of Actinic cheilitis, lip squamous cell carcinoma and squamous cell carcinoma of tongue, and that MMP-9 its main inhibitor, TIMP-1 also are understated in all our samples and that although statistically not significant, the expression of MMP-9 was found in AK lesions when compared to the control group.....

Made available in DSpace on 2014-06-11T19:33:24Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-06-30Bitstream added on 2014-06-13T21:06:02Z : No. of bitstreams: 1 hatakeyama_m_dr_sjc.pdf: 755363 bytes, checksum: 572c154cdca893a035a5408346a4fcd4 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A queilite actínica (QA) é uma lesão multifocal que acomete o vermelhão do lábio com potencial de malignização para carcinoma epidermóide (CE). O receptor para o fator de crescimento epidermal (EGFR) é membro da família dos receptores tirosina quinase que participa da transformação e progressão da neoplasia maligna. O objetivo desta pesquisa foi verificar a expressão de HER-1 e HER-2 totais e fosforilados e possíveis correlações das expressões destas proteínas com lesões de QA e CE de lábio inferior por imunoistoquímica. Foram um estudo de 50 casos de QA, 50 casos de CE e 14 de Controle. Expressão das proteínas foi baseado num escore. Os dados obtidos foram analisados pelo teste de Kruskal-Wallis e como análise post-hoc o teste de Mann-Whitney com correção de Bonferroni e, correlação de Spearman. O nível de significância escolhido foi o valor convencional de 5%. A análise da comparação foi estatisticamente significativa na membrana do pHER-2, grupos Controle x QA e QA x CE; no citoplasma do HER-1, grupos Controle x QA, do pHER-1, grupos Controle x QA e Controle x CE, do pHER- 2, grupos Controle x QA e Controle x CE; no núcleo do pHER-1, grupos Controle x QA, do HER-2, Controle x QA e Controle x CE (p<0,05). O estudo da correlação foi estatisticamente significativa na membrana do HER-1 x pHER-2 no grupo QA, HER-1 x HER-2, HER-1 x pHER-1, HER-2 x pHER-1 no grupo CE; no citoplasma entre HER-1 x HER-2 no grupo QA, HER-1 x HER-2 no grupo CE; no núcleo entre HER-2 x pHER-1 no grupo Controle (p<0,05). Estes dados sugerem que a maior marcação no grupo Controle poderia ser decorrente da variedade de lesões benignas que compõem esse grupo e que poderiam apresentar proliferação aumentada. Localização nuclear poderia estar relacionada não apenas como iniciadores das cascatas intracelulares, mas também como fatores de transcrição... / Actinic cheilitis (AC) is a multifocal lesion that occurs in lip vermillion with potential of malignant transformation to epidermoid carcinoma (EC). Epidermal growth factor receptor (EGFR) is a member of tyrosine kinase family, involved in transformation and progression of malignant tumour. The aim of this study was to analyse the expression of total and phosphorylated HER-1 and HER-2 and correlate expression of these proteins with lesions of AC and CE in lower lip by immunohistochemistry. It was a study of 50 cases of AC, 50 of EC and 14 of Control. Proteins expressions were based on a score. Obtained datas were analysed by Kruskal-Wallis test and post-hoc analysis with Mann-Whitney test with Bonferroni correction and, Spearman correlation. The level of significance was 5%. The analysis of the comparison was statistically significant in membrane of pHER-2, group Control x AC and AC x EC; in cytoplasma of HER-1, Control x AC, pHER-1,Control x AC and Control x EC, pHER-2, Control x AC and Control x EC; in nucleus of pHER-1, Control x AC, HER-2, Control x AC and Control x EC (p<0,05). The study of the correlation was statistically significant in membrane of HER-1 x pHER-2 expression in AC, HER-1 x HER-2, HER-1 x pHER-1and HER-2 x pHER-1 in EC; in cytoplasma, HER-1 x HER-2 in AC, HER-1 x HER-2 in EC; in nucleus, HER-2 x pHER-1 in Control (p<0,05). Our findings suggested that a higher expression in Control group could be due to a composition of this group by a variety of benign lesions that could present increased proliferation. Nuclear localization could be related not only with the action of intracellular cascade beginners, but also to action as transcription factors. Phosphorylation of HER-1 and HER-2 by MAPK pathway can be independent of total level of proteins in AC and EC lip lesions, because phosphorylation might be increased indirectly by UV radiation in a ligand independent way... (Complete abstract click electronic access below)