eRF3a/GSPT1 12-GGC allele increases the susceptibility for breast cancer development

It is now widely recognized that translation factors are involved in cancer development and that components of the translation machinery that are deregulated in cancer cells may become targets for cancer therapy. The eukaryotic Release Factor 3 (eRF3) is a GTPase that associates with eRF1 in a complex that mediates translation termination. eRF3a/GSPT1 first exon contains a (GGC)n expansion coding for proteins with different N-terminal extremities. Herein we show that the longer allele (12-GGC) is present in 5.1% (7/137) of the breast cancer patients analysed and is absent in the control population (0/135), corresponding to an increased risk for cancer development, as revealed by Odds Ratio analysis. mRNA quantification suggests that patients with the 12-GGC allele overexpress eRF3a/GSPT1 in tumor tissues relative to the normal adjacent tissues. However, using an in vivo assay for translation termination in HEK293 cells, we do not detect any difference in the activity of the eRF3a proteins encoded by the various eRF3a/GSPT1 alleles. Although the connection between the presence of eRF3a/GSPT1 12-GGC allele and tumorigenesis is still unknown, our data suggest that the presence of the 12-GGC allele provides a potential novel risk marker for various types of cancer.

5' and 3' UTR thymidylate synthase polymorphisms modulate the risk of colorectal cancer independently of the intake of methyl group donors

Thymidylate synthase, as a rate-limiting step in DNA synthesis, catalyses the conversion of dUMP into dTMP using 5,10-methylenotetrahydrofolate as the methyl donor. Two polymorphisms have been described in this gene: a repeat polymorphism in the 5' promoter enhancer region (3R versus 2R) and a 6 bp deletion in the 3' unstranslated region. Both of these may affect protein levels. The present case control study was aimed at investigating the influence of these two polymorphisms on the development of colorectal cancer (CRC), as well as their potential interaction with folate, vitamin B6 and vitamin B12 intake. A total of 196 cases and 200 controls, matched for age and sex distribution, were included in the study. No association was found between CRC and the 28 bp repeat polymorphism, but it was observed that individuals with the 6 bp/del and del/del genotypes had a significantly lower risk of developing the disease (OR=0.47; 95% CI 0.30-0.72). A combined genotype (2R/2R; 6 bp/del+del/del) was also found, which was associated with an even lower risk of developing of the disease (OR=0.42; 95% CI 0.26-0.69). No significant interaction between these polymorphisms and vitamin intake was observed. These results indicate for the first time that the 6 bp/del allele might be a protective factor in the development of CRC, independent of the intake of methyl group donors.

The D1822V APC polymorphism interacts with fat, calcium, and fiber intakes in modulating the risk of colorectal cancer in Portuguese persons

Background - Both genetic and environmental factors affect the risk of colorectal cancer (CRC). Objective - We aimed to examine the interaction between the D1822V polymorphism of the APC gene and dietary intake in persons with CRC. Design - Persons with CRC (n = 196) and 200 healthy volunteers, matched for age and sex in a case-control study, were evaluated with respect to nutritional status and lifestyle factors and for the D1822V polymorphism. Results - No significant differences were observed in energy and macronutrient intakes. Cases had significantly (P < 0.05) lower intakes of carotenes, vitamins C and E, folate, and calcium than did controls. Fiber intake was significantly (P = 0.004) lower in cases than in controls, whereas alcohol consumption was associated with a 2-fold risk of CRC. In addition, cases were significantly (P = 0.001) more likely than were controls to be sedentary. The homozygous variant for the APC gene (VV) was found in 4.6% of cases and in 3.5% of controls. Examination of the potential interactions between diet and genotype found that a high cholesterol intake was associated with a greater risk of colorectal cancer only in noncarriers (DD) of the D1822V APC allele (odds ratio: 1.66; 95% CI: 1.00, 2.76). In contrast, high fiber and calcium intakes were more markedly associated with a lower risk of CRC in patients carrying the polymorphic allele (DV/VV) (odds ratio: 0.50; 95% CI: 0.27, 0.94 for fiber; odds ratio: 0.51; 95% CI: 0.28, 0.93 for calcium) than in those without that allele. Conclusion - These results suggest a significant interaction between the D1822V polymorphism and the dietary intakes of cholesterol, calcium, and fiber for CRC risk.

Modulation of translation factor's gene expression by histone deacetylase inhibitors in breast cancer cells

The histone deacetylase inhibitors sodium butyrate (NaBu) and trichostatin A (TSA) exhibit anti-proliferative activity by causing cell cycle arrest and apoptosis. The mechanisms by which NaBu and TSA cause apoptosis and cell cycle arrest are not yet completely clarified, although these agents are known to modulate the expression of several genes including cell-cycle- and apoptosis-related genes. The enzymes involved in the process of translation have important roles in controlling cell growth and apoptosis, and several of these translation factors have been described as having a causal role in the development of cancer. The expression patterns of the translation mechanism, namely of the elongation factors eEF1A1 and eEF1A2, and of the termination factors eRF1 and eRF3, were studied in the breast cancer cell line MCF-7 by real-time quantitative reverse transcription-polymerase chain reaction after a 24-h treatment with NaBu and TSA. NaBu induced inhibition of translation factors' transcription, whereas TSA caused an increase in mRNA levels. Thus, these two agents may modulate the expression of translation factors through different pathways. We propose that the inhibition caused by NaBu may, in part, be responsible for the cell cycle arrest and apoptosis induced by this agent in MCF-7 cells.

Oral health, hygiene practices and oral cancer

OBJECTIVE: To assess the association between oral health and hygiene practices and oral cancer. METHODS: Hospital-based case-control study in the metropolitan area of São Paulo, southeastern Brazil, from 1998 to 2002. A total 309 patients with squamous cell carcinoma of the mouth and the pharynx and 468 controls matched by sex and age were included in the study. Cases were recruited in seven reference hospitals and controls were selected in five out of the seven participating hospitals. Detailed information on smoking, alcohol consumption, schooling, oral health status and hygiene practices were obtained through interviews. Odds ratios (OR) and 95% confidence intervals (95% CI), adjusted by sex, age, schooling, smoking, alcohol consumption as well as the variables oral health status and hygiene practices were estimated using unconditional logistic regression analyses. RESULTS: The use of complete dental prosthesis was not associated with oral cancer but regular gum bleeding showed a strong association (OR 3.1; 95% CI 1.2-7.9). Those who never attended a dental visit were more likely to have oral cancer (OR 2.5; 95% CI 1.3-4.8). Daily mouthwash use showed a stronger association to pharynx (OR 4.7; 95% CI 1.8-12.5) than mouth cancer (OR 3.2; 95% CI 1.6-6.3). CONCLUSIONS: Gum bleeding, no dental care, and daily mouthwash use were factors associated with oral cancer regardless of tobacco and alcohol consumption.

Modelo de data mining para detecção de tumores em exames de rastreio

Dissertação para obtenção do grau de Mestre em Engenharia Informática

Idade como fator prognóstico no câncer de mama em estádio inicial

OBJETIVO: Analisar a idade como fator prognóstico no câncer de mama em estádio clínico inicial. MÉTODOS: Estudo retrospectivo que analisou as características clínicas e a sobrevida livre de doença de 280 pacientes entre 25 e 81 anos com câncer de mama estágio clínico I e II com acompanhamento em hospital de Porto Alegre (RS), de 1995 a 2000. Dados clínicos, patológicos, tratamento e desfechos foram extraídos dos prontuários das pacientes. As pacientes foram divididas em dois grupos conforme a idade ao diagnóstico (<40 anos e >40 anos). Os dois grupos foram comparados quanto ao estágio clínico, histologia, expressão de receptores hormonais, terapia e radioterapia utilizando o teste qui-quadrado e/ou exato de Fisher e para análise de sobrevida, o teste de long-rank e método de Kaplan-Meier. RESULTADOS: Do total de 280 mulheres estudadas, 54 (19,3%) tinham até 40 anos de idade. Ambos os grupos de pacientes eram similares em estágio clínico, histologia e expressão de receptores hormonais. A proporção de pacientes com sobrevida livre de doença em seguimento de 56 meses foi significativamente maior nas pacientes acima de 40 anos (84% versus 70%). Proporcionalmente, as pacientes mais jovens receberam mais terapia adjuvante (88,8% versus 77,8%). Houve diferença significativa na probabilidade das mulheres acima de 40 anos de permanecerem livre de doença (84%), sendo mais evidente quando comparadas às pacientes com < 40 anos em estágio clínico I. CONCLUSÕES: Os achados confirmam que mulheres de até 40 anos com câncer de mama inicial apresentam um pior prognóstico. Entretanto, tal prognóstico parece não estar relacionado a maior número de casos com receptores hormonais negativos. Pacientes jovens que permaneceram livre de doença receberam mais terapia adjuvante, sugerindo efeito positivo da quimioterapia e hormonioterapia.

Factors related to inadequate cervical cancer screening in two Brazilian state capitals

OBJECTIVE:To analyze factors associated with cervical cancer screening failure. METHODS:Population-based cross-sectional study with self-weighted two-stage cluster sampling conducted in the cities of Fortaleza (Northeastern Brazil) and Rio de Janeiro (Southeastern Brazil) in 2002. Subjects were women aged 25-59 years in the last three years prior to the study. Data were analyzed through Poisson regression using a hierarchical model. RESULTS: The proportion of women who did not undergo the Pap smear test in Fortaleza and Rio de Janeiro was 19.1% (95% CI: 16.1;22.1) and 16.5% (95% CI: 14.1;18.9), respectively. Higher prevalence ratios of cervical cancer screening failure in both cities were seen among women with low education and low per capita income, old age, unmarried, who never underwent mammography, clinical breast examination, and blood glucose and cholesterol level testing. Smokers also had lower screening rates compared to non-smoker women and this difference was only statistically significant in Rio de Janeiro. CONCLUSIONS:The study findings point to the need of intervention focusing particularly women in worse socioeconomic conditions and access to healthcare, old-aged and unmarried. Education activities must prioritize screening of asymptomatic women and early diagnosis for symptomatic women and access to adequate diagnostic methods and treatment should be provided.

Sobrevida de mulheres tratadas por câncer de mama no estado do Rio de Janeiro

OBJETIVO: Avaliar a associação entre sobrevida de mulheres com câncer de mama e estrutura e práticas observadas nos estabelecimentos de assistência oncológica. MÉTODOS: Estudo longitudinal retrospectivo, baseado em informações do Sistema de Autorização de Procedimentos de Alta Complexidade do Sistema Único de Saúde e em amostra aleatória de 310 prontuários de mulheres prevalentes atendidas em 15 unidades hospitalares e ambulatoriais oncológicas com quimioterapia entre 1999 e 2002, no estado do Rio de Janeiro. Foram consideradas como variáveis independentes características da estrutura das unidades oncológicas e as suas intervenções praticadas, controlando o efeito com variáveis sociodemográficas e clínicas das pacientes. Para análise dos dados, foram utilizados a técnica de Kaplan-Meier e o modelo de risco de Cox (pseudo-verossimilhança). RESULTADOS: As análises de Kaplan-Meier apontaram associações significativas entre sobrevida e tempo entre diagnóstico e início do tratamento, realização de cirurgia, utilização de hormonioterapia, tipo de hormonioterapia, combinações terapêuticas, tipo de unidade e plano de saúde, volume de atendimento em câncer de mama do estabelecimento e natureza jurídica da unidade. Estimativas obtidas pelo modelo de Cox indicaram associações positivas entre o hazard de morte e tempo entre diagnóstico e início do tratamento, volume de atendimento de câncer de mama do estabelecimento e tipo de unidade combinado ao uso de plano de saúde; e negativas entre sobrevida e cirurgia de mama e tipo de hormonioterapia. CONCLUSÕES: Os resultados mostram associação entre sobrevida de câncer de mama e o cuidado de saúde prestado pelos serviços credenciados, com implicações práticas para pautar novas propostas para o controle do câncer no Brasil.

Avaliação da caracterização de lesões em mamografia com recurso a sistemas CAD (Computer-Aided Diagnosis)

Os sistemas Computer-Aided Diagnosis (CAD) auxiliam a deteção e diferenciação de lesões benignas e malignas, aumentando a performance no diagnóstico do cancro da mama. As lesões da mama estão fortemente correlacionadas com a forma do contorno: lesões benignas apresentam contornos regulares, enquanto as lesões malignas tendem a apresentar contornos irregulares. Desta forma, a utilização de medidas quantitativas, como a dimensão fractal (DF), pode ajudar na caracterização dos contornos regulares ou irregulares de uma lesão. O principal objetivo deste estudo é verificar se a utilização concomitante de 2 (ou mais) medidas de DF – uma tradicionalmente utilizada, a qual foi designada por “DF de contorno”; outra proposta por nós, designada por “DF de área” – e ainda 3 medidas obtidas a partir destas, por operações de dilatação/erosão e por normalização de uma das medidas anteriores, melhoram a capacidade de caracterização de acordo com a escala BIRADS (Breast Imaging Reporting and Data System) e o tipo de lesão. As medidas de DF (DF contorno e DF área) foram calculadas através da aplicação do método box-counting, diretamente em imagens de lesões segmentadas e após a aplicação de um algoritmo de dilatação/erosão. A última medida baseia-se na diferença normalizada entre as duas medidas DF de área antes e após a aplicação do algoritmo de dilatação/erosão. Os resultados demonstram que a medida DF de contorno é uma ferramenta útil na diferenciação de lesões, de acordo com a escala BIRADS e o tipo de lesão; no entanto, em algumas situações, ocorrem alguns erros. O uso combinado desta medida com as quatro medidas propostas pode melhorar a classificação das lesões.

Análise quantitativa da saturação de gordura em ressonância magnética mamária: comparação das técnicas SPAIR e DIXON

Introdução – A ressonância magnética (RM) mamária com injeção de contraste é uma ferramenta indispensável para a caracterização de lesões mamárias. Para tal, é fulcral uma boa capacidade de saturação de gordura de forma a delimitar as lesões observadas. Este trabalho tem como objetivo analisar quantitativa e qualitativamente as técnicas de saturação de gordura em RM mamária, nomeadamente as técnicas SPAIR e Dixon. Metodologia – Utilizou-se um equipamento de RM de 1,5T com bobina específica para a mama. Aplicou-se, durante o exame, uma sequência adicional em que a técnica de saturação de gordura utilizada foi a Dixon. Posteriormente foram analisadas as imagens obtidas com as técnicas SPAIR e Dixon e colocadas regiões de interesse (ROI) na lesão, na glândula mamária, no tecido adiposo e no ar. Estes valores de sinal obtidos foram registados e calcularam-se as relações sinal-ruído (SNR), contraste-ruído (CNR) e uniformidade de saturação de gordura para as mesmas estruturas a analisar e nas distintas sequências. Resultados – Verificou-se que a técnica de supressão de gordura Dixon apresenta resultados quantitativos e qualitativos superiores à técnica SPAIR. Conclusões – Recomenda-se a utilização da técnica Dixon para saturação de gordura nas sequências de estudo dinâmico com agente de contraste, especificamente nos estudos de RM mamária.

Contributo da radioterapia na melhoria dos cuidados de saúde no Centro Nacional de Oncologia - Luanda

Mestrado em Radiações Aplicadas às Tecnologias da Saúde - Área de especialização: Terapia com Radiações

Macrophages as biomarkers in BCG treatment response in bladder cancer

Bladder cancer is a common urologic cancer and the majority has origin in the urothelium. Patients with intermediate and high risk of recurrence/progression bladder cancer are treated with intravesical instillation with Bacillus Calmette-Guérin, however, approximately 30% of patients do not respond to treatment. At the moment, there are no accepted biomarkers do predict treatment outcome and an early identification of patients better served by alternative therapeutics. The treatment initiates a cascade of cytokines responsible by recruiting macrophages to the tumor site that have been shown to influence treatment outcome. Effective BCG therapy needs precise activation of the Th1 immune pathway associated with M1 polarized macrophages. However, tumor-associated macrophages (TAMs) often assume an immunoregulatory M2 phenotype, either immunosuppressive or angiogenic, that interfere in different ways with the BCG induced antitumor immune response. The M2 macrophage is influenced by different microenvironments in the stroma and the tumor. In particular, the degree of hypoxia in the tumors is responsible by the recruitment and differentiation of macrophages into the M2 angiogenic phenotype, suggested to be associated with the response to treatment. Nevertheless, neither the macrophage phenotypes present nor the influence of localization and hypoxia have been addressed in previous studies. Therefore, this work devoted to study the influence of TAMs, in particular of the M2 phenotype taking into account their localization (stroma or tumor) and the degree of hypoxia in the tumor (low or high) in BCG treatment outcome. The study included 99 bladder cancer patients treated with BCG. Tumors resected prior to treatment were evaluated using immunohistochemistry for CD68 and CD163 antigens, which identify a lineage macrophage marker and a M2-polarized specific cell surface receptor, respectively. Tumor hypoxia was evaluated based on HIF-1α expression. As a main finding it was observed that a high predominance of CD163+ macrophage counts in the stroma of tumors under low hypoxia was associated with BCG immunotherapy failure, possibly due to its immunosuppressive phenotype. This study further reinforces the importance the tumor microenvironment in the modulation of BCG responses.

Survival of a cohort of women with cervical cancer diagnosed in a Brazilian cancer center

OBJECTIVE: To assess overall survival of women with cervical cancer and describe prognostic factors associated. METHODS: A total of 3,341 cases of invasive cervical cancer diagnosed at the Brazilian Cancer Institute, Rio de Janeiro, southeastern Brazil, between 1999 and 2004 were selected. Clinical and pathological characteristics and follow-up data were collected. There were performed a survival analysis using Kaplan-Meier curves and a multivariate analysis through Cox model. RESULTS: Of all cases analyzed, 68.3% had locally advanced disease at the time of diagnosis. The 5-year overall survival was 48%. After multivariate analysis, tumor staging at diagnosis was the single variable significantly associated with prognosis (p<0.001). There was seen a dose-response relationship between mortality and clinical staging, ranging from 27.8 to 749.6 per 1,000 cases-year in women stage I and IV, respectively. CONCLUSIONS: The study showed that early detection through prevention programs is crucial to increase cervical cancer survival.

Helical tomotherapy versus 3D conformal radiotherapy in dosimetric planning for patients with localized prostate cancer

Radiotherapy is one of the therapeutics selected for localized prostate cancer, in cases where the tumour is confined to the prostate, penetrates the prostatic capsule or has reached the seminal vesicles (T1 to T3 stages). The radiation therapy can be administered through various modalities, being historically used the 3D conformal radiotherapy (3DCRT). Other modality of radiation administration is the intensity modulated radiotherapy (IMRT), that allows an increase of the total dose through modulation of the treatment beams, enabling a reduction in toxicity. One way to administer IMRT is through helical tomotherapy (TH). With this study we intent to analyze the advantages of helical tomotherapy when compared with 3DCRT, by evaluating the doses in the organs at risk (OAR) and planning target volumes (PTV).