Controle de qualidade em rastreamento mamográfico no Brasil: experiência doHospital de Câncer de Barretos / Quality control in mammographic breast cancer screening in Brazil: the Barretos Cancer Hospital experience

O rastreamento mamográfico tem potencial de reduzir o estádio no momento do diagnóstico e, portanto, reduzir a mortalidade por câncer de mama. Cada programa deve estar atrelado a serviços de referência no diagnóstico e no tratamento específico da doença. Os resultados podem ser avaliados conforme indicadores de qualidade, descritos previamente por especialistas, tais como nas orientações da European Breast Cancer Network (EBCN). Parte dos indicadores propostos pela EBCN puderam ser adequadamente analisados nas mulheres com câncer de mama detectado pelo programa de rastreamento mamográfico do Hospital de Câncer de Barretos. A intenção foi detectar falhas, avaliar resultados e propor melhorias ao programa. Alguns desses indicadores, incluindo os relacionados ao diagnóstico, a análise anatomopatológica e o tratamento cirúrgico, foram descritos neste artigo e estiveram alinhados aos recomendados pela EBCN. Isto caracteriza a qualidade de um serviço de mastologia terciário, dedicado no tratamento multidisciplinar do câncer de mama. Entretanto, os intervalos de tempo necessitam ser adaptados à realidade nacional, muito provavelmente, em virtude das características sociais brasileiras. Alguns aspectos principais foram citados, para que futuros programas de rastreamento possam delinear a análise do seu programa de qualidade.

Mammographic screening has the potential to reduce the stage at diagnosis, and thus reduce mortality from breast cancer. Each program should be connected to reference departments in the diagnosis and treatment of breast cancer. The results of a mammographic screening program can be evaluated by means of indicators of quality, previously described by experts such as the guidelines of the European Breast Cancer Network (EBCN). Part of the indicators proposed by EBCN could be properly analyzed in women with breast cancer detected by the mammographic screening program of Barretos Cancer Hospital. The intention was to detect problems, evaluate results, and propose improvements to the program. Some of these indicators, including those related to the diagnosis, pathologic analysis and surgical treatment, are described in this article, and are aligned to the recommended by EBCN. These results reflect the quality of a tertiary breast surgery department dedicated to the multidisciplinary approach of breast cancer. However, the time intervals need to be adapted to the national reality, most likely due to the brazilian social aspects. Some key points were mentioned, in order to assist future screening programs in developing countries to outline the analysis of their quality program.

The value of a tumor bank in the development of cancer research in Brazil: 13 years of experience at the a C camargo hospital.

This article discusses the importance of biobanking to health research advancement in developing countries by analyzing the impact of the establishment of a tumor bank at the A C Camargo Hospital, a cancer care and research center located in Sao Paulo, Brazil. For the past 13 years, the human biological samples provided by the tumor bank have been used by investigators to study various types of cancer. We analyze the impact of biobanking in the overall quality of research projects performed at our institution. We also summarize the main findings of these investigations focusing on breast, prostate, head-neck, and gastroesophageal tumors, as well as the lessons learned over these years. We conclude that biobanking should be part of the strategy employed by scientists and research institutions dedicated to the study of human diseases.

Poly (A)+ transcriptome assessment of ERBB2-induced alterations in breast cell lines.

We report the first quantitative and qualitative analysis of the poly (A)⁺ transcriptome of two human mammary cell lines, differentially expressing (human epidermal growth factor receptor) an oncogene over-expressed in approximately 25% of human breast tumors. Full-length cDNA populations from the two cell lines were digested enzymatically, individually tagged according to a customized method for library construction, and simultaneously sequenced by the use of the Titanium 454-Roche-platform. Comprehensive bioinformatics analysis followed by experimental validation confirmed novel genes, splicing variants, single nucleotide polymorphisms, and gene fusions indicated by RNA-seq data from both samples. Moreover, comparative analysis showed enrichment in alternative events, especially in the exon usage category, in ERBB2 over-expressing cells, data indicating regulation of alternative splicing mediated by the oncogene. Alterations in expression levels of genes, such as LOX, ATP5L, GALNT3, and MME revealed by large-scale sequencing were confirmed between cell lines as well as in tumor specimens with different ERBB2 backgrounds. This approach was shown to be suitable for structural, quantitative, and qualitative assessment of complex transcriptomes and revealed new events mediated by ERBB2 overexpression, in addition to potential molecular targets for breast cancer that are driven by this oncogene.

Detailed haplotype analysis at the TP53 locus in p.R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect.

Due to patterns of migration, selection, and population expansion, founder effects are common among humans. In Southern Brazil, a recurrent TP53 mutation, p.R337H, is detected in families with cancer predisposition. We have used whole locus resequencing and high-density single nucleotide polymorphism (SNP) genotyping to refine TP53 locus haplotype definitions. Haplotyping of 12 unrelated p.R337H carriers using a set of 29 tag SNPs, revealed that all subjects carried the same haplotype, and presence of the mutation on this haplotype was confirmed by allele-specific PCR. The probability that this haplotype occurs independently in all index cases was of 3.1x10(-9), demonstrating a founder effect. Analysis of the patterns of 103 tumors diagnosed in 12 families showed that the presence of p.R337H is associated with multiple cancers of the Li-Fraumeni Syndrome (LFS) spectrum, with relatively low penetrance before the age of 30 but a lifetime risk comparable to classical LFS. The p.R337H families are mostly distributed along a road axis historically known as the main route used by merchants of Portuguese origin in the XVIII and XIX century. This historical circumstance and the relatively low penetrance before the age of 30 may have contributed to the maintenance of this pathogenic mutation in a large, open population.

PrPc on the road: trafficking of the cellular prion protein.

The glycosylphosphatidylinositol (GPI)-anchored cellular prion protein (PrPc) has a fundamental role in prion diseases. Intracellular trafficking of PrPc is important in the generation of protease resistant PrP species but little is known of how endocytosis affects PrPc function. Here, we discuss recent experiments that have illuminated how PrPc is internalized and what are the possible destinations taken by the protein. Contrary to what would be expected for a GPI-anchored protein there is increasing evidence that clathrin-mediated endocytosis and classical endocytic organelles participate in PrPc trafficking. Moreover, the N-terminal domain of PrPc may be involved in sorting events that can direct the protein during its intracellular journey. Indeed, the concept that the GPI-anchor determines PrPc trafficking has been challenged. Cellular signaling can be triggered or be regulated by PrPc and we suggest that endocytosis of PrPc may influence signaling in several ways. Definition of the processes that participate in PrPc endocytosis and intracellular trafficking can have a major impact on our understanding of the mechanisms involved in PrPc function and conversion to protease resistant conformations.

The biology of the cellular prion protein.

Prions are the etiological agents for infectious degenerative encephalopaties acting by inducing conformational changes in the cellular prion protein (PrPc), which is a cell membrane GPI anchored glycoprotein. Besides its conservation among species and expression in most tissues, and in particular, in high levels in the nervous system, the role for cellular prion protein remained obscure for some time. Initial skepticism about such a role was mainly due to the absence of a gross phenotype alteration in cellular prion protein null mice. In the last few years, some possible biological functions for cellular prion protein have been described. Copper binds to the molecule and the resulting complex may be responsible for cell protection against oxidative stress. Cellular prion protein is also a high-affinity ligand for laminin, and induces neuronal cell adhesion, neurite extension and maintenance. The binding site resides in a carboxy-terminal peptide of the gamma-1 chain, which is very conserved among all laminin types, indicating that this interaction may be relevant in other tissues besides the brain. Moreover, cellular prion protein association with a peptide that mimics a putative ligand at the cell surface, p66, triggers neuroprotective signals through a cAMP/PKA-dependent pathway. Since PrPc recycles from membrane to an intracellular compartment, which is induced by copper binding, it is also possible that the internalization mechanism allows switching off elicited signals.

Galectin-3 modulates carbohydrate-dependent thymocyte interactions with the thymic microenvironment.

The process of thymocyte differentiation occurs within the context of the thymic microenvironment, in which T cell precursors interact with thymic microenvironmental cells and extracellular matrix. Here we studied the expression of galectin-3, a beta-galactoside binding lectin, in the thymus of young adult mice. Galectin-3 was found mainly in the medulla and to a lesser extent in the cortex. We further showed that distinct microenvironmental elements, such as thymic epithelial cells, the epithelial component of thymic nurse complexes and phagocytic cells of the thymic reticulum produce, secrete and accumulate galectin-3 on the cell surface. Functionally, galectin-3-enriched medium inhibited in vitro thymocyte interactions with thymic microenvironmental cells, accelerated the release of thymocytes from thymic nurse cells and inhibited the reconstitution of these lymphoepithelial complexes. These effects were blocked by exogenous lactose (Galbeta1-4Glc), but not melibiose (Galalpha1-6Glc), and by a monospecific anti-galectin-3 antibody. Recombinant galectin-3 also inhibited thymocyte/thymic epithelial cell interactions. Our data indicate that intrathymically produced galectin-3 disrupts thymocyte/microenvironmental cell interactions, thus acting as a de-adhesion molecule.

Nova variante do gene do prionio em uma familia psicotica / New variant of the prion protein gene in a psychotic family

As doencas de prionio sao caracterizadas pelo acumulo no cerebro da PrP-sc, uma proteina prionica infectante e protease resistente. A Prp-sc difere da PrP-c, de funcao desconhecida, apenas em termos conformacionais. As doencas humanas de prionio conhecidas sao Kuru, Gertsman Straussler (GSS), Insonia Familiar Fatal(IFF) e doencas de Creutzfeldt-Jakob (CJD)...

Towards molecular oncology

A amplificacao do oncogenese e a perda de heterozigose dos genes supressores de tumores tem relacao com o prognostico em uma variedade de tumores humanos. A deteccao de mutacoes nos genes supressores de tumores foi reconhecida para servir como determinante de fator de risco nos adenocarcinomas gastrintestinais.