The RET polymorphic allele S836S is associated with early metastatic disease in patients with hereditary or sporadic medullary thyroid carcinoma.

The possible role of RET variants in modifying the natural course of medullary thyroid carcinoma (MTC) is still a matter of debate. Here, we investigate whether the RET variants L769L, S836S, and G691S/S904S influence disease presentation in hereditary or sporadic MTC patients. One hundred and two patients with hereditary MTC and 81 patients with sporadic MTC attending our institution were evaluated. The frequencies of RET polymorphisms in hereditary MTC were as follows: L769L, 17.3%; S836S, 7.95%; and S904S/G691S, 18.2%. No associations were observed between these polymorphisms and pheochromocytoma, hyperparathyroidism, lymph node, or distant metastasis. However, patients harboring the S836S variant were younger than those without this allele (17±8.2 vs 28.6±14.4 years, P=0.01), suggesting that these patients had metastases at a young age. Accordingly, the cumulative frequency of local and/or distant metastases as estimated by Kaplan-Meier curves showed that lymph node and distant metastases occurred earlier in patients harboring the S836S variant (P=0.003 and P=0.026 respectively). The S836S allele frequency was higher in sporadic MTC patients than in controls (10.5 vs 3.1%, P=0.01). Individuals harboring the S836S variant were younger (38.6±13.3 vs 48.5±16.7 years, P=0.02) and showed a higher percentage of lymph node and distant metastases (P=0.02 and P=0.04 respectively). Kaplan-Meier estimates of lymph node and distant metastases yielded distinct curves for patients with or without the S836S allele (P=0.002 and P=0.001 respectively). Additional analyses using a COX regression model showed that the S836S variant was independently associated with metastatic disease (hazard ratio 2.82 (95% confidence interval 1.51-5.26), P=0.001). In conclusion, the RET S836S variant is associated with early onset and increased risk for metastatic disease in patients with hereditary or sporadic MTC.

Clinical and oncological features of children and young adults with multiple endocrine neoplasia type 2A.

BACKGROUND: RET genotype analysis allows identification of asymptomatic carriers at risk of developing medullary thyroid carcinoma (MTC). However, there is still controversy regarding the ideal timing and extent of prophylactic thyroidectomy due to the wide spectrum of clinical presentation. Surveillance of a large number of young patients is crucial to advance our understanding of the natural course of the disease. This study aimed to describe the clinical presentation, oncological features, and treatment outcome of children and young adults harboring RET mutations followed at our institution from 1997 to 2007. METHODS: Forty-one individuals aged < or =25 years from 17 independent multiple endocrine neoplasia type 2A kindred were studied. Twenty-one individuals presented with thyroid nodules at diagnosis, and 20 were disease free at physical examination. RESULTS: Preoperative basal calcitonin levels were elevated in 85.7% of patients with clinical disease and in 54.5% of asymptomatic carriers. Thyroid ultrasonography (US) showed one or more nodules in 69.0% of the patients. A positive correlation between age at surgery and tumor-node-metastasis (TNM) stages was observed (p < 0.001). None of the patients under 15 years of age presented lymph node or distant metastasis. After a follow-up of 4.4 +/- 1.4 years all asymptomatic patients were disease free based on physical examination, cervical US, and undetectable serum calcitonin levels. In the group of patients with clinical disease, 47.6% have persistent disease (follow-up of 12.0 +/- 5.9 years). Indeed, palpable thyroid nodule at diagnosis was significantly associated with persistent disease (p < 0.001, odds ratio [OR] 1.9, 95% confidence interval [CI 95%] 1.27-2.87). Of note, none of the patients who presented lymph node metastasis at diagnosis were cured by surgical intervention (p < 0.001, OR 5.0, CI 95% 1.45-17.0). CONCLUSION: Our data show a time-dependent MTC progression. The presence of a palpable thyroid nodule and lymph node metastasis at diagnosis was associated with persistent or recurrent disease after surgical procedure.

[Establishment of a collaborative work team management for type 1 diabetes mellitus patient]. / Organização de um serviço de assistência ao paciente com diabetes melito tipo 1.

This article will provide the necessary information to establish a childhood and adolescence management center that would promote the integration and coordination of interdisciplinary members as healthcare teams. It will also show how Instituto da Criança com Diabetes from Rio Grande do Sul (ICD) was built, structured and how it works. The aim of this program is to decrease the frequency of hospitalization in acute cases, to decrease chronic complications and to qualify human resources. So far 1315 outpatients and day-care hospital patients, mostly type 1 diabetes, have been seeing free of charge in Public Health Service (PHS), in a partnership with Grupo Hospitalar Conceição (GHC) and the Ministry of Health. Among other activities an educational program (consisting of 45-minute daily classes) is given to the patient and his family. From 2004 to 2007 it could be seen a decrease from 7,5% to 2,7% in the diabetes related hospitalization concerning these patients. Clinical guidelines followed by the interdisciplinary ICD team will also be presented in this essay.

[How the continuous glucose monitoring system can contribute to HbA1c interpretation in type 1 diabetes mellitus?]. / Como a monitorização contínua de glicose subcutânea pode colaborar na interpretação dos valores da HbA1c no diabetes melito tipo 1?

The aim of the present study is a literature revision of the contribution of continuous glucose monitoring system (CGMS) in the interpretation of HbA1c levels in type 1 diabetes (T1DM). We performed a revision of the efficacy, benefits, interpretation of methods and experience with this system. The CGMS could be useful in T1DM patients that present great glycemic variability or severe hypoglycemia (mainly nocturnal) and postprandial hyperglycemia. The identification of altered patterns or the glycemic variability allows therapeutic adjustment and improvement of the metabolic control. CGMS is a safe method with a rare occurrence of side effects and it is well-tolerated by patients. The extension of the procedure for more days, over the 72h period recommended by the standard test, allows us to get important data to changes and adjustments on the insulin management of the type 1 diabetes mellitus patients.

[Endothelial dysfunction in type 1 diabetes]. / Disfunção endotelial no diabetes melito tipo 1.

Vascular complications are the main cause of mortality and morbidity in diabetes. Mechanisms involved in the development of micro and macrovascular disease are complex and partially understood, but invariably begin as a dysfunctional endothelium. Nitric oxide is an important regulator of endothelial function and the impairment of its activity is determinant of the endothelial dysfunction. In type 1 diabetes, many factors like acute, chronic and post-prandial hyperglycemia, as well as the duration of diabetes or autonomic neuropathy and microalbuminuria are associated to endothelial dysfunction. Oxidative stress, polyol pathway activation, protein kinase C activation and the presence of advanced glycation end-products are potential mechanisms involved in the development of endothelial dysfunction. Early detection of endothelial dysfunction has prognostic value for the development of vascular complications and may be important in strategies for primary prevention of cardiovascular endpoints in type 1 diabetes.

Como a monitorização contínua de glicose subcutânea pode colaborar na interpretação dos valores da HbA1c no diabetes melito tipo 1?: [revisão] / How the continuous glucose monitoring system can contribute to HbA1c interpretation in type 1 diabetes mellitus?: [review]

O objetivo desta revisão é avaliar como o sistema de monitorização contínua de glicose subcutânea (CGMS®) pode colaborar na interpretação dos valores da hemoglobina glicada (A1c) no diabetes melito tipo 1. Foi realizada uma revisão bibliográfica dos benefícios, dos métodos, da interpretação e da experiência com CGMS®. A utilização de sensores contínuos pode ser útil na avaliação de pacientes com diabetes melito com oscilações glicêmicas, hipoglicemias graves, especialmente as noturnas, e hiperglicemias pós-prandiais. A identificação de padrões glicêmicos alterados permite ajustes terapêuticos e melhora do controle metabólico. O CGMS® é um procedimento de fácil utilização, com efeitos adversos de pequena intensidade e boa tolerância pelos pacientes. Embora o fabricante preconize um período de utilização de até três dias, observa-se que o prolongamento do teste por mais dias permite a obtenção de dados que auxiliam em mudanças terapêuticas superiores às realizadas com os registros do tempo convencional.

The aim of the present study is a literature revision of the contribution of continuous glucose monitoring system (CGMS®) in the interpretation of HbA1c levels in type 1 diabetes (T1DM). We performed a revision of the efficacy, benefits, interpretation of methods and experience with this system. The CGMS® could be useful in T1DM patients that present great glycemic variability or severe hypoglycemia (mainly nocturnal) and postprandial hyperglycemia. The identification of altered patterns or the glycemic variability allows therapeutic adjustment and improvement of the metabolic control. CGMS® is a safe method with a rare occurrence of side effects and it is well-tolerated by patients. The extension of the procedure for more days, over the 72h period recommended by the standard test, allows us to get important data to changes and adjustments on the insulin management of the type 1 diabetes mellitus patients.

Disfunção endotelial no diabetes melito tipo 1: [revisão] / Endothelial dysfunction in type 1 diabetes: [review]

As complicações vasculares são a maior causa de morbimortalidade em pacientes com diabetes. Os mecanismos envolvidos no desenvolvimento das doenças micro e macrovasculares são complexos e parcialmente compreendidos, mas se iniciam invariavelmente por um endotélio que se torna disfuncionado. O óxido nítrico é um importante regulador da função endotelial e o comprometimento da sua atividade é fator determinante para a disfunção endotelial (DE). No diabetes tipo 1, diversos fatores, como a hiperglicemia aguda, mau controle glicêmico crônico, tempo de diagnóstico e presença de neuropatia autonômica ou microalbuminúria estão associados à DE. Tanto o estresse oxidativo, como a ativação da via dos polóis, via da proteína quinase C e formação dos produtos avançados de glicação não-enzimática são potenciais mecanismos patogenéticos da DE. A detecção precoce da disfunção endotelial tem valor prognóstico para o desenvolvimento de complicações vasculares e pode ser importante em estratégias de prevenção primária de eventos cardiovasculares no diabetes tipo 1.

Vascular complications are the main cause of mortality and morbidity in diabetes. Mechanisms involved in the development of micro and macrovascular disease are complex and partially understood, but invariably begin as a dysfunctional endothelium. Nitric oxide is an important regulator of endothelial function and the impairment of its activity is determinant of the endothelial dysfunction. In type 1 diabetes, many factors like acute, chronic and post-prandial hyperglycemia, as well as the duration of diabetes or autonomic neuropathy and microalbuminuria are associated to endothelial dysfunction. Oxidative stress, polyol pathway activation, protein kinase C activation and the presence of advanced glycation end-products are potential mechanisms involved in the development of endothelial dysfunction. Early detection of endothelial dysfunction has prognostic value for the development of vascular complications and may be important in strategies for primary prevention of cardiovascular endpoints in type 1 diabetes.

Organização de um serviço de assistência ao paciente com diabetes melito tipo 1 / Establishment of a collaborative work team management for type 1 diabetes mellitus patient

Neste artigo são apresentadas as bases para a organização de um serviço especializado em diabetes na infância e na adolescência. É mostrado o modo como foi implementado o Instituto da Criança com Diabetes do Rio Grande do Sul (ICD) e a esquematização de seu trabalho. Seus objetivos são: diminuir hospitalizações por situações agudas, diminuir a freqüência de complicações crônicas e capacitar recursos humanos. São atendidos, em regime ambulatorial e de hospital-dia, 1.315 pacientes, majoritariamente diabetes melito tipo 1, de maneira gratuita, pelo Sistema Único de Saúde (SUS), por meio de convênio com o Grupo Hospitalar Conceição, Ministério da Saúde. Um programa educativo diário é realizado, com aulas de 45 minutos de duração, que fazem parte da atenção ao paciente e à sua família. Mostra-se uma diminuição das internações hospitalares, de 2004 a 2007, de 7,5 por cento para 2,7 por cento. Também são apresentados os diversos esquemas terapêuticos seguidos pela equipe interdisciplinar do instituto no atendimento às diferentes faixas etárias.

This article will provide the necessary information to establish a childhood and adolescence management center that would promote the integration and coordination of interdisciplinary members as healthcare teams. It will also show how Instituto da Criança com Diabetes from Rio Grande do Sul (ICD) was built, structured and how it works. The aim of this program is to decrease the frequency of hospitalization in acute cases, to decrease chronic complications and to qualify human resources. So far 1315 outpatients and day-care hospital patients, mostly type 1 diabetes, have been seeing free of chargein Public Health Service (PHS), in a partnership with Grupo Hospitalar Conceição (GHC) and the Ministry of Health. Among other activities an educational program (consisting of 45-minute daily classes) is given to the patient and his family. From 2004 to 2007 it could be seen a decrease from 7,5 percent to 2,7 percent in the diabetes related hospitalization concerning these patients. Clinical guidelines followed by the interdisciplinary ICD team will also be presented in this essay.

[Medullary thyroid carcinoma: clinical and oncological features and treatment]. / Carcinoma medular de tireóide: aspectos moleculares, clínico-oncológicos e terapêuticos.

Medullary carcinoma of the thyroid (MTC) may be sporadic or may occur on a hereditary basis. Hereditary MTC can occur either alone -- familial MTC (FMTC) -- or as the thyroid manifestation of multiple endocrine neoplasia type 2 (MEN 2) syndromes (MEN 2A and MEN 2B) or other forms. Germ-line mutations in RET cause MEN 2. Genetic testing, now available, forms the basis for MTC screening procedures. In the past few years, several genotype-phenotype correlations have focused on the relationship between specific mutations and different MEN 2 syndrome variants. Differences in dimerization induction intensities are a reasonable explanation for the phenotypes resulting from mutations of the different cysteines. Here we described the molecular mechanisms, diagnose and treatment as well as our experience on the management of this rare form of thyroid cancer.

Carcinoma medular de tireóide: aspectos moleculares, clínico-oncológicos e terapêuticos / Medullary thyroid carcinoma: clinical and oncological features and treatment

O carcinoma medular de tireóide (CMT) pode ocorrer na forma esporádica ou familiar. O CMT hereditário é parte das síndromes de neoplasia endócrina múltipla (NEM) 2A e 2B, carcinoma medular de tireóide familiar (CMTF) ou outras formas. Mutações de linhagem germinativa do proto-oncogene RET causam a forma hereditária da neoplasia e os testes genéticos atualmente disponíveis formam a base para o manejo adequado da hereditariedade do tumor, visto que o diagnóstico precoce melhora significativamente o prognóstico no indivíduo afetado e nos carreadores. Nos últimos anos, vários estudos têm demonstrado uma correlação entre mutações codon-específica do RET e os diferentes fenótipos da NEM 2A, que pode, em parte, ser explicada por diferenças na intensidade da indução da dimerização do receptor. No presente artigo, revisamos os avanços nos mecanismos moleculares, diagnóstico e tratamento, bem como relatamos a nossa experiência no manejo dessa forma rara de neoplasia tireoidiana.

RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome.

Since the establishment of a protocol for molecular analysis of hereditary medullary thyroid carcinoma (MTC) in southern Brazil, in 1997, 17 independent families with RET germline mutation have been identified. Because neither molecular diagnosis nor the pentagastrin test were available before the establishment of this protocol, we had the opportunity to observe a large number of patients in whom the disease has evolved naturally without medical intervention, namely prophylactic thyroidectomy. We observed a wide spectrum in terms of clinical presentation and natural course of the disease even among genetically related individuals. Sixty-nine individuals from 12 different families presented a codon 634 mutation, the most prevailing missense mutation in our series. The specific mutations identified were C634Y (n = 49), C634R (n = 13), and C634W (n = 7). Individuals with the C634R mutation presented significantly more distant metastases at diagnosis than subjects with the C634Y or C634W mutations (54.5% vs. 19.4% vs. 14.3%, respectively, P = 0.03). Further analysis of the estimated cumulative frequency of lymph node and/or distant metastases by Kaplan-Meier curves showed that the appearance of lymph nodes and metastases occurred later in patients with C634Y than in those with C634R (P = 0.001). Our results suggest that specific nucleotide and amino acid exchanges at codon 634 might have a direct impact on tumor aggressiveness in MEN 2A syndrome.