Thyroid Diseases: Maciel RM

Maia AL, Ward LS, Carvalho GA, Graf H, Maciel RM, Maciel LM, Rosário PW, Vaisman M. · Departamento de Tireóide, Sociedade Brasileira de Endocrinologia e Metabologia, Serviço de Endocrinologia, Hospital de Clínicas de Porto Alegre, Universidad Federal do Rio Grande do Sul, RS, Brazil. · Arq Bras Endocrinol Metabol. · Pubmed #17891253 links to  free full text

Abstract: Thyroid nodules are a common manifestation of thyroid diseases. It is estimated that approximately 10% of adults have palpable thyroid nodules with the frequency increasing throughout life. The major concern on nodule evaluation is the risk of malignancy (5-10%). Differentiated thyroid carcinoma accounts for 90% of all thyroid malignant neoplasias. Although most patients with cancer have a favorable outcome, some individuals present an aggressive form of the disease and poor prognostic despite recent advances in diagnosis and treatment. Here, a set of clinical guidelines for the evaluation and management of patients with thyroid nodules or differentiated thyroid cancer was developed through consensus by 8 member of the Department of Thyroid, Sociedade Brasileira de Endocrinologia e Metabologia. The participants are from different reference medical centers within Brazil, to reflect different practice patterns. Each committee participant was initially assigned to write a section of the document and to submit it to the chairperson, who revised and assembled the sections into a complete draft document, which was then circulated among all committee members for further revision. All committee members further revised and refined the document. The guidelines were developed based on the expert opinion of the committee participants, as well as on previously published information.

Haugen BR, Cooper DS, Emerson CH, Luster M, Maciel RM, Biscolla RP, Mazzaferri EL, Medeiros-Neto G, Reiners C, Robbins RJ, Robinson BG, Schlumberger M, Yamashita S, Pacini F. · No affiliation provided · Thyroid. · Pubmed #18630995 links to  free full text

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Maciel RM. · No affiliation provided · Arq Bras Endocrinol Metabol. · Pubmed #15761504 links to  free full text

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de Paola AV, Cirenza C, Maciel RM. · No affiliation provided · Arq Bras Cardiol. · Pubmed #15257367 links to  free full text

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Maciel RM. · Departamento de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil. · Arq Bras Endocrinol Metabol. · Pubmed #17891252 links to  free full text

Abstract: The author reviews the literature on the new assays for serum thyroglobulin (sTg) presenting lower functional sensitivity and demonstrates that its use, whilst the patients are taking L-T4, presents better results than sTg following TSH stimulation in the follow-up of patients with differentiated thyroid carcinoma. Therefore, he suggests a revision on the guidelines for the follow-up of these patients (developed when the available assays present a sensitivity of 1 ng/mL), proposing the use of sTg assays with functional sensitivity of 0.1-0.2 ng/mL with the patients on L-T4 treatment instead of sTg stimulated by TSH.

Rosário PW, Tavares Júnior WC, Biscolla RP, Purisch S, Maciel RM. · Serviço de Endocrinologia, Santa Casa de Belo Horizonte, Belo Horizonte, MG. · Arq Bras Endocrinol Metabol. · Pubmed #17684621 links to  free full text

Abstract: Neck ultrasonography (US) is recommended for the assessment of all patients with thyroid carcinoma after initial therapy, since even low-risk patients with undetectable stimulated thyroglobulin (Tg) may present cervical metastases. In the case of these metastases, US is the most sensitive method and is superior to whole-body 131I scanning. Cervical lymph nodes with a diameter > 5 mm presenting thin calcifications and/or cystic degeneration have almost always a malignant etiology. In the absence of these characteristics, a round shape and the absence of an echogenic hilum are "suspicious" findings, whereas elongated lymph nodes with a visible echogenic hilum are considered benign. Doppler flow analysis helps with the differential diagnosis, usually revealing peripheral or mixed hypervascularization in malignant cases. In the presence of "suspicious" lymph nodes upon US, fine-needle aspiration cytology and measurement of Tg in the needle lavage fluid are useful and complementary exams for the definition of the etiology, with the combination of the two methods showing elevated sensitivity and 100% specificity. US is also useful before thyroidectomy, even contributing in some cases to modify the surgical planning, and before ablation for the measurement of thyroid remnants and detection of persistent lymph node metastases. Another application of this imaging method is to guide the injection of ethanol (sclerotherapy) or the introduction of electrodes for radiofrequency ablation in selected cases of isolated lymph node metastases as an alternative to traditional therapies.

Maciel RM, Kimura ET, Cerutti JM. · Departamento de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP. · Arq Bras Endocrinol Metabol. · Pubmed #16444351 links to  free full text

Abstract: Differentiated thyroid cancers (papillary--PTC and follicular--FTC) are the most common endocrine malignancies. The recent progresses in the understanding of PTC and FTC pathogenesis are summarized in this review. In PTC, a single mutation of BRAF (the gene for the B-type Raf kinase) (V600E) is responsible for the disease in 40-50% of patients, especially in older people and is associated with a poorer clinicopathological outcome. Due to these characteristics, its use as a specific diagnostic and prognostic marker for PTC in cytological specimens is being implemented. Another important cause of PTC is rearrangements of the RET tyrosine kinase receptor (RET/PTC), which represent a recombination of the promoter and N-terminal domain of a partner gene with the C-terminal region of the RET gene, resulting in a chimeric gene with a protein product containing a constitutively activated RET tyrosine kinase, responsible for 20-30% patients, specially the younger or after radiation. The pathogenesis of FTC is less understood. A chromosomal translocation between the transcription factor PAX8 and the peroxisome proliferator-activated receptorgamma (PPARgamma) occurs in 30-50% of patients; however, the presence of PAX8-PPARgamma is also demonstrated in follicular adenomas. Therefore, there is no complete evidence that PAX8-PPARgamma is the cause of FTC. Another finding in FTC is mutations on the RAS gene, which excludes PAX8-PPARgamma rearrangements. Several genes, as TRgamma, PTEN, PKAR1A, DDIT3, ARG2, ITM1 and C1orf24--some discovered by techniques of differential gene expression--, have been recently implicated in the pathogenesis of FTC.

Silva MR, Chiamolera MI, Kasamatsu TS, Cerutti JM, Maciel RM. · Laboratório de Endocrinologia Molecular, Centro de Pesquisas do Genoma J.F. Perez, Departamento de Morfologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP. · Arq Bras Endocrinol Metabol. · Pubmed #15611833 links to  free full text

Abstract: Thyrotoxic hypokalemic periodic paralysis (THPP) is a medical emergency characterized by acute attacks of weakness, hypokalemia, and thyrotoxicosis that resolve with the treatment of hyperthyroidism. Attacks are transient, self-limited, associated with hypokalemia and resemble those of familial hypokalemic periodic paralysis (FHPP), an autosomal dominant neurological channelopathy. This study reviews the clinical features and genetic findings of THPP in 25 Brazilian patients. Most patients had weight loss, taquicardia, goiter, tremor, and ophthalmopathy. Most often attacks arose during the night and recovered spontaneously but some patients evolved to total quadriplegia, and few experienced cardiac arrhythmias. All patients had suppressed TSH and elevated T4 and most had positive anti-thyroid antibodies, indicating autoimmunity thyrotoxic etiology. Potassium was low in all patients during the crisis. Prophylactic potassium therapy has not been shown to prevent attacks; however it was useful for curbing the paralysis during the crisis. We identified the mutation R83H in the KCNE3 gene in one sporadic case, and M58V in the KCNE4 gene in one case with family history. Furthermore, we identified other genetic polymorphisms in the CACNA1S, SCN4A, KCNE1, KCNE2, KCNE1L, KCNJ2, KCNJ8 e KCNJ11 genes. We conclude that THPP is the most common treatable cause of acquired periodic paralysis; therefore, it must be included in the differential diagnosis of acute muscle weakness.

Biscolla RP, Cerutti JM, Maciel RM. · Laboratory of Molecular Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Brazil. · J Clin Endocrinol Metab. · Pubmed #11061512 links to  free full text

Abstract: To investigate whether circulating thyroglobulin (Tg) messenger ribonucleic acid (mRNA) and sodium/iodide symporter (NIS) mRNA transcripts in peripheral blood are valuable in the follow-up of patients with thyroid cancer, we developed highly sensitive nested Tg and NIS mRNA detection assays and compared their accuracy with serum thyroglobulin (sTg) and whole body scan with 131I during the monitoring of 34 patients with well differentiated thyroid carcinoma who had undergone total thyroidectomy (17 of 34 also submitted to thyroid ablation with radioiodine) and were taking T4. Circulating Tg mRNA was found in 13 of 34 patients, 5 of 13 with detectable and 8 of 13 with undetectable sTg. From these 8 patients with undetectable Tg, 6 showed no cervical radioiodine uptake, and 3 presented proven metastatic disease (2 of them positive for antithyroglobulin antibodies). NIS mRNA was detected in 11 of 34 patients, but its measurement did not improve the ability to detect patients with metastases. Overall, identification of metastatic thyroid cancer was better associated with Tg mRNA than with NIS mRNA, sTg, or whole body scan (83% vs. 16.6% vs. 50% vs. 50%; P < 0.001). These data showed that circulating Tg mRNA is not only a more sensitive marker of residual thyroid tissue or thyroid cancer than sTg, particularly in patients during T4 therapy and with positive antithyroglobulin antibodies, but also was more sensitive than NIS mRNA in all patients.

Sgarbi JA, Maciel RM. · Faculdade de Medicina de Marília, Marília, SP, Brazil. · Arq Bras Endocrinol Metabol. · Pubmed #19347180 links to  free full text

Abstract: Autoimmune thyroid disease (AITD) is the most common organ-specific autoimmune disorder affecting 2% to 5% of the population in Western countries. Clinical presentation varies from hyperthyroidism in Graves' Disease to hypothyroidism in Hashimoto's thyroiditis. While the exact etiology of thyroid autoimmunity is not known, interaction between genetic susceptibility and environmental factors appears to be of fundamental importance to initiate the process of thyroid autoimmunity. It has been postulated that 79% of the susceptibility to develop AITD is attributed to genetic factors, while environmental factors contribute to 21%. The identified AITD susceptibility genes include immune-modulating genes, such as the major histocompatibility complex (MHC), cytotoxic T lymphocyte antigen-4 (CTLA-4), CD40 molecule, and protein tyrosine phosphatase-22 (PTPN22), and thyroid-specific genes, including TSH receptor (TSHR) and thyroglobulin (TG). The exact nature of the role environmental factors play in AITD is still not well known, but the involvement of several factors such as iodine diet content, stress, drugs and infections has been reported. However, there is no clear evidence of causality and the mechanisms by which environmental factors trigger thyroid autoimmunity in genetically predisposed individuals remain not fully understood. Knowledge of the precise mechanisms of interaction between environmental factors and genes in inducing thyroid autoimmunity could result in the development of new strategies for prevention and treatment.

Camacho CP, Hoff AO, Lindsey SC, Signorini PS, Valente FO, Oliveira MN, Kunii IS, Biscolla RP, Cerutti JM, Maciel RM. · Department of Medicine, Federal University of São Paulo, SP, Brazil. · Arq Bras Endocrinol Metabol. · Pubmed #19169500 links to  free full text

Abstract: BACKGROUND: The hereditary form of medullary thyroid carcinoma may occur isolated as a familial medullary thyroid carcinoma (FMTC) or as part of Multiple Endocrine Neoplasia 2A (MEN2A) and 2B (MEN2B). MEN2B is a rare syndrome, its phenotype may usually, but not always, be noted by the physician. In the infant none of the MEN2B characteristics are present, except by early gastrointestinal dysfunction caused by intestinal neuromas. When available, genetic analysis confirms the diagnosis and guides pre-operative evaluation and extent of surgery. Here we report four cases of MEN2B in which the late diagnosis had a significant impact in clinical evolution and, potentially, in overall survival. CASE REPORT: We report four cases, 2 men and 2 women, with differences in their phenotypes and with a late diagnosis. The first case has a history of severe gastrointestinal obstruction requiring a surgery intervention two days after his birth. The second told had nodules in the oral mucosa and constipation since childhood. The third case referred a history of constipation from birth until 5 months of life. The fourth has had a history of chronic constipation since childhood. DISCUSSION: New concepts have emerged since the RET oncogene was identified in 1993 as the responsible gene for hereditary medullary thyroid carcinoma. The majority of MEN2B individuals have M918T mutation in the exon 16 of RET, with a few cases having a mutation A883F or the association of V804M with E805K, Y806C or S904C mutations. The consensus classifies the RET mutation in codon 918 as of highest risk and recommends total thyroidectomy and central lymph node dissection until 6 months after birth. A fast and precise diagnosis is essential to reach these goals. The identification of early manifestations such as intestinal ganglioneuromatosis and oral mucosal neuromas should prompt the physician to initiate an investigation for multiple endocrine neoplasia type 2B. CONCLUSION: The diagnosis of MEN2B is very important to allow appropriate investigation of associated diseases and to allow counseling and appropriate screening of relatives for a RET mutation. Even patients with MEN2B, which often have typical physical features, may not be properly recognized and be followed as a sporadic case. Based on this, all suspicious cases of multiple endocrine neoplasia should undergo a molecular genetic test.

Ramos HE, Nesi-França S, Boldarine VT, Pereira RM, Chiamolera MI, Camacho CP, Graf H, de Lacerda L, Carvalho GA, Maciel RM. · Laboratory of Molecular Endocrinology, Division of Endocrinology, Department of Medicine, Federal University of São Paulo , São Paulo, Brazil. · Thyroid. · Pubmed #18976153 No free full text.

Abstract: BACKGROUND: Congenital hypothyroidism (CH) is mainly due to developmental abnormalities leading to thyroid dysgenesis (TD). TD encompasses very distinct morphologic subtypes of disease. This study examined and compared the phenotype in TD variants and searched for genetic alterations in sporadic thyroid hypoplasia (TH), the most misdiagnosed form of CH. This was a longitudinal study over a 14-year period (1990-2004). METHODS: A continuous series of 353 children with TD was identified using thyroid function tests [thyroxine (T4) and TSH], scintigraphy, and ultrasound as diagnostic tools. Individual phenotypes were analyzed in 253 children with TD. Mutations in the most likely candidate genes were studied in 35 cases of TH. RESULTS: The overall birth prevalence of permanent CH was 1:4795. Ectopy represented 37% of all cases of permanent primary CH, dyshormonogenesis 28%, agenesis 24%, hypoplasia 10%, and hemiagenesis 1%. The lowest screening T4 level and the highest TSH level were in the agenetic group, followed by TH. The TH group had an improvement in the thyroid function showing less-severe phenotype with aging. In the molecular analysis, one patient was identified with a mutation in the PAX8 gene (155G>C; R52P); four patients had a heterozygous G>C substitution in position -569; two patients showed a (234C>A; P52T) or (2181C>G; D727E) polymorphic variants of the TSH-R gene; and one patient presented a novel heterozygous nonsynonymous substitution, 293G>A; S98N, in the NKX2.5 gene. CONCLUSIONS: The prevalence of CH was within the previously reported range of 1:3000-4000. Ectopy was the most common etiology. Clinical analysis revealed distinct hormonal patterns in TH subgroup when compared with other variants of TD, with genetic abnormalities identified only in few cases in the TSH-R, PAX8, and NKX2.5 genes.

Esteves RZ, Kasamatsu TS, Kunii IS, Furuzawa GK, Vieira JG, Maciel RM. · Departamento de Medicina, Centro de Ciências da Saúde, Universidade Estadual de Maringá, PR. · Arq Bras Endocrinol Metabol. · Pubmed #18209890 links to  free full text

Abstract: In this study we developed a semi-automated method for the measurement of urinary iodine using firstly ammonium persulfate for digestion of urine followed by estimation of iodine content in the Sandell-Kolthoff reaction, in which iodine acts as a catalyst for the reduction of cerium. This method was validated in the 3rd Brazilian National Survey of iodine deficiency in 1994. We studied 16,803 casual urine samples from schoolchildren of 401 cities and found 4 moderately-deficient towns (Almas, Arraias, and Parana, in the State of Tocantins, and Cocos, in the State of Bahia), and 116 mildly-deficient. This work suggests that despite the salt iodization program, there was some iodine-deficient areas in Brazil in 1994. Recent surveys, involving less cities, are indicating an excess of iodine ingestion. Therefore, in a country of continental dimensions and very heterogeneous in terms of public health, periodical evaluations are necessary to monitor the real situation of iodine nutrition in Brazil. The method developed in this paper is suitable for these surveys.

Biscolla RP, Ikejiri ES, Mamone MC, Nakabashi CC, Andrade VP, Kasamatsu TS, Crispim F, Chiamolera MI, Andreoni DM, Camacho CP, Hojaij FC, Vieira JG, Furlanetto RP, Maciel RM. · Disciplina de Endocrinologia, Departamento de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo. · Arq Bras Endocrinol Metabol. · Pubmed #17546240 links to  free full text

Abstract: The widespread use of neck ultrasonography (US) during the follow-up of patients with papillary thyroid carcinoma (PTC) has led to the discovery of small cervical lymph nodes (LN). Although US has a high sensitivity for diagnosing LN, fine needle aspiration biopsy (FNA) and measurement of thyroglobulin in fine needle aspirates (FNA-Tg) have proven to be invaluable tools. The aim of this study is to determine the sensitivity of the combined use of neck US, FNA biopsy and FNA-Tg for diagnosis of cervical lymph nodes. We have studied 32 patients with 44 LN detected by US, 19 classified as inflammatory and 25 as suspicious. 15 of those 25 suspicious LN had high FNA-Tg (13 of the 15 had positive cytology and 2 indeterminate). All of these 15 LN (11 patients) were proven to be PTC metastasis by histopathology. All 19 inflammatory LN and those 10/25 suspicious LN, had cytology negative for malignancy and undetectable FNA-Tg. We conclude that fine needle aspiration biopsy and FNA-Tg combined with neck US are essential for detecting positive cervical lymph nodes due to its high sensitivity and specificity and it should be considered the standard for investigating locally recurrent disease in patients with PTC.

Stamato FJ, Maciel RM, Manso PG, Wolosker AM, Paiva ER, Lopes AC, Furlanetto RP. · Division of Endocrinology, Department of Medicine, Universidade Federal de São Paulo, Alameda Jaú, 310/91 São Paulo, SP, Brazil CEP 01420-000. · Arq Bras Oftalmol. · Pubmed #17273672 links to  free full text

Abstract: PURPOSE: To investigate if colchicine is valuable in the treatment of Graves' ophthalmopathy (GO), we compared its effect with prednisone in 22 patients during the inflammatory phase of GO. METHODS: All patients, similar in age, sex and smoking habits, were euthyroid for at least 3 months and randomly divided into two groups, one treated with colchicine (1.5 mg/day) and the other treated with prednisone (0.75 mg/kg/day). They were monitored with ophthalmologic assessment (clinical activity score-CAS) and magnetic resonance imaging, using a signal intensity ratio (SIR) of the recti muscles in comparison to the cerebral substantia alba. RESULTS: Amelioration of CAS was seen in 68% of the orbits in both groups. SIR also had a significant reduction after treatment: the initial median of 1.14 in G1 and 1.27 in G2, evolved, after treatment, to 1.07 in G1 and 0.69 in G2. The variation between both groups after treatment was not significant (p=0.22). None of the patients treated with colchicine had side effects; on the other hand, side effects in G2 were weight gain, edema, gastric complaints, hirsutism, weakness, depression, and alterations in blood pressure. CONCLUSION: Colchicine had a beneficial effect on the inflammatory phase of GO without the side effects of prednisone.

Vieira JG, Maciel RM, Hauache OM, Nishida SK, Boelter DM, Pinheiro MF. · Setor de Endocrinologia, Laboratório Fleury, Av. General Waldomiro de Lima 508, 04344-070 São Paulo, SP. · Arq Bras Endocrinol Metabol. · Pubmed #16936984 links to  free full text

Abstract: The laboratory methods usually employed for the measurement of serum TSH present sensitivity and specificity levels, both analytical and clinical, are highly satisfactory. Additionally, the methodologies are quite robust, so that false-positive and false-negative results are rare and unexpected. In this paper we describe two individuals quoted as euthyroid clinically, with no reference to autoimmune diseases, and no reference to the use of exogenous TSH, that presented with normal to extremely high serum TSH levels, depending on the method employed for analysis. In the three tested methods, serial dilution showed that the real TSH levels were between 250 and 300 mUI/L. In both cases the increment in TSH levels were due to the presence of TSH-binding proteins, forming high molecular weight complexes ("macro TSH"), well characterized by gel filtration chromatography on Superdex S-200 column. In one of the patients the binding protein was characterized as being IgG by protein-G binding study. In the other case, protein-G binding as well as anti-IgM binding failed to characterize the protein. These two cases call attention to the importance of the clinical-laboratory correlation and suggest the need that the presence of "macro TSH" must be investigated in patients with unexpectedly high TSH values.

Cerutti JM, Latini FR, Nakabashi C, Delcelo R, Andrade VP, Amadei MJ, Maciel RM, Hojaij FC, Hollis D, Shoemaker J, Riggins GJ. · Department of Neurosurgery, Johns Hopkins University Medical School, Baltimore, Maryland 21231, USA. · Clin Cancer Res. · Pubmed #16740752 links to  free full text

Abstract: PURPOSE: Fine-needle aspiration (FNA) cytology, a standard method for thyroid nodule diagnosis, cannot distinguish between benign follicular thyroid adenoma (FTA) and malignant follicular thyroid carcinoma (FTC). Previously, using expression profiling, we found that a combination of transcript expression levels from DDIT3, ARG2, C1orf24, and ITM1 distinguished between FTA and FTC. The goal of this study was to determine if antibody markers used alone or in combination could accurately distinguish between a wider variety of benign and malignant thyroid lesions in fixed sections and FNA samples. EXPERIMENTAL DESIGN: Immunohistochemistry was done on 27 FTA, 25 FTC, and 75 other benign and malignant thyroid tissue sections using custom antibodies for chromosome 1 open reading frame 24 (C1orf24) and integral membrane protein 1 (ITM1) and commercial antibodies for DNA damage-inducible transcript 3 (DDIT3) and arginase II (ARG2). FNA samples were also tested using the same antibodies. RNA expression was measured by quantitative PCR in 33 thyroid lesions. RESULTS: C1orf24 and ITM1 antibodies had an estimated sensitivity of 1.00 for distinguishing FTA from FTC. For the expanded analysis of all lesions studied, ITM1 had an estimated sensitivity of 1.00 for detecting malignancy. Because all four cancer biomarkers did well, producing overlapping confidence intervals, not one best marker was distinguished. Transcript levels also reliably predicted malignancy, but immunohistochemistry had a higher sensitivity. Malignant cells were easily detected in FNA samples using these markers. CONCLUSIONS: We improved this diagnostic test by adding C1orf24 and ITM1 custom antibodies and showing use on a wider variety of thyroid pathology. We recommend that testing of all four cancer biomarkers now be advanced to larger trials. Use of one or more of these antibodies should improve diagnostic accuracy of suspicious thyroid nodules from both tissue sections and FNA samples.

Guimarães GS, Latini FR, Camacho CP, Maciel RM, Dias-Neto E, Cerutti JM. · Laboratory of Molecular Endocrinology, Department of Medicine, Federal University of São Paulo, Brazil. · Genes Chromosomes Cancer. · Pubmed #16493598 No free full text.

Abstract: Alternative splicing is the differential processing of exon junctions to produce a new transcript variant from one gene. Some aberrant splicing, however, has been shown to be cancer specific. Identification of these specific splice variations will provide important insight into the molecular mechanism of normal cellular physiology as well as the disease processes. To gain knowledge about whether alternative splicing is linked to thyroid tumorigenesis, we used our prediction database to select targets for analysis. Fifteen putatively new alternative splicing isoforms were selected on the basis of their expression in thyroid libraries and/or their origin in genes previously associated with carcinogenesis. Using a set of 66 normal, benign, and malignant thyroid tissue samples, new splicing events were confirmed by RT-PCR for 13 of 15 genes (a validation rate of 87%). In addition, new alternative splicing isoforms not predicted by the system and not previously described in public databases were identified. Five genes (PTPN18, ABI3BP, PFDN5, SULF2, and ST5) presented new and/or additional unpredicted isoforms differentially expressed between malignant and benign or normal thyroid tissues, confirmed by sequencing. PTPN18, ABI3BP, and PFDN5 revealed a statistically significant differential splicing profile. In addition, real-time PCR analysis revealed that expression of an alternative PFDN5 variant was higher in malignant lesions than in benign lesions or normal tissues.

Alves ML, Maciel RM, Kunii I, Iazigi N. · Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, Ribeirão Preto, SP. · Arq Bras Endocrinol Metabol. · Pubmed #16358079 links to  free full text

Abstract: The safest and most efficient way to diagnose congenital hypothyroidism (CH) is through screening programs using serum thyroid stimulating hormone (TSH). CH occurs in one in 1:2,300-1:5,000 births but higher rates are found in iodine-deficient areas. Iodine was measured in the urine of 141 newborns (87 males and 54 females) from Ribeirão Preto to complement the screening program developed by the School of Medicine of Ribeirão Preto (FMRP-USP) and Federal University of São Paulo (UNIFESP). TSH values did not disclose any case of CH, although we have seen an elevated ratio (0.96%) of calls for retests. The iodine urinary levels ranged from 2.1 to 194 microg/l (mean 58.3+/-36.2 microg/l). No differences between the levels of urinary iodine and gender or gestational ages were observed. A negative correlation between urinary iodine and TSH of blood from umbilical cord was found (r= -0.20, p= 0.02).

Arnaldi LA, Borra RC, Maciel RM, Cerutti JM. · Laboratory of Molecular Endocrinology, Division of Endocrinology, Department of Medicine, Federal University of São Paulo, Rua Pedro de Toledo 781-12 andar 04039-032, São Paulo, Brazil. · Thyroid. · Pubmed #15785240 No free full text.

Abstract: To investigate the molecular events involved in the pathogenesis and/or progression of thyroid tumors, we compared the gene expression profiles of three thyroid carcinoma cell lines, which represent major tumor subtypes of thyroid cancer and normal thyroid tissue. Using cDNA array methodology, we investigated the expression of 1807 open reading frame expressed sequence tags (ORESTES), selected from head and neck tumor libraries generated through the Brazilian Human Cancer Project-LICR/FAPESP. We found that 505 transcripts were differentially expressed in the thyroid carcinoma cell lines. Using a more stringent criterion, transcripts underexpressed or overexpressed more than fivefold in 1 of 3 or 3 of 3 carcinoma cell lines, a list of 55 ESTs were detected. Five candidate genes were further validated by quantitative polymerase chain reaction (qPCR) in an independent set of 52 thyroid tumors and 22 matched normal thyroid tissues. DCN was found underexpressed in a high percentage of the follicular thyroid adenomas, follicular thyroid carcinomas, and follicular variant of papillary thyroid carcinomas. DIO1 and DIO2 were underexpressed in nearly all papillary thyroid carcinomas. These genes not only could help to better define a tumor signature for thyroid tumors, but may, in part, also become useful as potential targets for thyroid tumor treatment.

Reis EM, Ojopi EP, Alberto FL, Rahal P, Tsukumo F, Mancini UM, Guimarães GS, Thompson GM, Camacho C, Miracca E, Carvalho AL, Machado AA, Paquola AC, Cerutti JM, da Silva AM, Pereira GG, Valentini SR, Nagai MA, Kowalski LP, Verjovski-Almeida S, Tajara EH, Dias-Neto E, Bengtson MH, Canevari RA, Carazzolle MF, Colin C, Costa FF, Costa MC, Estécio MR, Esteves LI, Federico MH, Guimarães PE, Hackel C, Kimura ET, Leoni SG, Maciel RM, Maistro S, Mangone FR, Massirer KB, Matsuo SE, Nobrega FG, Nóbrega MP, Nunes DN, Nunes F, Pandolfi JR, Pardini MI, Pasini FS, Peres T, Rainho CA, dos Reis PP, Rodrigus-Lisoni FC, Rogatto SR, dos Santos A, dos Santos PC, Sogayar MC, Zanelli CF, Anonymous00309. · Departamento de Bioquímica, Faculdade de Medicina, Universidade de São Paulo, Brazil. · Cancer Res. · Pubmed #15753364 links to  free full text

Abstract: A detailed genome mapping analysis of 213,636 expressed sequence tags (EST) derived from nontumor and tumor tissues of the oral cavity, larynx, pharynx, and thyroid was done. Transcripts matching known human genes were identified; potential new splice variants were flagged and subjected to manual curation, pointing to 788 putatively new alternative splicing isoforms, the majority (75%) being insertion events. A subset of 34 new splicing isoforms (5% of 788 events) was selected and 23 (68%) were confirmed by reverse transcription-PCR and DNA sequencing. Putative new genes were revealed, including six transcripts mapped to well-studied chromosomes such as 22, as well as transcripts that mapped to 253 intergenic regions. In addition, 2,251 noncoding intronic RNAs, eventually involved in transcriptional regulation, were found. A set of 250 candidate markers for loss of heterozygosis or gene amplification was selected by identifying transcripts that mapped to genomic regions previously known to be frequently amplified or deleted in head, neck, and thyroid tumors. Three of these markers were evaluated by quantitative reverse transcription-PCR in an independent set of individual samples. Along with detailed clinical data about tumor origin, the information reported here is now publicly available on a dedicated Web site as a resource for further biological investigation. This first in silico reconstruction of the head, neck, and thyroid transcriptomes points to a wealth of new candidate markers that can be used for future studies on the molecular basis of these tumors. Similar analysis is warranted for a number of other tumors for which large EST data sets are available.

Yamazaki CA, Mamone MC, Ikejiri ES, Hidal JT, Matsumura LK, Hojaij FC, Cervantes O, Abrahão M, Furlanetto RP, Maciel RM. · Departamento de MEdicina, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP. · Arq Bras Endocrinol Metabol. · Pubmed #15640884 links to  free full text

Abstract: INTRODUCTION: To study the frequency of malignant lesions in patients with clinically benign thyroid nodules and the value of the repetition of fine needle aspiration biopsy (FNAB). METHODS: Observational and prospective 2-year study in a cohort of 50 patients with clinically benign thyroid nodules. Patients were initially submitted to clinical examination, ultrasound (US) and FNAB1 patients, followed by a second FNAB and US. RESULTS: Palpation is not a good test for diagnosis and follow-up of thyroid nodules. On the other hand, the initial consideration that these patients should harbor benign lesions is a very useful parameter, since 47/50 patients (94%) did not present malignant lesions during the follow-up. FNAB1 and FNAB2 were concordant in 33/39 patients when FNAB1 was negative (85%); 11 patients were operated, 8 by suspicious FNAB and 3 due to nodule growth. We observed 2 patients with non-invasive papillary microcarcinoma and 1 patient with papillary carcinoma outside of the main nodules. CONCLUSION: there was concordance between initial clinical benign diagnosis, FNAB and the follow-up. In one case there was a papillary carcinoma. In addition, ultrasonography should be considered for all patients with suspected thyroid nodules. Finally, we demonstrated that a second cytology usually confirms the result of the first cytology in benign thyroid nodules.

Martins JR, Furlanetto RP, Oliveira LM, Mendes A, Passerotti CC, Chiamolera MI, Rocha AJ, Manso PG, Nader HB, Dietrich CP, Maciel RM. · Division of Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, Brazil. · Clin Endocrinol (Oxf). · Pubmed #15163337 No free full text.

Abstract: OBJECTIVE: Immunosuppressive treatment of Graves' opthalmopathy (GO) should be restricted to patients with active eye disease, but assessing disease activity is difficult. Several methods to evaluate GO activity have been introduced, but none of them is satisfactory. Glycosaminoglycans (GAGs) are complex polysaccharides that participate on the pathogenesis of GO and attempts to correlate its local increase to urinary GAGs (uGAGs) or serum hyaluronan (sHA) have been made, but the available techniques are labourious, time-consuming and difficult for routine use. The aim of the present study is to develop practical and simple methods for uGAGs and sHA and compare them to the activity and severity of thyroid-associated ophthalmopathy. DESIGN, PATIENTS AND MEASUREMENTS: We developed a microelectrophoresis technique for uGAGs and a fluoroassay for sHA and assessed each in 152 patients with Graves' disease, 25 without GO and 127 with GO, classified according to the Clinical Activity Score (CAS). All patients had been euthyroid for > 2 months. RESULTS: Patients with inactive disease (CAS = 2, n = 100) had uGAGs (4.2 +/- 1.3 micro g/mg/creatinine) and sHA (11.1 +/- 7.2 micro g/l) that did not differ from normal subjects (3.1 +/- 1.1 micro g/mg/creatinine, n = 138 and 13.9 +/- 9.6 micro g/l, n = 395). In contrast, patients with active eye disease (CAS = 3, n = 27) had uGAGs (8.4 +/- 2.7 micro g/mg/creatinine) and sHA (32.3 +/- 17.8 micro g/l) 2-3 times higher than those patients with inactive eye disease. Using a cut-off of 6.1 micro g/mg creatinine for uGAGs and 20.7 micro g/l for sHA we found, respectively, 85% and 81% sensitivity and 93% and 91% specificity for each test. The positive and negative predictive values were 77% and 96% for uGAGs and 71% and 95% for sHA. CONCLUSION: Employing these two new methods we have established a significant relationship between the levels of uGAGs and/or sHA and the clinical activity of GO. Therefore, together with CAS, uGAGs determination, and, to a lesser degree, sHA, would be very useful in the discrimination from active and inactive ocular disease and aid in deciding on the best therapy for GO patients.

Cerutti JM, Delcelo R, Amadei MJ, Nakabashi C, Maciel RM, Peterson B, Shoemaker J, Riggins GJ. · Laboratory of Molecular Endocrinology, Division of Endocrinology, Department of Medicine, Federal University of São Paulo, Brazil. · J Clin Invest. · Pubmed #15085203 links to  free full text

Abstract: Accurate diagnosis of thyroid tumors is challenging. A particular problem is distinguishing between follicular thyroid carcinoma (FTC) and benign follicular thyroid adenoma (FTA), where histology of fine-needle aspirates is not conclusive. It is often necessary to remove healthy thyroid to rule out carcinoma. In order to find markers to improve diagnosis, we quantified gene transcript expression from FTC, FTA, and normal thyroid, revealing 73 differentially expressed transcripts (P < or = 0.0001). Using an independent set of 23 FTCs, FTAs, and matched normal thyroids, 17 genes with large expression differences were tested by real-time RT-PCR. Four genes (DDIT3, ARG2, ITM1, and C1orf24) differed between the two classes FTC and FTA, and a linear combination of expression levels distinguished FTC from FTA with an estimated predictive accuracy of 0.83. Furthermore, immunohistochemistry for DDIT3 and ARG2 showed consistent staining for carcinoma in an independent set 59 follicular tumors (estimated concordance, 0.76; 95% confidence interval, [0.59, 0.93]). A simple test based on a combination of these markers might improve preoperative diagnosis of thyroid nodules, allowing better treatment decisions and reducing long-term health costs.

Da Silva AM, Maciel RM, Da Silva MR, Toledo SR, De Carvalho MB, Cerutti JM. · Laboratory of Molecular Endocrinology, Division of Endocrinology, Department of Medicine, Escola Paulist de Medicina, Federal University of São Paulo, Brazil. · J Clin Endocrinol Metab. · Pubmed #14602786 links to  free full text

Abstract: Familial medullary thyroid carcinoma is related to germ-line mutations in the RET oncogene, mainly in cysteine codon 10 or 11, whereas noncysteine mutations in codons 13-15 are rare. We now report a new missense point mutation in exon 8 of the RET gene (1597G-->T) corresponding to a Gly(533)Cys substitution in the cysteine-rich domain of RET protein in 76 patients from a 6-generation Brazilian family with 229 subjects, with ascendants from Spain. It is likely that the mutation causes familial medullary thyroid carcinoma (FMTC), because no other mutation was found in RET, the mutation cosegregates with medullary thyroid carcinoma (MTC) or C cell hyperplasia (CCH) in patients subjected to surgery, and family members without the mutation are clinically unaffected. The histological analysis of 35 cases submitted to thyroidectomy revealed that 21 patients had MTC after the age of 40 yr and 8 before the age of 40 yr, 4 presented MTC or CCH before the age of 18 yr, 2 died due to MTC at the age of 53 and 60 yr, and CCH was found in a 5-yr-old child, suggesting a clinical heterogeneity. To improve the diagnosis of FMTC, analysis of exon 8 of RET should be considered in families with no identified classical RET mutations.