Thyroid Diseases: Ward LS

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.

Ward LS. · No affiliation provided · Arq Bras Endocrinol Metabol. · Pubmed #16358072 links to  free full text

This publication has no abstract.

Ward LS, Morari EC, Leite JL, Bufalo NE, Guilhen AC, Araujo PP, Tincani AJ, Assumpção LV, Matos PS. · Molecular Genetics of Cancer Laboratory, Department of Medicine, Head and Neck Surgery, State University of Campinas, SP, Brazil. · Arq Bras Endocrinol Metabol. · Pubmed #17891234 links to  free full text

Abstract: The large use of simple and effective diagnostic tools has significantly contributed to the increase in diagnosis of thyroid cancer over the past years. However, there is compelling evidence that most micropapillary carcinomas have an indolent behavior and may never evolve into clinical cancers. Therefore, there is an urgent need for new tools able to predict which thyroid cancers will remain silent, and which thyroid cancers will present an aggressive behavior. There are a number of well-established clinical predictors of malignancy and recent studies have suggested that some of the patients laboratory data and image methods may be useful. Molecular markers have also been increasingly tested and some of them appear to be very promising, such as BRAF, a few GST genes and p53 polymorphisms. In addition, modern tools, such as immunocytochemical markers, and the measure of the fractal nature of chromatin organization may increase the specificity of the pathological diagnosis of malignancy and help ascertain the prognosis. Guidelines designed to select nodules for further evaluation, as well as new methods aimed at distinguishing carcinomas of higher aggressiveness among the usually indolent thyroid tumors are an utmost necessity.

Ward LS, Marrone M, Camargo RY, Watanabe T, Tincani AJ, Matos PS, Assumpção LV, Tomimori E, Kulcsar MA, Nunes MT, Nogueira CR, Kimura ET. · Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas/UNICAMP, 13081-970 Campinas, SP. · Arq Bras Endocrinol Metabol. · Pubmed #16936997 links to  free full text

Abstract: The trend of increasing thyroid cancer has been recognized in Brazil as well as all over the world for several decades. The large use of simple and effective diagnostic tools has significantly contributed to this trend. It is estimated that small carcinomas found at surgery for benign thyroid disorders and by ultrasonography will be identified at greater frequency in the further years. Part of these tumors occurs in low-risk patients that may benefit of less aggressive management strategies. However, the characterization of low-risk patient is still confusing and we lack adequate markers to tell apart patients that may present a troublesome progression of the disease. Furthermore, the use of new follow-up methods has recently changed some guidelines. A multidisciplinary team, including basic scientists, endocrinologists, nuclear medicine physicians, thyroid surgeons and endocrine pathologists reviewed the pertinent literature and, based on their experience, propose some management guidelines for Brazilian patients with low-risk thyroid carcinomas.

Ward LS, Assumpção LV. · Laboratório de Genética Molecular do Câncer & Endocrinologia, Departamento de Clínica Médica, Faculdade de Ciências Médicas, UNICAMP, Campinas, SP. · Arq Bras Endocrinol Metabol. · Pubmed #15611825 links to  free full text

Abstract: Because most differentiated thyroid carcinomas have an excellent prognosis, some authors have claimed that these patients are suffering from over treatment. Grouping patient- and tumor-specific factors have been proposed for prognostic stratification, but no clinicopathologic staging was demonstrated to be useful at the present time. More recently, molecular genetic tools have been used to identify and understand how the primary tumor progresses and many molecular markers have been proposed in order to distinguish the subset of patients at risk of developing metastasis. Here we analyzed some of them, with emphasis on the expression of NIS, a determinant of prognosis since the functional integrity of the iodine transport is essential to assure an uptake of radioiodine high enough to detect and destroy any tumoral thyroid tissue. More recent observations on how some relevant molecular genetics aspects of thyroid cancer impact new potential therapeutic approaches are also discussed.

Santos RB, Romaldini JH, Ward LS. · Division of Endocrinology, School of Medicine-Catholic University of Campinas (PUC), Campinas, SP, Brazil. · Thyroid. · Pubmed #15307942 No free full text.

Abstract: In order to assess the effect of propylthiouracil (PTU) or methimazole (MMI) pretreatment on patient outcome after radioiodine therapy, we examined 100 patients with Graves' disease 3, 6, 9, and 12 months after administration of a 10-mCi standard single dose of 131I. They were assigned to one of three groups: no drug (ND) treatment (30 cases); MMI (45 cases); and PTU (25 cases). Antithyroid drugs (ATD) were withdrawn 15 days before radioiodine administration. The groups were similar concerning age, gender, ATD pretreatment duration, goiter size, and initial serum triiodothyronine (T3), thyroxine (T4), free thyroxine (FT4), antithyroid autoantibody levels, 24-hour radioiodine uptake and 131I dose administered per gram of thyroid tissue. ND and MMI groups presented a similar rate of cure of 73.3% and 77.8% respectively (p = NS). In contrast, the PTU group showed a rate of cure of only 32% (p < 0.05). Logistic regression analysis indicated that PTU administration (p = 0.003) and thyroid size (p = 0.02) were the variables related to radioiodine therapy failure. Our data demonstrate that the chance of 131I treatment failure is higher in individuals using PTU than in patients using MMI or not using any ATD before radioiodine (odds ratio [OR] 5.84; 95% confidence interval [CI] 1.82-18.76) suggesting that PTU should be avoided in the treatment of patients with Graves' disease.

Ward LS, Kunii IS, de Barros Maciel RM. · Department of Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil. · Sao Paulo Med J. · Pubmed #11018848 links to  free full text

Abstract: CONTEXT: Screening programs not only offer the opportunity to trace and treat almost all cases of congenital hypothyroidism but also mean large savings to the health system. However, carefully planned strategies are necessary to extend their benefits and reduce costs. OBJECTIVE: To determine the possible influence of maternal diseases that affect maternal-fetal placenta dynamics on primary thyroid stimulating hormone (TSH) screening for congenital hypothyroidism. DESIGN: Prospective non-randomized clinical trial with at least 3 months of follow-up. SETTING: A public university referral center [CAISM/Hospital das Clínicas, Faculty of Medicine, University of Campinas, Campinas, SP]. PARTICIPANTS: 415 neonates divided into 5 groups: eighty-three infants born from cardiac mothers; 98 from mothers that had toxemia; 54 of the mothers had diabetes mellitus; 40 were HIV positive and 140 had no diseases. INTERVENTION: All newborns had cord blood samples collected on filter paper at birth. MAIN MEASUREMENTS: TSH was measured from dried blood spots using a homemade immunofluorescence assay (sensitivity in dried blood spots = 0.1 mU/L). RESULTS: There was no significant difference in the mean TSH levels among the 5 groups. Moreover, TSH levels were around 5 mU/L in 48% of the newborns, indicating that our region is severely deficient in iodine. CONCLUSIONS: Our results indicate that primary TSH screening programs using cord blood are not affected by maternal diseases. We suggest that, besides its technical advantages over heel punctures with T4 primary approaches, neonatal screening using primary cord blood TSH may also be used as a monitoring tool for evaluation and control of iodine deficiency disorders (IDD).

Guilhen AC, Bufalo NE, Morari EC, Leite JL, Assumpcao LV, Tincani AJ, Ward LS. · Laboratory of Cancer Molecular Genetics, Faculty of Medical Sciences School, State University of Campinas, São Paulo, Brazil. · Clin Cancer Res. · Pubmed #19118072 No free full text.

Abstract: PURPOSE: Genetic polymorphisms in genes encoding for enzymes involved in the biotransformation of carcinogens have been shown to be relevant as risk for cancer and may be of considerable importance from a public health point of view. Considering that N-acetyltransferase 2 (NAT2) polymorphisms modulate the response to ionizing radiation, the strongest risk factor recognized to cause differentiated thyroid cancer (DTC) thus far, we sought to determine the influence of NAT2 detoxification system on thyroid cancer susceptibility. EXPERIMENTAL DESIGN: We conducted a prospective case-control study, comparing 195 patients presenting with DTC that were previously genotyped for GSTT1, GSTM1, GSTP1, and CYP1A1, comprising 164 papillary carcinomas and 31 follicular carcinomas, with 196 control individuals paired for gender, age, ethnicity, diet routine, lifetime occupational history, smoking history, general health conditions, and previous diseases. We used PCR-RFLP assays and the combination of 6 variant alleles to define 18 NAT2 haplotypes that characterized slow, intermediate, or rapid phenotypes. RESULTS: A multivariate logistic regression analysis identified the presence of *12A and the absence of *12B, *13, *14B, *14D, *6A, and *7A NAT2 haplotypes as risk factors for DTC. The inheritance of a rapid acetylation phenotype doubled the risk for a papillary carcinoma (odds ratio, 2.024; 95% confidence interval, 1.252-3.272). We found no relationship between genotypes and clinical, pathologic, or laboratory features of patients or between genotypes and outcome. CONCLUSIONS: We showed that NAT2 genotypes and the NAT2 rapid acetylation phenotype are important susceptibility factors for DTC, suggesting that NAT2 detoxification system is involved in this tumor pathogenesis.

Bufalo NE, Santos RB, Cury AN, Andrade RA, Morari J, Morari EC, Leite JL, Monte O, Romaldini JH, Ward LS. · Molecular Genetics of Cancer Laboratory, Department of Internal Medicine, Medical Science School-FCM, State University of Campinas, Sao Paulo, Brazil. · Clin Endocrinol (Oxf). · Pubmed #17980001 No free full text.

Abstract: OBJECTIVE: Cigarette smoking is a well-recognized risk factor of Graves' disease and, particularly, Graves' ophthalmopathy. Hence, germline polymorphisms of detoxification genes and genes belonging to the major DNA repair-apoptosis pathways might have an important role in disease susceptibility. In addition, as some of these genes are regulated by thyroid hormones, they may affect the patients' outcomes. We aimed to assess the influence of the GST, CYP and TP53 gene polymorphisms in the risk of Graves' disease and its outcome. DESIGN: Prospective case-control study. PATIENTS: A PCR-based strategy was used for GSTT1, GSTM1, GSTP1, CYP1A1 and TP53 codon 72 genotypes in a group of 400 Graves' disease patients, and to compare them to 574 control individuals with similar environmental exposure features. RESULTS: GSTM1 and GSTT1 genotypes were equally distributed in cases and controls, respectively. However, GSTP1 (P < 0.0001), CYP1A1 (P < 0.0033) and Pro/ProTP53 (P < 0.0035) variants appeared more frequently in Graves' disease patients than in controls. A multivariate analysis indicated that cigarette smoking and inheritance of GSTP1, CYP1A1 and Pro/ProTP53 variants were important risk factors for Graves' disease, but only smoking appeared as an independent risk factor for Graves' ophthalmopathy. There was no association between clinical features, including ophthalmopathy or treatment outcome, and the studied genotypes. CONCLUSION: We concluded that GSTP1, CYP1A1 and TP53, but not GSTT1 and GSTM1 germline polymorphisms, may be associated with smoking-related Graves' disease susceptibility and configure a risk profile for the disease. However, these polymorphisms do not influence the patients' response to treatment.

Fagin JA, Ward LS, Kimura ET. · Division of Endocrinology, Memorial Sloan-Kettering Cancer Center, New York, NY. · Arq Bras Endocrinol Metabol. · Pubmed #17891227 links to  free full text

This publication has no abstract.

Martins L, Leoni SG, Friguglietti CU, Ward LS, Kulcsar MA, Kimura ET. · Departamento de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade de São Paulo. · Arq Bras Endocrinol Metabol. · Pubmed #17221114 links to  free full text

Abstract: Galectin-3 is a multifunctional protein highly expressed in thyroid cancer. The galectin-3 gene (LGALS3) has several annotated candidates SNPs, however the relationship between galectin-3 SNPs and specific phenotypic variations relevant to health has not been evaluated. In this study, we investigated SNPs in the galectin-3 gene and a putative association with thyroid tumorigenesis. The presence of LGALS3 SNPs in thyroid carcinoma cell lines (NPA, TPC-1, WRO, ARO), thyroid tissues of 55 patients with multinodular goiter or papillary carcinoma diagnosis and lymphocytes of peripheral blood of 45 healthy individuals was evaluated by sequencing and SSCP. The analysis of LGALS3 coding sequence showed that the T98P site presents a great genotypic variation, since we observed both homozygous (AA or CC) and heterozygous (AC) patterns. In thyroid carcinoma cell lines, the genotype of NPA in the LGALS3 T98P site is CC, while TPC-1, WRO and ARO are AC. The genotypic frequency of T98P SNP observed in multinodular goiter (AC= 67%; AA= 23%; CC= 10%) and papillary carcinoma (AC= 68%; AA= 20%; CC= 12%) were similar to the frequency observed in the control population (AC= 60%, AA= 24%, CC= 16%). In conclusion, no association between LGALS3 T98P genotype and the phenotype of the benign or malignant thyroid tumor was observed.

de Matos PS, Ferreira AP, Ward LS. · Department of Pathology, School of Medicine FCM, State University of Campinas, Sao Paulo, Brazil. · Endocr Pathol. · Pubmed #17159249 No free full text.

Abstract: In order to search for parameters to differentiate patients at low and high risk for development of thyroid cancer, we studied thyroids from 166 consecutive autopsies and 261 thyroids that were surgically resected for thyroid diseases in general. We found 32 papillary microcarcinomas, corresponding to 7.8% of autopsies and 7.2% of surgical material, with a higher incidence between 30 and 49 yr of age. Both genders were similarly affected: 9.3% of the men and 8.8% of the women in autopsy series, and 6.2% of the men and 7.3% of the women in surgical series, suggesting that hormonal factors may favor the subsequent development of clinical lesions in women. Although associated nodular goiter has been observed in 54% of autopsies and 26% of surgical specimens, while Hashimoto's thyroiditis only in surgical material (15% of the cases), we were not able to correlate risk of malignancy with any concomitant lesion. The smallest papillary microcarcinomas presented most frequently as nonencapsulated nonsclerosing tumors without inflammatory infiltrate or fibrosis, suggesting that they may represent the early stages of development. Our data show a relatively high and similar frequency of papillary microcarcinomas in surgical and autopsy series, but do not demonstrate risk factors for clinical evolution.

Bufalo NE, Leite JL, Guilhen AC, Morari EC, Granja F, Assumpcao LV, Ward LS. · Laboratory of Cancer Molecular Genetics, Medical Sciences School, State University of Campinas - UNICAMP, Sao Paulo, Brazil. · Endocr Relat Cancer. · Pubmed #17158763 links to  free full text

Abstract: In contrast to most human malignancies, epidemiologic studies have frequently reported a reduced risk of differentiated thyroid cancer in tobacco consumers. Cytochrome P4501A1 (CYP1A1) gene variants may be related to an increased capacity to activate polycyclic aromatic hydrocarbons, producing highly reactive electrophilic intermediates that might damage DNA. Hence, the germline inheritance of a wild-type CYP1A1 gene may decrease the susceptibility for thyroid cancer. The present study was designed to investigate CYP1A1 (m1 and m2) role in thyroid tumorigenesis and its connection with GSTM1, GSTT1, GSTP1, GSTO1, and codon 72 of p53 genotypes. A total of 248 patients with thyroid nodules, including 67 benign goiters, 13 follicular adenomas, 136 papillary carcinomas, and 32 follicular carcinomas, and 277 controls with similar ethnic backgrounds were interviewed on their lifetime dietary and occupational histories, smoking habit, previous diseases, and other anamnestic data. DNA was extracted from a blood sample and submitted to PCR-restriction fragment length polymorphism assays. The wild-type CYP1A1m1 genotype was more frequent among papillary carcinoma patients (74.26%) than in the control population (62.45%; P=0.0147), reducing the risk for this type of cancer (odds ratio=0.564; 95% confidence interval=0.357-0.894). A multiple logistic regression analysis showed an inverse correlation between cigarette smoking (P=0.0385) and CYP1A1 germline inheritance (P=0.0237) with the susceptibility to papillary carcinomas. We were not able to find any correlation between smoking, clinical features, parameters of aggressiveness at diagnosis or during follow-up, and any of the GST or CYP genotypes considered separately or in different combinations. We suggest that CYP1A1 genotype might be associated with the reported reduced risk to papillary carcinomas among smokers.

Chueire VB, Romaldini JH, Ward LS. · Endocrinology, Department of Medicine, Pontificia Universidade Catolica (PUC), Av. John Boyd Dunlop s/n, 13059-900 Campinas, SP, Brazil. · Arch Gerontol Geriatr. · Pubmed #16678286 No free full text.

Abstract: In order to determine if subclinical hypothyroidism is a risk factor for depression in the elderly, a total of 323 individuals over 60 years old were interviewed using the Structured Clinical Interview for Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) for mood disturbances. Patients were divided into Group I: 252 patients (184 females, 68 males; median age: 67 years, range: 60-89 years) with elevated serum thyrotropin (TSH) levels and Group II: 71 patients (45 females, 26 males; median age: 67 years, range: 60-92 years) with diagnosis of depression. Serum TSH and free thyroxine (fT4) were measured by sensitive assays. Thyroid antibodies were determined by IRMA. Depression was observed in 24 (9.5%) Group I patients and was frequent in subclinical hypothyroidism patients (14/24 = 58.3%). On the other hand, elevated TSH levels were found in 22 (30.9%) Group II patients. Depression was observed more frequently among individuals with subclinical (74/149 = 49.7%) hypothyroidism than among individuals with overt hypothyroidism (21/125 = 16.8%) (p < 0.001). Indeed, subclinical hypothyroidism increased the risk for a patient to present depression more than four times (OR = 4.886; 95% confidence interval = 2.768-8.627). Our results demonstrate that subclinical hypothyroidism increases the risk for depression and emphasize the importance of thyroid screening tests in the elderly.

de Matos PS, Ferreira AP, de Oliveira Facuri F, Assumpção LV, Metze K, Ward LS. · Department of Pathology, Division of Endocrinology, School of Medicine (FCM), State University of Campinas (UNICAMP), Sao Paulo, Brazil. · Histopathology. · Pubmed #16178894 No free full text.

Abstract: AIMS : To investigate the usefulness of immunohistochemical expression and immunolocalization of a panel of thyroid malignancy markers including HBME-1, cytokeratin (CK) 19 and galectin-3. METHODS AND RESULTS : We evaluated 170 thyroid lesions including 148 neoplastic lesions [84 papillary carcinomas (PC), 38 follicular carcinomas (FC), 18 follicular adenomas, one hyalinizing trabecular tumour, five medullary carcinomas, two anaplastic carcinomas] and 22 non-neoplastic lesions (12 adenomatous nodules and 10 Hashimoto's thyroiditis). HBME-1, galectin-3 and CK 19 were expressed in 94%, 72.6%, 72.6% of PCs and in 63%, 21%, 21% of FCs. The three markers were mostly negative in all normal tissues. Although the most helpful marker in terms of sensitivity and specificity for the follicular variant of PC and for FC diagnosis was HBME-1, when we consider the differentiation between cases of follicular variant of papillary carcinoma (FVPC) and FC or adenoma, in terms of percentage of positive cells, galectin-3 and CK 19 were more relevant. CONCLUSIONS : HBME-1 is the most sensitive marker for thyroid malignancy but the three markers may be useful in specific cases. This panel of markers is useful to differentiate the follicular patterned lesions, with special reference to the FVPC.

Granja F, Morari EC, Assumpção LV, Ward LS. · Laboratory of Cancer Molecular Genetics, Department of Medicine, State University of Campinas, Tessalia Vieira de Camargo 126, 13084-970 Campinas, São Paulo, Brazil. · Eur J Cancer Prev. · Pubmed #15901998 No free full text.

Abstract: A new class of glutathione S-transferase enzymes named omega (GSTO) has been recently identified and shown to be expressed in a wide range of human tissues. A genetic polymorphism of the GSTO1 gene causing an alanine-to-aspartate (A140D) substitution in amino acid 140 produces a variant with lowered enzyme activities in the biotransformation of inorganic arsenic, a common contaminant of drinking water in many regions of the world and a well-known carcinogen. In order to investigate the role of GSTO1 inheritance pattern on thyroid cancer risk we used a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP)-sequencing approach to compare the genotypes of 173 (87 women, 86 men; 18-81 years old; 47+/-18 years old) healthy control individuals with those of 145 patients with thyroid nodules (84 women, 61 men; 17-81 years old; 49+/-14 years old) including 17 follicular carcinomas, 76 papillary carcinomas, 21 follicular adenomas and 31 multinodular goiters. The incidence of GSTO1 variants was similar in the control population and population with the benign and malignant nodules. There was no association between genotype and the patients' clinical features, tumour parameters of aggressiveness at diagnosis or behaviour during follow-up. We conclude that GSTO1 variants do not influence the risk for thyroid nodules or their pathologic and clinical characteristics.

Santarosa PL, Granja F, Morari EC, Leite JL, Assumpção LV, Ward LS. · Laboratory of Cancer Molecular Genetics, Department of Medicine, Faculty of Medical Sciences, State University of Campinas (FCM/UNICAMP), Campinas, São Paulo, Brazil. · Rev Med Chil. · Pubmed #15743163 links to  free full text

This publication has no abstract.

Innocencio RM, Romaldini JH, Ward LS. · Department of Medicine, Faculdade de Ciências Médicas/UNICAMP, Campinas, São Paulo, Brazil. · Medicina (B Aires). · Pubmed #15239536 No free full text.

Abstract: Abnormalities in the thyroid function and thyroid autoantibodies have been frequently described in patients with autoimmune diseases but seldom in antiphospholipid syndrome patients. In order to determine the prevalence of thyroid function and autoimmune abnormalities, we compared serum thyrotropin (TSH, serum free thyroxine (T4) levels, thyroid antithyroglobulin (TgAb) and antithyroperoxidase (TPOAb) levels of 25 patients with systemic sclerosis, 25 patients with rheumatoid arthritis and 13 patients with antiphospholipid syndrome to a control group of 113 healthy individuals. Evaluation included a thorough clinical examination with particular attention to thyroid disease and a serologic immune profile including rheumatoid factor, antinuclear and anticardiolipin antibody measurements. Subclinical hypothyroidism (4.2<TSH<10 mU/L) was diagnosed in five patients (8%), and subclinical hyperthyroidism (undetectable<TSH<0.34 mU/L) in four patients (6%). Anti-thyroglobulin (TgAb) and/or anti-thyroperoxidase (tPOAb) antibodies were present in 21/63 (33%) of our patients: 13/25 (52%) of the systemic sclerosis cases, 8/25 (32%) of the rheumatoid arthritis patients, but 0 (0/13) of the antiphospholipid syndrome patients. In conclusion, our data confirm a high prevalence of silent autoimmune thyroid diseases in association with systemic sclerosis and rheumatoid arthritis (p<0.02), but not with antiphospholipid syndrome. Elevated antibody titres may reflect an epiphenomenon of the underlying autoimmune disorders and play an additive role in the development of the euthyroid sick syndrome in these patients, but our data suggest that the antiphospholipid syndrome presents a different pattern of response. Subclinical thyroid diseases should be considered when evaluating patients with autoimmune diseases.

Granja F, Morari J, Morari EC, Correa LA, Assumpção LV, Ward LS. · Laboratory of Cancer Molecular Genetics, Department of Medicine, State University of Campinas, Olympio Pattaro 45, Campinas, São Paulo, Brazil. · Cancer Lett. · Pubmed #15183530 No free full text.

Abstract: A common germline polymorphism of p53 gene produces an Arginine to Proline change at aminoacid position 72. The resulting codon 72 variants have been reported associated with tumor susceptibility since they reduce p53 ability to activate apoptosis. Codon 72 polymorphism may play a role in subside vulnerability to different carcinogens and might account for ethnic variations in cancer frequency. Using an allele-specific polymerase chain reaction (PCR), we tested peripheral blood samples from 98 patients with thyroid cancer, including 21 follicular (FC) and 77 papillary carcinomas (PC), 44 patients with benign nodules, including 14 follicular adenomas and 30 goiters and 153 healthy individuals from the same geographical region. Data on lifetime occupational history, smoking history, general health conditions, previous diseases and other anamnestic data were obtained through interviews. Patients with FC (Pro/Pro = 19.0%, Arg/Arg = 42.9%, Arg/Pro = 38%) and with PC (Pro/Pro = 10.3%, Arg/Arg = 36.36%, Arg/Pro = 53.24%) showed a significant overrepresentation of codon 72 variants compared to the control population (Pro/Pro = 1.9%, Arg/Arg = 33.3%, Arg/Pro = 64.7%) (P = 0.0015). The Pro/Pro genotype, after adjusting for gender, age, tobacco and drugs, was associated with a markedly higher risk of FC (OR=9.714; CI: 2.334-40.436) and of PC (OR=5.299; CI: 2.334-40.436). These results provide evidence that p53 polymorphism is implicated in thyroid carcinogenesis and that individuals harboring the Pro/Pro genotype have an increased risk of developing thyroid cancer.

Granja F, Morari J, Morari EC, Correa LA, Assumpção LV, Ward LS. · Laboratory of Cancer Molecular Genetics, Department of Medicine, State University of Campinas, São Paulo, Olympio Pattaro 45, 13085-857. Brazil. · Cancer Lett. · Pubmed #15159014 No free full text.

Abstract: Screening tools are of utmost necessity in order to identify individuals at risk for thyroid nodule cancer. The polymorphic inheritance of human drug-metabolizing enzymes, such as those encoded by the Glutathione-S-Transferase (GST) system, plays an important role in the development of most human cancers. GSTP1 enzyme is the most important detoxification enzyme in human head and neck tissues. An aminoacid substitution (1105V) in the GSTP1 gene result in two genotypes, GSTP1AB and GSTP1BB. Those produce a variant enzyme with lower activity and less capability of effective detoxification of carcinogens than the wild type GSTP1AA. In order to look for the influence of GSTP1 enzymes inheritance pattern on thyroid cancer risk we used a PCR-SSCP-sequencing approach to compare the genotypes of 98 malignant nodules, including 77 papillary carcinomas (PC) and 21 follicular carcinomas (FC), to 44 benign nodules and to 157 healthy control individuals. Individuals with history of previous thyroid disease, exposure to radiation and antecedents of malignancy were excluded. Patients with PC and FC showed a significant over-representation of the variants of GSTP1 allele compared to the control population (p < 0.0001 The risk for thyroid cancer in individuals with the variant GSTP1 enzymes, after adjusting for gender, age, tobacco and drugs use, increased 7,092 (CI: 2,307-21,802) and 9,625 (CI: 2.484-37.291) times for PC and FC, respectively. We suggest that GST genotype may be associated with an increased susceptibility to thyroid cancer. GSTP1 profiling from peripheral blood may be a simple and useful tool in the screening for thyroid nodule malignancy. Glutathione-S-Transferase system; GSTP; Thyroid cancer; Screening.

Innocencio RM, Romaldini JH, Ward LS. · No affiliation provided · Clin Rheumatol. · Pubmed #14677039 No free full text.

This publication has no abstract.

Ward LS, Santarosa PL, Granja F, da Assumpção LV, Savoldi M, Goldman GH. · Laboratory of Cancer Molecular Genetics, FCM, Department of Medicine, School of Medicine, State University of Campinas, Rua Olympio Pattaro 45, São Paulo 13085-857, Campinas, Brazil. · Cancer Lett. · Pubmed #14550956 No free full text.

Abstract: A decreased radioiodine uptake is frequently detected in differentiated thyroid carcinomas (DTC) and is associated with high recurrence rate and reduced survival. We investigated the correlation between NIS mRNA expression levels in the primary tumor and patient outcome using a quantitative real-time RT-PCR method. NIS expression was decreased in 17 DTC (21.04+/-39.66 pg Eq) compared to four autoimmune thyroid disease (180.51+/-92.63 pg Eq) and 14 normal tissues (75.71+/-66.98 pg Eq) (p<0.0001). The 17 thyroid differentiated carcinoma patients were submitted to surgery complemented by radioiodine ablation and had at least 24 months of follow-up, under levothyroxine continued suppressive therapy. According to their outcome, we could characterize a group of papillary carcinoma patients with aggressive carcinomas, whose NIS mRNA levels were markedly lower than a group with non-aggressive carcinomas (0.62+/-0.79 versus 54.87+/-53.79; p<0.005). We suggest that the quantification of NIS mRNA relative levels in the primary tumor may predict poor outcome.

Souza SL, Montalli Da Assumpção LV, Ward LS. · Laboratory of Cancer Molecular Genetics, Department of Medicine, State University of Campinas, São Paulo, Brazil. · Thyroid. · Pubmed #12855017 No free full text.

Abstract: Autoimmune phenomena are frequently associated with differentiated thyroid carcinomas. However, the significance of thyroid gland autoimmune aggression on the outcome of these patients is still controversial. To address this issue, we studied 173 patients (123 with papillary and 50 with follicular carcinomas) who underwent surgery complemented by radioiodine ablation and followed up for 0.5-29 (6 +/- 5.76) years. Analysis of the prognostic factors revealed that higher age, male gender, larger nodule size, follicular tumors, presence of metastases at diagnosis, grade of differentiation, and stage correlated positively with the occurrence of death, metastasis and/or recurrence, while the presence of antibodies and the previous history of autoimmune disease correlated negatively with these events. Long distant metastases increased the odds for a lower disease-free rate for patients with papillary (8.366 times) and follicular (7.373 times) carcinoma. However, univariate and multivariate analysis failed to demonstrate that neck node involvement could influence the outcome for patients with well-differentiated thyroid carcinoma. The odds for patients with previous history of thyroid autoimmune disease (p < 0.02) or with thyroid autoantibodies (p < 0.001) to have a worse outcome were lower than for patients with no evidence of autoimmune activity, suggesting that autoimmune activity against the gland may exert a protective effect on the outcome of differentiated thyroid carcinoma patients.

Chueire VB, Silva ET, Perotta E, Romaldini JH, Ward LS. · Internal Medicine, Department of Medicine, Faculdade de Ciências Médicas (FCM-UNICAMP), State University of Campinas, Rua Alexander Fleming 181, Cidade Universitária 'Zeferino Vaz', s/n degrees, Barão Geraldo, 13083-970, SP, Campinas, Brazil. · Arch Gerontol Geriatr. · Pubmed #12849083 No free full text.

Abstract: In order to investigate the association between elevated serum TSH levels and depression in the elderly, we conducted a population-based study of 451 over 60-year-old outpatients of a general University Hospital. Patients were divided into Group I (GI) (248 individuals) with high serum TSH levels, but otherwise no important condition or disease, and Group II (GII) (203 patients) with no previous diagnosis of thyroid or mood disease, referred to the hospital because of nonthyroidal severe diseases. All patients were clinically examined and classified according to DMS-IV for mood disturbance and had serum TSH, free T4 levels and antithyroid antibodies measured. High serum TSH levels (11.6+/-14.8 mU/l) were observed in 65/203 (32%) patients of GII. Among these patients, 42/65 (65%) had normal free T4 concentrations (1.23+/-0.98 ng/dl), no clinical manifestation of hypothyroidism and thus were considered to present subclinical hypothyroidism. Depression was observed in 24 cases from GI (9.7%) and 29 from GII (14.3%) and was frequent in the subclinical hypothyroid patients (49%). Our results suggest that mood disturbances are frequent in the elderly with elevated serum TSH levels, but they do not differ in the primary hypothyroid and the nonthyroidal sick patients.

Morari EC, Leite JL, Granja F, da Assumpção LV, Ward LS. · Laboratory of Cancer Molecular Genetics, Department of Medicine, State University of Campinas, 13085-857 Campinas, São Paulo, Brazil. · Cancer Epidemiol Biomarkers Prev. · Pubmed #12433731 links to  free full text

Abstract: Susceptibility to chemical carcinogens plays an important role in the development of most cancers. Several polymorphisms of human drug-metabolizing enzymes influence this individual susceptibility. The genes that encode the isoenzymes of the glutathione s-transferase (GST) system present a polymorphic inheritance. The GST mu 1 (GSTM1) and GST theta 1 (GSTT1) genes have a null allele variant in which the entire gene is absent. The null genotype for both enzymes has been associated with many different types of tumors. To look for the influence of the inheritance pattern of these enzymes on thyroid cancer risk, we used a triplex PCR that included beta-globin gene as a DNA quality control to compare 300 normal individuals of our population to 116 goiter patients. There were 49 cases of benign and 67 cases of malignant nodules: 50 papillary and 17 follicular carcinomas. Comparison between thyroid tumor specimens and normal corresponding samples of 35 cancer patients demonstrated identical patterns, suggesting that the GST system is not involved in the process of follicular dedifferentiation. There was no statistical difference between the prevalence of the deleted alleles in the normal individuals and in the goiter patients. However, papillary carcinoma patients (10%) and follicular carcinoma patients (17%) presented a higher prevalence of the null genotype than the normal population individuals (5%; P < 0.05). We found a 2.6 increased risk of thyroid cancer in individuals with the GSTT1 and GSTM1 combined null inheritance, suggesting that this genotype may be associated with an increased susceptibility to thyroid cancer.